University of Southern California Dissertations and Theses

Identifying predictors of cytogenetic relapse and death for patients undergoing allogeneic blood or marrow transplantation for treatment of chronic myeloid leukemia in chronic phase: The City of...

(USC Thesis Other)

Identifying predictors of cytogenetic relapse and death for patients undergoing allogeneic blood or marrow transplantation for treatment of chronic myeloid leukemia in chronic phase: The City of...

PDF

Download a page range

Download transcript

Copy asset link

Request this asset

Transcript (if available)

Content IDENTIFYING PREDICTORS OF CYTOGENETIC RELAPSE AND DEATH FOR PATIENTS UNDERGOING ALLOGENEIC BLOOD OR MARROW TRANSPLANTATION FOR TREATMENT OF CHRONIC MYELOID LEUKEMIA IN CHRONIC PHASE: THE CITY OF HOPE EXPERIENCE by Joycelynne Michelle Palmer A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (EPIDEMIOLOGY) December 2004 Copyright 2004 Joycelynne Michelle Palmer R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. UMI Number: 3197572 INFORMATION TO USERS The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleed-through, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. ® UMI UMI Microform 3197572 Copyright 2006 by ProQuest Information and Learning Company. All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code. ProQuest Information and Learning Company 300 North Zeeb Road P.O. Box 1346 Ann Arbor, Ml 48106-1346 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. A C K N O W L E D G E M E N T S To God Be the Glory. R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. T A B L E OF C O N TE N T S ACKNOWLEDGEMENTS.................................................................................................. ii LIST OF TABLES................................................................................................................. iv LIST OF FIGURES............................................................................................................... vi ABSTRACT............................................................................................................................ vii CHAPTER 1 DISSERTATION OVERVIEW............................................................. 1 2 AN OVERVIEW OF CHRONIC MYELOID LEUKEMIA 7 3 THE CHANGING LANDSCAPE OF CHRONIC MYELOID LEUKEMIA PROGNOSIS.................................................................... 39 4 IDENTIFYING PREDICTORS OF CYTOGENETIC RELAPSE AND DEATH FOR PATIENTS UNDERGOING ALLOGENEIC BLOOD OR MARROW TRANSPLANTATION FOR TREATMENT OF CHRONIC MYELOID LEUKEMIA IN CHRONIC PHASE: THE CITY OF HOPE EXPERIENCE 58 5 LEUKEMIA: INVESTIGATING CAUSES OF DEATH AND DISEASE RECURRENCE................................................................... 110 REFERENCES .............................................................................................................. 130 APPENDICES Appendix A: Qualitative and Quantitative PCR Access 97® Research Database................................................................................. 141 Appendix B: Chronic Myeloid Leukemia (CML) Case Report Forms..................... 144 Appendix C: California Cancer Research Program (Graduate Student Award Application)............................................................................... 201 iii R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. LIST OF T A B L E S Table 1: Formed Elements of the Blood -Composition and Function.................. 17 Table 2: Summary of CML Definitions: Clinical Diagnostic Criteria and Staging................................................... 19 Table 3: Summary of CML Definitions: Disease Response.................................... 28 Table 4: Summary of Patient Characteristics at Diagnosis..................................... 62 Table 5: Summary of Patient Characteristics at Transplant..................................... 63 Table 6: Summary of Prognostic Features Collected at Diagnosis and Transplantation.................................................................................... 72 Table 7: Comparison of Patient Characteristics Reported at Diagnosis............... 75 Table 8: Summary of Complications and Outcomes Post Transplant................... 80 Table 9: Summary of Death Information and Survival/Relapse Probabilities.... 81 Table 10: Results of Modeling Approaches for Missing Data................................... 86 Table 11: Testing of Proportional Hazards Assumption............................................ 93 Table 12: Results of Univariate Cox Regression Analysis Overall Survival, Disease-Free Survival and Relapse............................................................. 98 Table 13: Summary of Features Included in the Mulitvarible M odel...................... 102 Table 14: Final Model for Multivariable Cox Regression Analysis........................ 103 Table 15: Comparison of City of Hope Results to Results Published by Sokal and Hasford...................................................................................... 106 Table 16: Factors Shown to be Predictive of Overall Survival............................... 117 Table 17: Allogenic Blood or Marrow Transplantation for Treatment of CML in CP. Summary of Patient Characteristics Pre-Transplant 118 Table 18: Allogenic Blood or Marrow Transplantation for Treatment of CML in CP. Summary of Patient Characteristics Pre-Transplant. Sibling and Syngenic Transplant Patients Only...................................... 120 iv R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Table 19: Allogenic Blood or Marrow Transplantation for Treatment of CML in CP. Summary of Patient Characteristics at Transplantation... 121 Table 20: Allogenic Blood or Marrow Transplantation for Treatment of CML in CP. Summary of Complications and Outcomes Post Transplantation. Sibling and Syngenic Transplant Patients Only 122 Table 20: Allogenic Blood or Marrow Transplantation for Treatment of CML in CP. Summary of Death Information and Survival/Relapse Probabilities. Sibling and Syngenic Transplant Patients Only 123 Table 21: Results of Power Analysis-Comparing survival time between two groups; two-sided log-rank test, a-level .05, total sample size 393 patients.................................................................... 127 v R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. LIST OF FIG URES Figure 1: Hematopoiesis................................................................................................ 8 Figure 2: The Philadelphia Chromosome: t(9;22)..................................................... 13 Figure 3: Normal Human Chromosome Structure (Karyotype).............................. 21 Figure 4: Sensitivity of Laboratory Tests................................................................... 49 Figure 5: Cumulative Probability of Overall Survival.............................................. 82 Figure 6: Cumulative Probability of Disease-Free Survival..................................... 83 Figure 7: Cumulative Probability of Cytogenetic Relapse........................................ 84 Figure 8: Overall Survival by Sokal Risk Category................................................ 88 Figure 9: Overall Survival by Hasford Risk Category............................................ 90 Figure 10: Overall Survival by Gratwohl Risk Levels............................................. 91 vi R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. ABSTRACT While treatment is believed to influence disease outcome, the wide variation in published survival and remission rates among chronic myeloid leukemia (CML) patients demonstrates that the effectiveness of treatment appears to be modified by patient characteristics, disease features, and disease management approaches. Future improvements in the treatment of CML are dependent on our ability to distinguish between patients who are likely to have long-term disease free survival and those who are not. Between June 1982 and December 2002, 234 patients with CML in first chronic phase (CP) were treated at City of Hope with an allogeneic blood or marrow transplant (Allo-BMT) using histocompatible sibling donors. This retrospective case-series study examined the role of patient, disease, and treatment factors collected both at the time of diagnosis and Allo- BMT to assess the predictive value of these factors on a patient’s risk for cytogenetic relapse (CR) and/or death following Allo-BMT. This study also explored the predictive value of three generally accepted prognostic scoring systems (Sokal, Hasford, Gratwohl) in this large single center Allo-BMT population. Multivariable Cox regression analysis was used to identify risk factors for both CR and death. While no significant factors at diagnosis or Allo-BMT were shown to be predictive of CR, patients who underwent Allo-BMT over the age of 40 had two-times the risk of dying following Allo-BMT when compared to those who were transplanted <40 years of age (p<0.01). Similarly, patients who were out more than one-year from diagnosis and vii R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. underwent Allo-BMT had two-times the risk of dying relative to patients transplanted within the first year following diagnosis (p<0.01). Surprisingly, the Sokal/Hasford prognostic scoring systems and features at diagnosis were not found to be significantly predictive of death. While a difference in survival could be seen across the four-levels of the Gratwohl risk classification schema (p=0.03), after accounting for the effect of acute graft-versus-host disease (GvHD), chronic GvHD and GvHD prophylaxis, these differences were no longer significant. The findings of this study suggest that a patient under 40, with a sibling donor that has been recently diagnosed and receives a methotrexate based preparative regimen may benefit most from Allo-BMT. R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. CHAPTER 1 DISSERTATION OVERVIEW The neoplastic process that leads to the development of chronic myeloid leukemia (CML) is the most well studied molecular model of leukemia. CML was the first human malignancy to be associated with a single and consistent acquired genetic abnormality. The cause (or causes) of this crucial genetic event and the eventual development of CML remains largely unknown in the majority of cases. The elucidation of risk factors through population based case-control studies or cohort/ecologic studies has been hindered by the rarity of the disease; CML has an annual incidence of 1-2 cases per 100,000 per year. Because of the limited number of cases diagnosed annually with CML and the sporadic aggressiveness of this leukemia subtype, CML does not follow the standard research approach that has been applied to the majority of chronic diseases that undergo epidemiologic investigation. For the past 20 years, the goals of CML epidemiologic research have been to: 1) identify and understand appropriate disease measures/indicators, 2) study the strength of evidence regarding the benefits and risks of available treatment options, 3) help identify the optimal timing of the intervention and monitoring of disease based on disease and patient characteristics, and 4) identify prognostic indicators of disease relapse and death. In an effort to improve the long-term survival for this patient population, this research examines remaining questions in the area of prognosis for patients that undergo allogeneic blood or 1 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. marrow transplantation (Allo-BMT). This research effort builds on the current body of literature related to the natural course of CML, treatment and prognosis. The clinical course, for patients diagnosed with CML, is heterogeneous. Previous studies have demonstrated that prognosis varies widely depending on the risk profiles of patients; risk profiles are usually based on demographic characteristics, clinical features at presentation and prior therapy (type, amount and duration). Multivariable risk classifications and scoring systems based on pretreatment features have been the subject of numerous prognostic studies (Tura, Baccarani, and Corbelli 1981; Cervantes and Rozman 1982; Sokal et al. 1984; Sokal et al. 1985; Kantarjian, Smith, et al. 1985; Kantarjian et al. 1990; Italian Cooperative Group 1991; Thiele et al. 1991; Hehlmann et al. 1992; Thiele et al. 1993; Italian Cooperative Group 1994; Cortes 1997; Hasford et al. 1998). In most cases, studies were limited to evaluating the relative impact of pretreatment features on overall survival. Several models have been established that categorize patients into different groups with distinctive survival characteristics (Sokal et al. 1984; Kantarjian et al. 1990; Hasford et al. 1998), however, the reproducibility and generalizability of most of these staging systems have been repeatedly questioned because these systems were generally restricted to certain therapeutic regimens. Application of the various risk models and scoring systems to cohorts that include other treatment modalities, in particular blood/marrow transplantation (BMT), frequently demonstrate a significant lack of prognostic efficiency with overlapping risk discrimination (Gratwohl et al. 1998; Clark et al. 2001; Michallet et al. 2001; Radich et al. 2001; Gratwohl 2003). While a number of prognostic models for non-BMT patients have been developed and are well documented in the literature, a useful scoring system/prognostic model for CML has not been developed for patients that undergo Allo-BMT. 2 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. To date, Allo-BMT from a human leukocyte antigen (HLA) matched sibling, related or unrelated donor is the only known curative treatment for CML. It is most successful when performed in chronic phase (CP), where 3-year to 5-year disease free survival rates range from 38%-80%, with the higher values reported by experienced transplant centers (Silver et al. 1999). Because Allo-BMT continues to be a viable treatment option for a significant number of patients, it is critical to identify those factors at diagnosis and BMT that affect cytogenetic relapse events and survival in this patient population; factors that will need to be considered in determining when to initiate Allo-BMT. To examine this issue, a case-series of 234 CML-CP Allo-BMT patients have been identified at the City of Hope National Medical Center (COH) and will be used for this study. The specific aims of this project are: 1. to complete a written review on CML, this chapter provides the background necessary to understand the proposed research project (Chapter 2) 2. to complete a review of the significant prognostic models and scoring (staging) systems for CML (Chapter 3) 3. to identify a series of patients who have undergone Allo-BMT for the treatment of CML in CP at COH (Chapter 4: Part 1 of 8) 4. to, based on the results of the literature review, collect and summarize data on: 1) the significant pretreatment disease and patient characteristics; 2) the patient’s treatment history (from diagnosis to Allo-BMT); and 3) the potentially relevant clinical features at Allo-BMT (Chapter 4: Part 2 of 8) 5. to update the outcome data for this large case-series; time to evidence of cytogenetic relapse and/or death post Allo-BMT (Chapter 4: Part 3 of 8) 3 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. 6. to use the updated database to examine the predictive value of pretreatment characteristics on survival and cytogenetic relapse post Allo-BMT (Chapter 4: Part 4 of 8) 7. to assign weighted risk scores, for the most widely accepted scoring systems, and test the prognostic reproducibility in this independent patient population (Chapter 4: Part 5 of 8) 8. to determine the clinical features at Allo-BMT that are predictive of cytogenetic relapse and survival post Allo-BMT after adjusting for pretreatment characteristics (developing a prognostic model) (Chapter 4: Part 6 of 8) 9. to compare the prognostic factors seen at diagnosis with those at Allo-BMT (identifying through statistical analysis potentially new clinical features at BMT that are predictors of disease recurrence, disease free survival and overall survival post Allo-BMT) (Chapter 4: Part 7 of 8) 10. to summarize results/present overall conclusions of this research project (limitations, future directions) (Chapter 4: Part 8 of 8) 11. to produce a quality grant application using the California Cancer Research Program Announcement (graduate student award) to define the grant requirements (Chapter 5) The following is an outline of the dissertation by chapter. Chapter 1 - Dissertation Overview Chapter 1 provides the reader a broad overview of the dissertation. This chapter includes a brief background on the research area, the rationale that supports the research objectives and the specific aims of the research project. R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Chapter 2 - Overview: Chronic Myeloid Leukemia A review of CML, the disease under investigation, is presented in chapter 2. Chapter 2 provides the background necessary to understand the proposed research project. This chapter includes information on blood formation, CML etiology and pathogenesis, clinical features of CML and disease staging, secular trends, molecular techniques used to diagnose and monitor the disease, and outcomes as they relate to treatment modalities. Chapter 3 - Review Paper: The Changing Landscape of CML Prognosis The objective of this review paper is to examine the evolution of CML prognosis from 1980 to 2003 and identify, as part of the background for the data collection effort and statistical analysis, the relevant patient, disease and treatment factors that will be collected and analyzed in Chapter 4. Chapter 3 documents how prognosis has been studied over the last three decades, and focuses on the evolution of the relative contribution of patient, disease, treatment characteristics and prognostic models/scoring systems. The issue of CML prognosis shares a fascinating and complex history with the fields of genetics and molecular medicine. This chapter reviews how improvements in treatment and disease characterization have advanced the area of prognosis for newly diagnosed patients. This review also highlights the remaining limitations associated with the information currently available and what the future of outcome prediction holds for this patient population. Chapter 4 - Data Analysis and Conclusions Chapter 4 uses the results of the review paper to set the data collection requirements for this study. The research hypotheses, methods used for data collection/statistical analysis, and results are 5 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. presented in chapter 4. The overall conclusions of this research project, limitations, and directions for future research are also summarized. Chapter 5 - Grant Proposal A quality grant application was produced using the California Cancer Research Program Announcement (graduate student award) to define the grant requirements. R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. CHAPTER 2 AN OVERVIEW OF CHRONIC MYELOID LEUKEMIA Composition and Formation of Blood Blood is composed of cells, or formed elements, suspended in plasma. The major cell types include erythrocytes (red blood cells), leukocytes (white blood cells), and thrombocytes (platelets). All of the formed elements of the blood are produced in the ‘blood producing bone marrow’ (red marrow), which is located in the inner part of the bones. Blood cells are commonly referred to as formed elements because the precursor of blood cells is the pluripotent hematopoietic stem cell. The term pluripotent means that these cells can differentiate into more than one mature blood cell type. The pluripotent hematopoietic stem cell is what gives rise to the different types of blood cells by differentiating into developmentally committed stem cells, which are the precursors of distinct cell lineages (Cohen and Wood, 2000). There are two major cell lineages: lymphoid and myeloid (Figure 1). The lymphoid stem cell gives rise to B cells (which mature into immunoglobulin secreting plasma cells) and T cells. The tri-lineage myeloid stem cell is what gives rise to the three major subsets of committed stem cells, which are the precursors of mature thrombocytes, erythrocytes, monocytes, neutrophils, eosinophils, and basophils (Damjanov 2000). R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission. Figure 1: Hematopoiesis Pluripotent Hematopoietic Stem Cell Trilineage Myeloid Stem Cell Megakaryocyte Thrombocyte Erythrocyte Platelet RBC Lymphoid Stem Cell Lymphocyte T cell Lymphocyte B cell Plasma Cell Leukocyte Leukocyte Leukocyte Leukocyte Leukocyte WBCa WBC WBC WBC WBC Monocyte Neutrophilic Eosinophilic Basophilic Mast (Macrophage) Granulocyte Granulocyte Granulocyte (Mast Cell) Source: Leukine® sargramostim Heamtopoietic Cascade 2002. Berlax Laboratories, Inc., Seattle, WA. Retrieved September 19, 2004 from http://www.leukine.com/ a White Blood Cell oo Early on in development, the precursor stem cells are small, undifferentiated cells that are indistinguishable from one another, differing only with regard to their developmental potential. This developmental potential is made manifest only in the presence of specific growth factors, called colony-stimulating factors (CSFs) (Damjanov 2000). These hematopoietic growth factors are named after the lineages they regulate [e.g., erythropoietin (EPO) for the erythroid cell lineage, thrombopoietin (TPO) for the thromboid cell lineage] or after the assay used for discovery [e.g., granulocyte colony-stimulating factor (G-CSF), macrophage colony-stimulating factor (M-CSF), and granulocyte-macrophage colony- stimulating factor (GM-CSF)] (Rosenberg 2000). Most CSFs are produced in the bone marrow by bone marrow derived cells present in extra-medullary sites (e.g., peripheral blood, lymph nodes, spleen), which forms the ideal environment for the growth and development of stem cells. EPO, produced in the kidney, is the only hematopoietic growth factor produced exclusively outside of the bone marrow. CSFs belong to a large family of cytokines that often have overlapping functions. Cytokines are hormone-like proteins that are secreted by many different cell types to regulate the intensity and duration of immune responses and are involved in cell-to-cell communication (Damjanov 2000). Cytokines are released by the stromal cells of the spleen and thymus, by epithelial, endothelial, and mast cells and by fibroblasts and lymphocytes (Damjanov 2000). Cytokines operate in all tissues, but some of the first to be studied were involved in immune and inflammatory processes (Rosenberg 2000). Functionally, cytokines are proteins released by cells that react with receptors on other cells, triggering a response (Rosenberg 2000). Since cytokines are involved in mediating immunity and regulating lymph activity (lymphohematopoiesis), and themselves act as hematopoietic growth factors, it can be said 9 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. that these proteins serve both antiviral and antitumor functions (Damjanov 2000). Other growth factors, such as interleukins (Ils) produced by macrophages and T lymphocytes, also stimulate blood cell formation. Although Ils are primarily produced by and act on leukocytes, many Ils can be produced by non-leukocytic populations. While hundreds of cytokines are known, only 18 are currently recognized as Ils, which are numbered consecutively in their order of discovery. Overall cytokines are difficult to harness and study; as a result not many have found a direct use in the clinic, with the exception of IL-2, interferons (IFNs), colony-stimulating factors, and erythropoietin. Hematopoiesis is a complex process that includes the continuous generation of a spectrum of highly specialized and differentiated blood cell types. The lifespan of these cells ranges from hours to years (Rosenberg 2000). There is a continual generation of these multiple lineages from the self-renewing stem cell. Stem cells maintain steady state conditions by responding to conditions of increased demand for one or more lineages. In the I990’s a remarkable revolution occurred in the understanding of hematopoiesis at molecular levels (Rosenberg 2000). These recent molecular advances help to guide the current understanding of cancer development and assist with the identification of possible areas of treatment. Hematopoiesis is close to being defined as an expression of more than 50 gene products variously defined as hematopoietic growth factors, cytokines, and chemokines, which are produced within hematopoietic tissues and manage the complex process of multi-lineage proliferation and differentiation (Rosenberg 2000). Advances in biologic therapy will increasingly affect the practice of oncology. Understanding this complex pattern of autocrine, paracrine, and endocrine regulation provides a molecular basis for understanding malignant hematopoiesis (Rosenberg 2000). 10 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Malignancies of the Bone Marrow Malignant transformation of blood cells results in lymphomas or leukemia. Given that the bone marrow and lymph nodes are where the blood components are produced, malignancies of hematopoietic cells most often arise in the bone marrow or lymph nodes, but can spread to the blood, lymph nodes, spleen, liver, or central nervous system. Leukemia is a malignant disease that involves the white blood cell precursors (Damjanov 2000). Leukemias are considered a heterogeneous group of cancers that can be broadly classified into two major categories based on the different cell types from which leukemias start: myeloid (granulocytic-monocytic) and lymphoid (lymphocytic). Histologic typing of the malignant cells identifies the hematopoietic cell lineage and leukemia sub-type. Clinically, both myeloid and lymphoid leukemias can be further classified as acute or chronic. Acute leukemia cells grow rapidly and are not able to mature properly. Acute leukemia is characterized by a block in cellular differentiation, which results in a massive accumulation of immature cells (blasts) (Cohen and Wood 2000). Acute leukemias (both myeloid and lymphoid) have a relatively sudden onset and rapid progression if left untreated. In contrast, chronic leukemia cells (both myeloid and lymphoid) under the microscope appear mature but they are not completely normal or able to carry out their intended function. Chronic leukemia cells live too long and cause a build up of certain kinds of white blood cells. Chronic leukemia has a slow onset and slow progression, which leads to unregulated proliferation, and results in an over-expansion of a spectrum of differentiated cells (Cohen and Wood 2000). 11 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Chronic Myeloid Leukemia (CML): Etiology and Pathogenesis Chronic myeloid leukemia (CML) (also termed chronic myelogenous leukemia, chronic myelocytic leukemia, chronic granulocytic leukemia) is one entity within a group of diseases called ‘the myeloproliferative disorders’ (MPDs). [Other related MPD entities include polycythemia vera, myelofibrosis and essential thrombocythemia.] CML is considered a clonal hematopoietic ‘disorder’ (malignancy) because the leukemic cells originate from one cell that underwent an oncogenic transformation; this oncogenic transformation is the result of an acquired genetic defect in the pluripotent stem cell (Andreeff and Pinkel 1999). The clinical manifestation/result of this acquired genetic defect is normal hematopoiesis being gradually replaced by an increasing proliferation of differentiated cells that have a characteristic expansion of the myeloid elements (CancerNet 2001). CML was the first human malignancy to be associated with a single and consistent cytogenetic abnormality, the Philadelphia (Ph+) chromosome, thereby providing a model for molecular oncogenesis. The Ph+ chromosome is the hallmark of CML, originally described by Nowell and Hungerford in 1960 as a ‘minute chromosome’ (Nowell and Hungerford 1960). Later the Ph+ chromosome was identified as one partner in a reciprocal translocation between the long arm of chromosome 9 at band q34.1 and chromosome 22 at band q ll.2 , which is seen in all hematopoietic precursors (Rowley 1973) (Figure 2). This chromosomal translocation results in the transfer of the Abelson (ABL) oncogene to the area of chromosome 22 termed the breakpoint cluster region or BCR (CancerNet 2001). This translocation in the hematopoietic stem cell, t(9;22)(q34.1;ql 1.2), creates two new hybrid genes, BCR/ABL on the 22q- or Ph+ chromosome, and the reciprocal ABL/BCR 12 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission. Figure 2: The Philadelphia Chromosome: t(9;22) I t d e r(9) to> 11 13 it 1 9 2 1 der (22) Philadelphia Chromosome # Note: This figure shows the Philadelphia (Ph+) chromosome, the exchange o f material between chromosomes 9 and 22 Source: Provided by the City o f Hope National Medical Center Cytogenetics Laboratory. on the derivative 9q+ (Groffen et al. 1984). The ABL/BCR gene, although transcriptionally active, does not appear to have any functional role in the disease (Melo et al. 1993). The BCR/ABL gene, however, encodes for a fusion protein with elevated tyrosine kinase activity. This elevated activity is regarded as central to the mechanism that underlies the chronic phase of CML. The breakpoints within the ABL gene at 9q34 can occur anywhere over a large (>300kb) area at its 5 ’ end, either upstream of the first exon lb, downstream of the second exon la or more frequently between the two. Regardless of the exact location of the breakpoint, splicing of the primary hybrid transcript yields a mRNA molecule where BCR sequences are fused to ABL exon a2. In contrast to ABL, breakpoints within BCR localize to one of three breakpoint cluster regions. In most CML cases and in approximately one third of the cases of Ph+ acute lymphoblastic leukemia (ALL) the break occurs within a 5.8kb area spanning BCR exons 12-16 defined as the major breakpoint cluster region (M-BCR) (Hochhaus 2002). Due to alternative splicing, fusion transcripts of either b2a2 (the smaller splice 2) or b3a2 (the larger splice 1) can be formed. Both transcripts give rise to a 210kDa chimeric protein (p210 bcr-abl) and roughly 5-10% of patients express both b2a2 and b3a2 mRNA [p210 reflects the size of the protein] (Deininger, Goldman, and Melo 2000). The remaining cases of ALL and very rare cases of CML have breakpoints further upstream in BCR exon 1, the minor breakpoint cluster region or m-BCR. The resulting ela2 mRNA is translated into a 190kDa protein. A third breakpoint cluster region also occurs in the m-BCR, downstream of exon 19 giving rise to a 230kDa fusion protein. This type of BCR/ABL hybrid gene is sometimes associated with the rare Ph+ chronic neutrophilic leukemia, but can also be found (rarely) in cases of classic CML. The p210 protein is seen in virtually 100% of patients with 14 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. CML and in up to 50% of adult cases with de novo ALL. Similarly the pi 90 form is seen in approximately 50% of adult patients with ALL and in most pediatric patients with Ph+ ALL (Abeloff et al. 2000). While the prognostic significance of the p210 splice location (b2a2/b3a2) has been the subject of more recent studies, the impact of splice location on outcome is not yet known and remains under investigation (Melo 1996; Pinilla-Ibarz et al. 2000; Hochhaus 2002). The fused BCR/ABL gene and the production of an abnormal tyrosine kinase protein are related to the disordered myelopoiesis (formation of the myeloid blood cells) found in CML (CancerNet 2001). The chimeric fusion protein (bcr-abl) functions as a constitutively activated tyrosine kinase, and several studies have demonstrated that the transforming function of the bcr-abl protein is dependent on this activity (Lugo et al. 1990; Oda et al. 1995). BCR/ABL transcript types have been shown to be stable over time in individual patients and there is no convincing evidence that clonal evolution may occur. CML: Clinical Features and Disease Staging The median age at diagnosis of CML is between 50 and 60 years of age (American Cancer Society 2001; Ries et al. 2001). Although CML can occur in children, cases are rare; 2-3% of all childhood leukemias are CML (Ries et al. 2001). Children diagnosed with Ph+ CML tend to have a better prognosis (survival) when compared to adults (CancerNet 2001). CML is usually easily diagnosed because the leukemic cells of more than 95% of patients have the distinctive cytogenetic abnormality (the Philadelphia chromosome) (CancerNet 2001). Approximately 30% of people with CML have no symptoms (asymptomatic) at the time their cancer is diagnosed (American Cancer Society 2001), and 20% have no physical signs 15 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. at diagnosis (Abeloff et al. 2000). In these cases the cancer is usually revealed by blood tests done for some other reason. Even in patients who experience symptoms consistent with CML, the early stage symptom profile is considered non-specific and could be caused by something other than cancer. Most symptoms of CML are caused by an overabundance of leukemic white cells or by a shortage of normal blood cells, a result of the crowding out of normal blood cell-producing bone marrow by leukemic clones. The result of this ‘crowding out’ is that the patient does not have enough properly working red blood cells, white blood cells and platelets. Although patients with CML usually have an abnormally high number of white blood cells (leukocytosis), typically exceeding 11,000/pL, the cells are not normal and do not protect against infection as well as normal white blood cells (American Cancer Society 2001). As a result CML patients are at an increased risk for developing infections. Table 1 outlines the normal composition and function of the formed elements of the blood. Spread of leukemia outside of the bone marrow to other organs or the central nervous system can cause a variety of symptoms such as headaches, weakness, seizures, vomiting, trouble maintaining balance, and blurred vision (American Cancer Society 2001). Patients with advanced disease experience bone pain or joint pain caused by the spread of cancer cells to the surface of the bone or into the joints (American Cancer Society 2001). Leukemia can also cause swelling of the liver and spleen. If the disease has spread to the lymph nodes, the affected region may be swollen. More general symptoms of CML can include shortness of breath, fatigue, weakness, pale skin color, weight loss, fever and bone pain (American Cancer Society 2001). Anemia (lack of red blood cells -normal functioning) is what causes the shortness of breath, fatigue and pale skin color (American Cancer Society 2001). Low platelet count may 16 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Table 1: Formed Elements of the Blood-Composition and Function Constituent: Formed Elements Normal Relative Percentage/Volume: Healthy Adult Function Platelets (Thrombocytes) 150-450 x 103 /pL Essential clotting factors Red Blood Cells (Erythocytes) Male: 4.7-6.1 x 106 /pL Female: 4.2-5.4 x lOVpL Child: 3.8-5.5 x 106 /pL Transport oxygen from lungs into the peripheral tissues White Blood Cells (WBC) (Leukocytes) Total: 4.8-10.8 x 103 /pL Participate in the body’s defense against infection WBC: Agranulocytes/ Monocytes 200-800 per cubic mm Macrophage, responsible for Phagocytosis WBC: Agranulocytes/ Lymphocytes 1,000-4,000 per cubic mm Immunity (T cells and B cells) WBC: Granulocytes/ Neutrophils 2,000-8,000 per cubic mm Phagocytosis, defense against bacterial infections WBC: Granulocytes/ Eosinophils 50-300 per cubic mm Allergic reactions: defense against parasites WBC: Granulocytes/ Basophils 0-100 per cubic mm Allergic reactions: inflammatory reactions Source: Schauf, CL, Moffett DF, and Moffett SB. 1990. Human physiology: foundations andfrontiers. St. Louis, MO: Times Mirror/Mosby College Publishing. lead to bruising, unusual bleeding (e.g., gums), and frequent or severe nosebleeds. The most common finding on physical examination at diagnosis is splenomegaly (enlarged spleen). Often the spleen is so enormous that it fills most of the abdomen. Histopathologic examination of bone marrow in patients with CML reveals a shift in the myeloid cell lineage to immature forms that increase in number as patients progress to the more advanced stages 17 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. of the disease (CancerNet 2001). Upon examination, normal red marrow is hypercellular, and differential counts of both marrow and blood show a spectrum of mature and immature granulocytes (Cohen and Wood 2000). The progressive course (continuum) of CML can be divided into three clinical phases: stable or chronic disease (CP), accelerated phase (AP) and an acute phase also known as blast crisis (BC) (Table 2). Ninety percent of CML patients present in CP. Transition from the CP to the accelerated and later to the blastic phase may occur gradually over a period of one year or more, or it may appear abruptly (‘blast crisis’). The annual rate of progression from CP to BC is 5% to 10% in the first two years and 20% in subsequent years. Survival after development of AP CML is usually less than one year if left untreated and only a few months after blastic transformation (CancerNet 2001). The signs and symptoms commonly seen as the disease advances are progressive leukocytosis, thrombocytosis or thrombocytopenia, anemia, increasing and painful splenomegaly or hepatomegaly, fever, bone pain, development of destructive bone lesions, and thrombotic or bleeding complications. In the accelerated phase, differentiated cells persist, although they often show increasing morphologic abnormalities, increasing anemia, thrombocytopenia, and marrow fibrosis are apparent (CancerNet 2001). 18 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Table 2: Summary of Chronic Myeloid Leukemia (CML) Definitions: ___________________Clinical Diagnostic Criteria and Staging________ Clinical Diagnostic Criteria: Leukocytosis (WBC) 4.000-11,000 (normal) > 11,000 Splenomegaly Thrombocytosis (Platelets) 150.000-350,000 (normal) >350,000 BCR/ABL positive (FISIP, PCRb ) Philadelphia Chromosome Positive (Ph+) by classic cytogenetics Staging: Chronic Phase a. Meets the clinical diagnostic criteria for CML b. No features of Accelerated Phase or Blast Crisis CML Rule: a and b Accelerated Phase a. Meets the clinical diagnostic criteria for CML b. > 10% blasts in blood or marrow c. > 20% blasts plus promyelocytes in blood or marrow d. > 20% basophils plus eosinophils in blood e. Additional chromosome changes (evolving new clone or any additional abnormality) f. Development of chloromas (Equivalent to extramedullary disease) g. In a second (subsequent) Chronic Phase after Blast Crisis Rule: a and (b or c or d or e or f or g) Blast Crisis a. Meets the clinical diagnostic criteria for CML b. > 30% blasts plus promyelocytes in the blood or bone marrow Rule: a and b a : Fluorescent In Situ Hybridization b : Polymerase Chain Reaction Patients may present in AP where symptoms characteristic of CP develop over a relatively shorter period than that of CP. Patients in AP are more likely to be symptomatic with fever, bone pain, and/or bleeding. In the majority of patients the progression from CP to AP is 19 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. insidious but distinct (Abeloff et al. 2000). The blood count and spleen size may surpass the control of previously adequate treatment. Some patients may have symptoms indicative of meningitis due to central nervous system infiltration, particularly in lymphoid blastic transformation (Abeloff et al. 2000). Progression of CML to myelofibrosis occurs in 5% of patients and is regarded as a feature of advanced disease. (Myelofibrosis is a progressive disease of the bone marrow where neoplastic bone marrow stem cells lodge and grow in multiple sites outside the bone marrow.) In the advanced stages there is prominent splenomegaly that is usually greater than 10 cm below the costal margin, features of bone marrow failure with increasing anemia and thrombocytopenia supervene and there is usually extramedullary hematopoiesis with enlargement of the liver and occasionally the lymph nodes (Abeloff et al. 2000). [If the hematopoietic bone marrow is destroyed, extramedullary hematopoiesis may resume in the spleen, liver, and lymph nodes (Damjanov 2000).] Genetic Techniques/Biology: Classic Cytogenetics, Molecular Cytogenetics, Recombinant DNA Technology The study of chromosomes at the metaphase of the cell cycle is referred to as cytogenetics. Chromosomes are located in the cell’s nucleus and are made up of genes that facilitate the reproduction and the maintenance of a species (Mueller and Young 1998). In humans, the normal cell nucleus contains 46 chromosomes comprised of 22 pairs of autosomes (non-sex chromosomes) and a single pair of sex chromosomes: XX in female and XY in male. Each parent passes on one member (homolog) of each of these pairs (Figure 3). Chromosomes are not uniform in width or length and have a point of constriction, which is referred to as the centromere. Unlike the arms of the chromosome, the structure of the centromere is unclear, but is known to be responsible for the movement of the chromosome during cell division 20 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. (Mueller and Young 1998). The centromere divides the chromosome into short and long arms. By convention the shorter arm is denoted as ‘p ’ and the longer arm is denoted as ‘q’. The tip of each arm is referred to as the telomere. The role of the telomere is to seal the ends of the chromosome, in doing so the telomere maintains the chromosome’s stability and integrity. Figure 3: Normal Human Chromosome Structure (Karyotype) Homolog Centromere m za Vt/fi Source: Heim S, and Mitelman, F. 1995. Cancer Cytogenetics, Second Edition. New York: John Wiley & Sons, Inc., Publications. 21 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. There is an international standard for human chromosome nomenclature, which is based on the results of several international conferences (ISCN 1995). The International Standard for Human Cytogenetic Nomenclature (ISCN) summarizes the most recent conference (as of 1995), and incorporates and supersedes all previous ISCN recommendations (ISCN 1995). After analyzing the chromosomes, a person’s karyotype is used to describe a photomicrograph of an individual’s chromosomes, arranged in order by number. Microscopic examination of chromosome size and banding patterns allows clinical laboratories/cytogeneticists to identify and arrange each of the 23 different chromosome pairs into a karyotype, which then (when compared to the normal human cytogenetic profile) serves as a tool in the diagnosis of genetic diseases and malignancies. This is the basis upon which cytogeneticists are able to analyze and interpret human karyotypes, assessing the karyotype for chromosomal aberrations that are of prognostic significance. The laboratory methods created to examine chromosomes in 1956 are now universally used in all cytogenetic laboratories to analyze the ‘chromosome constitution’ of an individual (Heim 1995). When examining the chromosomes for constitutional aberrations, just about any somatic tissue with a nucleus that undergoes cell division can be used for studying human chromosomes. Circulating lymphocytes from the peripheral (venous) blood are most often used to determine an individual’s constitutional karyotype (Mueller and Young 1998). However, in cancer, the genetic aberrations observed in the tumor karyotype are acquired (not constitutional). Hence, in cancer cytogenetic analyses, the tumor tissue must be analyzed. For the leukemias, bone marrow is the first choice; blood is the second choice - assuming spontaneously mitotic cells are present. During chromosome preparation, cells are arrested at metaphase, which is the time when the chromosomes are maximally condensed 22 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. and therefore most easily visible. A hypotonic saline solution is added which causes the cells to swell and release the chromosomes, which are then fixed, mounted on a slide and stained for analysis. During chromosome analysis by classic cytogenetics, the first step is to count the number of chromosomes present in a minimum of 20 cells. The next step is to carefully analyze the banding pattern of each chromosome. This careful analysis of the banding pattern compares each pair of homologs. Deviations from the known standard are the basis upon which diagnoses of various human genetic (malignant and non-malignant) diseases are made. The technical developments made to assist with the analysis of chromosomes over the past 40 years have had a major impact on the diagnosis and treatment of patients with cancer. The basic unit of hereditary information is the gene, which codes for an enzyme or a structural protein. While the molecular structure of a gene is complex, genes can still be thought of as discrete units located at specific sites along a chromosome (Khoury, Beaty, and Cohen 1993). Because genes specify the coding of proteins that in turn constitute the structural and functional building blocks of the human organism, any alteration in the genetic material that leads to a disturbance in the structure and/or function of a vital protein can result in disease or malignancy (e.g., the BCR/ABL chimeric gene encodes for a fusion protein with elevated tyrosine kinase activity). Mutation is broadly defined as any change in the genetic material, and thus many mutations will disrupt the structure and function of gene products. While mutations can occur in both somatic and germ cells, only germline mutations are heritable and transmitted to subsequent generations. Cancer, with a few exceptions, such as BRCA1 and BRCA2, is a somatic disease process, the result of an acquired genetic defect. CML is a malignancy characterized by an acquired, not inherited, 23 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. genetic abnormality. Because somatic mutations are limited to the non-germ cells (germ cells are the cells of the body that transmit genetic information to the next generation), the integration of molecular biology in the diagnosis and treatment of CML is critical. The commonly used genetic analysis method of classic cytogenetics detects of the presence of a 9;22 translocation, more specifically t(9;22)(q34.1;ql 1.2). The molecular counterpart of this translocation is the BCR/ABL fusion gene rearrangement. In patients with CML, the presence of a 9;22 translocation or bcr-abl message is a definitive diagnostic criterion. Additional molecular techniques and recombinant DNA technologies are now used to supplement the detection of the presence of the 9;22 translocation in patients without a visible Ph+ chromosome by classic cytogenetics. A small subset of patients has bcr-abl detectable only by reverse transcription-polymerase chain reaction (RT-PCR), which is the most sensitive technique currently available. Patients with RT-PCR evidence of the BCR/ABL fusion gene appear clinically and prognostically identical to patients with classic Ph+ chromosome. However, patients who are Ph negative and bcr-abl negative by RT-PCR have a clinical course more consistent with chronic myelomonocytic leukemia, a distinct clinical entity categorized as a myelodysplastic syndrome (Heim 1995). The application of recombinant DNA technology has made it possible to produce large amounts of biologic molecules previously only available in minute quantities. Another technique, Fluorescent In Situ Hybridization (FISH), combines conventional cytogenetics with molecular genetic technology (probes). Unlike classic cytogenetics, FISH can be used to study chromosomes in cells that are ‘non-dividing’ or in the interval of cell division known as interphase. By analyzing an unselected cell population, FISH allows for a 24 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. quantitative screening of both mitotic and non-mitotic cells. Like RT-PCR, FISH is also able to detect the BCR/ABL gene in the 5% of CML cases that are negative by classic cytogenetics, and has recently been used to identify deletions on the derivative chromosome 9 in Ph+ CML. Deletions of the derivative chromosome 9 have been associated with poor response to conventional therapies (Sinclair et al. 2000; Huntly et al. 2001). FISH is now used widely for clinical diagnostic purposes and has a major advantage relative to classic cytogenetics in that results are usually obtained very rapidly. FISH and PCR also test for differences between normal cells and CML cells in the detection of minimal residual disease. In addition to studies related to diagnosis, both tests are often used for the diagnosis of early relapse following allogeneic blood or marrow transplantation (Allo-BMT) or for assessment of preparation of cells for autologous transplantation (Thomas, Blume, and Forman 1999). Factors that affect the occurrence of mutations and interact with the environment, as well as the genetic structure of the population in producing disease, are central to the study of genetic epidemiology. Although not inheritable, evidence suggests that somatic mutations play an important role in the pathogenesis of cancer. For example, in CML and many other types of cancer, several consistent changes have been observed. In addition to chromosomal changes in neoplasia, a group of cellular genes called oncogenes have been shown to increase activity in some cancers. Oncogenes are also important in the genesis of cancer by other mechanisms (e.g., chromosomal rearrangements). Age effects are seen for many chronic diseases such as coronary artery disease and many cancers; for such diseases the incidence and prevalence increases with advanced age. Increasing risk of CML occurs during the course of an average human lifetime. During each cell division there is an opportunity for the occurrence of numerical chromosome abnormalities due to errors in 25 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. chromosome separation. Accumulating somatic mutations and chromosome abnormalities are known to account for a large proportion of malignancy and probably explain the rising incidence with age. CML Incidence, Trends and Risk Factors Annually CML constitutes about 0.3% of all incident cancers in the United States, accounting for 13-20% of all cases of leukemia (Perkins et al. 2000; Ries et al. 2001). CML has an annual incidence of 1-2 cases per 100,000 per year and affects about 4500 Americans each year (465 annually in California) (American Cancer Society 2001). Although CML occurs in all decades of life, it is mainly a disease of adults with a median age of onset between 50 and 60 years of age. CML incidence rates rise with increasing age. Age-adjusted incidence rates reported by Surveillance, Epidemiology and End Results (SEER) for all races from 1994-1998 were 0.7 and 7.2 per 100,000 for persons diagnosed <65 years and >65 years respectively (Ries et al. 2001). Males have an age-adjusted incidence rate that is 1.7 times higher than females. While rates were higher in the United States among whites than blacks prior to the mid-1970’s, an excess of CML has been observed among blacks since then due to a more rapid decline of age-adjusted CML incidence rates among whites compared to blacks (Schottenfeld and Fraumeni 1996). Based on SEER program data, in the US the 5-year survival rates during 1992-97 for persons of all ages with CML range from 34.7% among white males and 31.9% among white females to 36.7% among black males and 35.1% among black females. In the majority of cases, the specific cause of CML is largely unknown. However, the risk of developing CML is higher following exposure to high doses of irradiation. This is evident from the numerous studies of survivors of the atomic bomb explosions in Japan in 1945, and of patients treated with radiation for 26 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. ankylosing spondylitis and cervical cancer (Court-Brown and Doll 1965; Kato and Schull 1982; Boice et al. 1985). There is no known etiologic association of CML with any infectious agent, and no familial predisposition or specific HLA genotype has been implicated or studied (Abeloff et al. 2000). The elucidation of risk factors through population based case-control studies has been hindered by the rarity of the disease. As a result, the majority of the research efforts continue to focus on disease biology, treatment and prognosis. Current Therapeutic Strategies and Related Outcomes The primary objective of standard treatment options for patients diagnosed with CML is to eradicate the Philadelphia (Ph+) clone while minimizing therapy-related side effects (toxicities) and complications. Often the primary measure for defining treatment efficacy is survival, however other intermediate treatment evaluation parameters include, response indication (hematologic, cytogenetic or molecular), strength of the response (complete or partial remission) and durability of the response (duration) (Table 3). Historically, the therapeutic options for CML have included: 1) chemotherapy with Busulfan (Myleran) (first introduced in 1953) (Haut et al. 1961) or Hydroxyurea (first introduced in 1963) (Kennedy 1972, 1992); 2) HLA matched sibling or related allogeneic bone marrow transplantation (first successful Allo-BMT reported in 1979) (Fefer et al. 1979; Thomas et al. 1986); 3) Interferon-alpha (IFN-a) based treatments (first introduced in 1983) (Talpaz et al. 1986); 4) HLA matched unrelated allogeneic bone marrow transplantation (first introduced in 1990) (McGlave et al. 1990); and 5) the molecularly targeted Gleevec (Imatinib Mesylate) (formerly Signal Transduction Inhibitor 571) (first introduced in 1998) (Druker, Talpaz, et al. 2001). More recently scientists have begun devoting resources to studying treatments that 27 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Table 3: Summary of Chronic Myeloid Leukemia (CML) Definitions: ____________________________ Disease Response___________________________ Remission A. Complete Remission i. Clinical: Hematologic: a White Blood Cell (WBC) < 10,000/ul b Hemoglobin >11.0 gm/dl c Platelet count < 500,000/ul d No immature cells in peripheral blood e No palpable splenomegaly (Rule: a and b and c and d and e) ii. Cytogenetic: 0% Ph+ metaphases (minimum # of cells 20) or < 1% by FISH*a (minimum of 200 cells) *: Depends on FISH strategy used, for outside institutions conducting FISH analysis, note background for outside institution. iii. Molecular: No detectable bcr-abl mRNA by RT-PCRb B. Partial Remission i. Clinical: Hematologic: a. WBC > 10,000/ul but < 50,000/ul and 50% below pretreatment values b. Hemoglobin > 9.0 but < 11.0 gm/dl c. Platelet Count > 500,000/ul d. Differential > 1% precursor cells e. Palpable splenomegaly (Rule: a or b or c or d or e) ii. Cytogenetic: Record actual percentage of Ph+ metaphases or # of interphase cells that are positive Relapse A. Hematologic: Clinical: i Persistent leukocytosis with immature forms (promyelocytes and blasts) in the peripheral blood ii Extramedullary manifestations of the disease with documented Ph+ cells B. Cytogenetic: i. No hematologic abnormalities ii. No extramedullary abnormalities (e.g., chloromas present) iii. Have Ph+ cells in blood or bone marrow, on two or more occasions C. Molecular: lOx or greater increase in the relative expression of the marker gene detected and confirmed by a minimum of 3 consecutive quantitative PCR analysis. Sample can be either blood or bone marrow. a: Fluorescent In Situ Hybridization b :Reverse Transcription-Polymerase Chain Reaction 28 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. are considered investigational/experimental (e.g. intensified Chemotherapy with autologous stem cell rescue, non-myeloablative blood or marrow transplantation in the elderly). Chemotherapy with Busulfan and Hydroxyurea The duration of survival after diagnosis is highly variable in CML CP patients treated with non-transplantation methods, the reason for this heterogeneity is largely unknown (Goldman and Druker 2001). For many years the principal choices for chemotherapy included Busulfan (BU) and Hydroxyurea (HU) (Bolin et al. 1982; Rushing et al. 1982). The superiority of HU was finally established in patients with CP CML after a randomized controlled clinical trial compared the agents and showed that the median survival was significantly shorter for BU treated patients than for those treated with HU (45 versus 58 months, p<0.01) (Hehlmann et al. 1993). The 5-year survival rates were 32% and 44% for BU and HU respectively (Hehlmann et al. 1993; Silver et al. 1999). The same trial showed that patients treated with HU had a significantly longer median survival with significantly fewer severe adverse effects. Other studies have also demonstrated that BU causes more frequent and serious complications of irreversible cytopenia (a reduction in the number of cells circulating in the blood) and pulmonary, hepatic and cardiac fibrosis. BU has also been shown to be associated with unpredictable prolonged myelosuppression and Addison’s-like disease. The availability of more effective and less toxic therapies (e.g., HU, interferon-alpha) has limited BU use to rare patients in exceptional circumstances (Berman et al. 2000). While BU and HU are able to achieve hematologic responses initially in over 70% of patients, neither one has been associated with meaningful cytogenetic responses (Berman et al. 2000). 29 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Interferon-alpha (IFN-a) The bulk of the evidence for the effectiveness of interferon-alpha (IFN-a) therapy consists of at least 30 uncontrolled observational studies initiated in the 1980’s (Sliver et al. 1999). The largest number of patients have been treated and followed at the M.D. Anderson Cancer Center (Houston, TX) in observational studies where the probability of complete and partial hematologic remission in CML after interferon therapy is 70% to 80% and 6% to 10% (Talpaz et al. 1986; Talpaz et al. 1987; Kantarjian et al. 1995; Silver et al. 1999). Remission rates reported by other investigators are generally lower and vary more widely. In studies where only IFN-a is used, the rates of complete and partial hematologic remissions range from 7% to 81% and 6% to 50%. Reported rates for complete and partial cytogenetic remissions range from 0% to 38% and 0% to 16%, respectively (Silver et al. 1999). The wide variations in reported outcomes stem largely from differences among studies in patient makeup (health status and risk factors): age, stage of disease, the number of months elapsed from diagnosis, the presence or absence of symptoms or physical findings, treatment regimens (IFN regimens vary considerably in preparation, dose, duration and criteria for changing the dose based on clinical response and toxicity), and criteria for measuring outcomes, all of which influence prognosis (Silver et al. 1999). In practice, one of the most effective ways of predicting survival for patients treated with IFN-a is to assess the hematologic response to IFN-a at six months and cytogenetic response at one year (Mahon et al. 1998). The greatest survival advantage is seen in IFN-a treated patients who achieve a major cytogenetic response (less than 35% Ph+ metaphases, by FISH), though the median time to optimal cytogenetic response may be one to two years 30 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. (Goldman and Druker 2001). However, patients who do not achieve complete hematologic response at six months or who fail to achieve even a minor cytogenetic response (less than 65% Ph+ metaphases, by FISH) at one year are unlikely to obtain a major cytogenetic response. The literature suggests then that patients not achieving these landmarks could be considered candidates for alternative therapies (Goldman and Druker 2001). Although proven to be more effective than HU or BU, IFN-a can produce toxic effects that can result in dosage modification or discontinuation of therapy in many cases. Published side effects include influenza-like syndrome, nausea, anorexia, weight loss, and neuropsychiatric symptoms. Unlike HU and BU these side effects are completely reversible with cessation of therapy. Immune mediated complications, such as hyperthyroidism, hemolysis, and connective tissue diseases may occur rarely after long-term treatment. Long-term follow-up of the interferon-treated patients from a randomized trial comparing interferon with chemotherapy showed that the median survival had not been reached at 10 years for patients who had complete or major cytogenetic responses to interferon. Seventy-four percent of patients with complete cytogenetic responses and 55% of patients with major cytogenetic responses were alive and had shown no disease progression when published (median follow- up time was not provided). However, using molecular methods of analysis, small numbers of Ph+ cells can still be detected in the majority of patients having long-term cytogenetic remissions, and longer follow-up will be required to ascertain whether the disease will recur. Patients older than 60 years with chronic phase CML have a hematologic and cytogenetic response rate and duration of cytogenetic response similar to that in younger patients; however, the incidence of complications is greater in elderly patients. 31 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Even though IFN-a is quite costly and the daily injections can be troublesome, IFN-a is used routinely in patients with CML who are not candidates for Allo-BMT. IFN-a also appears effective for patients who have relapsed after Allo-BMT. IFN-a induces durable cytogenetic responses and prolongs duration of CP and survival compared to conventional chemotherapy (Talpaz et al. 1991; Hehlmann et al. 1994; Italian Cooperative Group 1994; Allan, Richards, and Shepherd 1995; Chronic Myeloid Leukemia Trialists 1997, Italian Cooperative Group 1998; Faderl et al. 1999; Kantarjian et al. 2000). Questions regarding IFN-a include a) mechanisms of action; b) the best IFN-a dose; c) the long-term outcomes of patients on IFN-a therapy; d) the relationships between features of CML and probability of response to IFN-a and expected benefits; and e) definitions of clinical and biological targets of treatment, including the concept of cure (Kantarjian et al. 2000). For patients who do not respond well to IFN therapy, Allo-BMT becomes, in most cases, the only possibility for long term survival. There has been much speculation that prior treatment with IFN-a might adversely affect the result of a subsequent Allo-BMT. To answer this question the results of a multicenter study, conducted in Germany, implied that the potential negative impact of IFN on transplant outcome appears to be limited to patients receiving transplantation from a matched, unrelated donor, and may be improved by withdrawal of interferon for at least 90 days prior to transplantation (Hehlmann et al. 1999). In addition, the study demonstrated that Allo-BMT cases who discontinued IFN-a at least 90 days prior to transplant were no worse off than those who had never received IFN-a (Hehlmann et al. 1999; Goldman and Druker 2001). 32 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Allogeneic Blood or Marrow Transplantation Currently the literature demonstrates that the only consistently successful curative treatment of CML has been high-dose chemotherapy followed by Allo-BMT, but the 100-day to six- month morbidity and mortality post transplantation are high. The literature supports a clear course of action for patients under the age of 40. It is recommended that for patients < 40 years of age, Allo-BMT with a sibling, related or unrelated donor should be the ‘standard’ course of action and should be considered within the first year following diagnosis. For patients > 40 years of age who have a related donor, the literature also strongly supports Allo-BMT, although morbidity and mortality rates rise with increasing age. Because of the increased morbidity and mortality from unrelated donors in patients over 40 years of age, alternative therapeutic strategies are/have been studied extensively in the literature. The same is true for poor risk CML, defined in the literature as patients in AP or BC. For patients >40, trials using IFN-a with or without cytarabine is fairly consistently recommended. After treatment with IFN-a, patients without a major cytogenetic response would then proceed to transplantation when feasible (HLA compatible donor available). IFN-a, HU, or both are standard treatments used to stabilize patients prior to BMT. In a randomized clinical trial, disease-free and overall survival, were comparable when allogeneic transplantation followed preparative therapy with cyclophosphamide (CY) and total body irradiation (TBI) or BU and CY without TBI. The latter regimen was associated with less grafit-versus-host disease and fewer fevers, hospitalizations, and hospital days. 33 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. It was accepted practice that all patients younger than 60 years of age with an identical twin or with HLA-identical siblings would be considered for BMT early in CP. Although the procedure is associated with considerable acute morbidity and mortality within the first 100 days, in several large series, 50% to 70% of patients transplanted in CP survived 2 to 3 years, with the results better in younger patients and progressively worse in the accelerated and blastic phases of the disease. Most transplant series suggest improved survival when the procedure is performed within one year of diagnosis. The data supporting early transplant have never been confirmed in controlled trials. On average, about 70% of otherwise eligible CML patients lack a suitably matched sibling donor. HLA-matched unrelated donors or donors mismatched at one HLA antigen can be found for about 50% of eligible participants through the National Marrow Donor Program. CML is the most common indication for unrelated donor transplants and represents 35% of all unrelated donor transplants done in the United States (Faderl et al. 1999). However, there are still major obstacles in using unrelated donors, especially in older patients. As a result, patients receiving unrelated donor transplants are typically younger and have a longer interval from diagnosis to transplant (a direct consequence of the lengthy donor search process). Two retrospective series following allogeneic BMT from an HLA-matched unrelated donor showed a 5-year relapse rate of 3% to 10% and a 5-year overall survival rate of 31% to 57% (most deaths were treatment-related, e.g., graft failure and infection). [BMT from an unrelated donor is associated with a higher risk of post-transplant graft failure and infection (viral and fungal).] While the majority of relapses occur within five years of transplantation, relapses have occurred as late as nine years following BMT. The incidence of relapse is lower with BMT from unrelated donors than it is from sibling donors although 34 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. most studies show no significant difference in relapse rates when examining donor type. Overall the risk of relapse appears to be less among those patients who are transplanted early on in the disease process, and among those who develop chronic grafit-versus-host disease (GVHD) post-BMT. Even though GVHD is a life-threatening transplant complication, there is clinical evidence that demonstrates a positive effect of the GVHD reaction. The effect appears to be most powerful in diseases that progress slowly like chronic leukemia and less effective in the rapidly growing acute leukemias. This phenomenon is called the graft-versus-leukemia (GVL) or graft-versus-tumor effect and is one of the reasons that allogeneic transplants can be curative. While the biological mechanism(s) underlying the GVL effect is poorly understood, one theory proposes that as the donor product attacks the tissues of the patient, the new stem cells will also attack the cancer cells that still may be present after transplant. In recent years, transplant physicians have learned to apply the GVL effect to treat (e.g., non-myeloablative transplants) or prevent disease recurrence after stem cell transplantation by infusion of donor white cells. [In some patients who relapse after transplant, the disease- killing capability of the donor’s white blood cells can be harnessed again, by infusing the patient with more of the donor’s white blood cells through the donor leukocyte infusion (DLI) process.] Intensified Chemotherapy with Autologous Stem Cell Rescue Grafting with unpurged autologous bone marrow or stem cells results in transient cytogenetic responses, but a survival advantage has not been proven (Reiffers et al. 1994). Relapse due to reinfused Ph+ cells may occur (Deisseroth et al. 1994; Reiffers et al. 1994). 35 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. To reduce contamination by Ph+ cells, several purging strategies have been developed. These include manipulations with cyclophosphamide derivatives, biological response modifiers, tyrosine kinase inhibitors, antisense oligonucleotides, and ribozymes. Intensive chemotherapy to eradicate Ph+ clones was patterned after that used in acute leukemia programs. Although cytogenetic remissions could be induced in 60-70% of patients, they were brief and were not improved by maintenance with IFN (Kantarjian et al. 1995). Gleevec (Imatinib Mesylate) (formerly Signal Transduction Inhibitor 571 or STI571) The maturing results of treatment with Gleevec may soon change current recommendations regarding the relative roles of established therapies (e.g., Allo-BMT and IFN-a) (Kantarjian et al. 2000). Gleevec, an Abl specific tyrosine kinase inhibitor, competitively blocks the ATP-binding site of the Abl kinase; the kinase activity of the stem-cell-receptor factor (c- KIT) and platelet-derived growth factor receptors are also blocked. Gleevec inhibits the proliferation of CML-derived cell lines and the clonal growth of cells from the bone marrow of patients with CML. The drug is given orally (at a dose of 400mg/day for CP and 600mg/day for AP and BC), is well tolerated, and thus far has a manageable side-effect profile. The first presentation of clinical data using STI571, an investigational drug then, was made at the American Society of Hematology in December 1999. In the preliminary results of a phase I trial, Gleevec induced hematologic remission in all 31 patients with interferon- resistant CP CML; of 20 patients on treatment for five months or longer, 45% showed some degree of cytogenetic response. Responses were also seen in patients with myeloid and lymphoid blast crises. These preliminary results demonstrated activity that appears greater than that of any other agent used in the treatment of CML. Although the durability of these responses and the incidence of molecular remission cannot yet be assessed, an ongoing 36 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. phase 2 study of 532 patients in CP, for whom IFN-a therapy failed, was designed to address this issue (Goldman and Druker 2001). The short-term results suggest that Gleevec is a major advance in comparison with the use of IFN-a or IFN-a + cytarabine in chronic phase CML. Even though hematologic and cytogenetic responses to IFN-a have prognostic value, at this stage we cannot assume that the same will apply for Gleevec. (From Goldman and Druker 2001: ‘Will such responses be equally maintained?’ ‘Will the patient who obtains a good or complete cytogenetic response with Gleevec survive as long or longer than a patient who obtains a comparable response with IFN-a?’) Patients treated with IFN-a rarely achieve complete molecular remission when a sensitive reverse-transcription PCR is used (Hochhaus et al. 2000). Will Gleevec-treated patients do better in this regard? The data produced by ongoing trials targeted at answering this question are essential before we can be certain that a patient treated with Gleevec is likely to gain substantial prolongation of life (Goldman and Druker 2001). The effectiveness of Gleevec is further complicated by the fact that patients treated with Gleevec in combination with other agents may survive longer than those treated with Gleevec alone. There are plans to launch a three-arm randomized multicenter study comparing Gleevec with Gleevec + IFN-a and Gleevec + cytarabine in patients newly diagnosed with CML. In addition the results of Allo-BMT could be improved by prior or subsequent use of Gleevec (Goldman and Druker 2001), or as was studied with IFN-a, it 37 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. remains to be determined whether prior treatment with Gleevec negatively impacts survival after Allo-BMT (Kantarjian et al. 2000; Goldman and Druker 2001). The treatment approach (choice of initial therapy) for patients with CP CML who lack an HLA matched sibling or related donor has become increasingly difficult. Even experts differ on the best treatment for this patient population. While the treatment selection is influenced by disease characteristics, the availability of a suitable donor and advent of new treatment options (e.g., tyrosine kinase inhibitors) are becoming key factors in the decision making process. On the one hand, the availability of non-transplant strategies that can effectively achieve cytogenetic remissions (e.g., IFN-a and Gleevec) offers the possibility of long-term disease control for some patients without Allo-BMT (Kantarjian et al. 2000). On the other hand, because Allo-BMT is the only proven curative therapy for CML in CP, and given the increasing size and number of volunteer donor registries, as well as improvements in tissue typing and supportive care, the outcomes of unrelated donor transplantation continue to improve and should be considered when available. 38 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. CHAPTER 3 THE CHANGING LANDSCAPE OF CHRONIC MYELOID LEUKEMIA PROGNOSIS Introduction The importance of predicting the likely long-term outcome of treatment for cancer is seen throughout the literature. Prognostic studies are popular in oncology because many factors have been shown to affect a cancer patient’s prognosis. A PubMed® search for papers with prognosis or predictive in the title (or listed as a keyword) yields more than 20,000 basic science and clinical research papers published from the mid-1960’s to December 2003. Most prognostic studies within oncology focus on either a) identifying new factors that are of independent prognostic importance (+/- specifying an actual prognostic model or staging system) or b) using previously reported prognostic factors to define/validate subgroups of patients with good or bad prognosis. Physicians and people facing cancer are naturally interested in the information these studies provide. Prognostic factors serve a variety of important functions in medicine, in addition to educating/informing the patient, other clinical/research functions include the selection of optimal treatment, development of risk- adjusted treatment strategies, adjustment of treatment imbalances in clinical trials, and comparative assessment of the outcomes across different studies (Byar 1984). While prognostic factors and the resulting prognostic scores-staging systems are often used to benchmark health care standards, the creation of prognostic indices for patients diagnosed 39 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. with chronic myeloid leukemia (CML) were originally devised to describe severity of illness and predict outcome given existing treatment options. Outcome prediction for CML patients has been in a constant state of evolution (refinement) since Minot et al. generated the first survival estimates using a case-series of 166 CML patients whose data was collected over a 10-year period (Minot, Buckman, and Isaacs 1924). Over the last three decades, advances/improvements in molecular biology, molecular diagnostics, and treatment (approach to disease management) have greatly improved our understanding of the relative influence of patient, disease and treatment characteristics on CML prognosis. O f the significant associations seen among these factors, the literature shows that treatment has the most central impact on prognosis, whereby the influence of patient and disease features on disease free survival can be more accurately described/estimated. Today we have an enormous amount of new knowledge related to the underlying neoplastic process of CML and those factors that predict an altered disease course (outcome) in the presence of effective treatment. However, we also face the frustrating reality that the different genetic alterations and expressions seen among CML patients generate different malignant behaviors (manifestations) as it relates to treatment response (resistance) and survival. This reality leaves us with some remaining questions around the issue of prognosis. Because the clinical heterogeneity of CML continues to be an enigma, there is currently no single, simple answer for the treatment of newly diagnosed CML patients. The fact that there is no agreed upon standard treatment (or disease management) approach that is based on the significant patient and disease features demonstrates that the story of CML prognosis does not end here. 40 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. The objective of this paper is to provide a review of the evolution of prognosis for CML patients from the early 1980’s through 2003. This review will examine the way the issue of prognosis has been studied, focusing on the evolution of the relative contribution of patient, disease and treatment characteristics and prognostic models/scoring systems for CML. The issue of CML prognosis shares a fascinating and complex history with the fields of genetics and molecular medicine. This paper will review how improvements in treatment and disease characterization have advanced the area of prognosis for newly diagnosed patients. This review will also highlight the remaining limitations in the information currently available and what the future of outcome prediction holds for this patient population. While the research (literature) in this area supports the examination of various clinical endpoints and phases of CML, this review is limited to assessing the influence of prognostic factors (prognostic models/scoring systems) found to be predictive of survival for CML patients in chronic phase (or newly diagnosed patients). (Brief History 1845-1960) CML: Disease Etiology, Characteristics and Early Treatment In 1845 John Hughes Bennett, a pathologist, presented the first description of CML. As with most newly discovered diseases, in the (roughly) 100 years following, there were numerous research efforts in the United States and abroad focused on gaining insight into the cause, pathophysiology, tempo, and treatment of CML. Although the natural course of CML would not be more fully characterized until the 1900’s, Bennett and others realized early that CML followed a persistent, progressive and eventually fatal course; this characterization was the first hint that CML might be neoplastic. The cause of CML (and other leukemia subtypes) baffled investigators for many years following its discovery; early epidemiological studies 41 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. into the cause of CML were primitive and anecdotal. Even though there was a significant amount of research in this area, virtually nothing was known about the etiology until many years later when the hematologic sequelae of the atomic bomb explosions in Japan were analyzed and CML was identified as one of these (Kato and Schull 1982; Geary 2000). Although identifying the cause of CML was important to the patients and physicians of the 19th century, investigators at that time believed that insight into the cause(s) of CML would be gained as their understanding of the underlying disease process and associated physiologic/organ changes improved. With that, the literature (research) of the late- 1800’s/early-1900’s marks a shift away from disease etiology to, an almost exclusive emphasis on, cellular morphology and treatment. From 1860 to 1895, CML was generally accepted as a chronic disease with limited therapeutics. The first report of the use of arsenic in the treatment of CML was by Lissauer, a German physician who administered it to a woman in 1865. Because the patient was temporarily restored to health for some months, arsenic trioxide (Fowler’s solution) became the first agent of some beneficial use in the treatment of CML. Later the discovery of the X- ray in 1895 by Wilhelm RRntgen brought forth a new treatment for CML. Radiation therapy produced initial temporary results that were similar to those produced by arsenic. (The assessment of the value of radiation therapy continued for some 30 years thereafter.) While arsenic and radiation therapies were able to extend survival for some months, neither was able to alter the course of the disease or restore the bone marrow to normal functioning. Inevitably all patients receiving either therapy died due to complications of their illness, making these ‘single’ treatment options ineffective. 42 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. As more cases of this relatively uncommon disease were reported and treated, the increasingly predictable features of its natural history were defined and the goals of treatment became clearer (and the characteristics of an effective treatment became more obvious). By 1930 a standard diagnostic approach had been developed which included a review of the physical symptoms, a peripheral blood smear in conjunction with physical findings (e.g., spleen size, presence of extramedullary disease) and laboratory data (e.g., complete counts of the blood components). By 1935, the first edition of Whitby and Britton’s textbook on diseases of the blood gave the first comprehensive description of the clinical picture and hematologic features of the disease, including bone marrow morphology and staging (Whitby and Britton 1935). Although the term ‘blast crisis’ was not used until much later, these authors noted that myeloblast cells, in increasing numbers, could be seen in the later stages of the disease as it became refractory to treatment (Geary 2000). By the 1960’s the progressive course (continuum) of CML, which was first noted almost 100 years earlier, had been divided into three defined clinical phases (stages): stable or chronic disease (CP), accelerated phase (AP) and an acute phase also known as blast crisis (BC). (It was estimated that -90% of CML patients present in CP, and that transition from the CP to the accelerated and later the blastic phase may occur gradually over a period of one year or more, or it may appear abruptly (‘blast crisis’). The annual rate of progression from CP to BC is 5% to 10% in the first two years and 20% in subsequent years.) Since then, this disease classification schema (staging system) has been well studied and is still used in clinical practice today to stage newly diagnosed CML patients and monitor hematologic response post treatment (Thompson and Stainsby 1982; Sokal et al. 1988; Faderl et al. 1999). It was also during the 1960’s that CML was found to be associated with a single and consistent cytogenetic abnormality, the Philadelphia (Ph+) chromosome, thereby providing a 43 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. model for molecular oncogenesis. Since the discovery of the Ph+ chromosome, originally described by Nowell and Hungerford in 1960 as a ‘minute chromosome’ (Nowell and Hungerford 1960), and later shown to be a translocation between chromosome 9 and 22, that is, t(9;22)(q34.1;ql 1.2) (Rowley 1973), this cytogenetic abnormality has become the hallmark of CML and continues to be used to diagnose patients. The Sokal Score: Prognosis -Conventional Chemotherapy Evidence that the therapeutic options for CML patients were improving came in the 1950’s/60’s with the introduction of busulfan (in 1953) (Haut et al. 1961) and hydroxyurea (in 1963) (Kennedy 1972). For newly diagnosed CP patients treated with these therapies, the death rate dropped to 5-10% during the first year following diagnosis (Monfardini et al. 1973; Sokal 1976). This reduction was attributable to the fact that patients were now able to achieve and sustain a hematologic remission (complete normalization of peripheral blood counts) for an extended period of time. While this was a meaningful outcome for the CML therapeutics researchers, extended follow up confirmed that although many patients achieved a hematologic remission, the normal course of the disease -with progression to blast crisis, was very rarely altered, and consequently survival was not significantly prolonged. The one- year death rate was found to increase from ~7% to 23% and 28% during the third and fifth years post diagnosis. When pooled assessments of survival were conducted across treatment centers, investigators noted that the duration of survival following diagnosis (treatment) was highly variable (Tura, Baccarani, and Corbelli 1981). (Which remains true today.) Further investigation revealed that after adjusting for differences in treatment schedules, the clinical course of CML remained heterogeneous. While the experts could not refute the diversity seen among these ‘same stage’ patients, there was considerable disagreement as to whether 44 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. pretreatment prognostic determination was possible for CP CML patients. Some believed that these patients could not be further segregated into subgroups with different life expectancies (Woodruff 1981; Thompson and Stainsby 1982; Goldman and Lu 1982; Sokal et al. 1984). To prove or disprove critics, in 1984 Joseph Sokal organized a large cooperative study to retrospectively evaluate the prognostic significance of various disease features recorded at diagnosis. The goal of this effort was to develop and validate a prognostic classification for CP CML. Whether or not this classification could be generalized to other CP CML patient populations only future validation studies could determine. What went on to be called the ‘Sokal Score’, was based on 813 confirmed CP CML patients, diagnosed from 1962-1981, across six different treating institutions. Of the 18 patient and disease features that were collected and then analyzed by univariate Cox regression, four factors were found to be of primary prognostic significance by multivariable analysis: age, spleen size (cm), platelet count and percent blasts in the blood. (The multivariable analysis- derived prognostic model was helpful in defining the associations among the significant factors.) The Sokal score was found to work well as a prognostic discriminator for survival of three different patient strata: low risk (RR: <0.8), intermediate risk (RR: 0.8-1.2) and high risk (RR: >1.2) of death. Confirmation of the prognostic validity has occurred in many studies for patients receiving chemotherapy since the paper was published in 1984. The work of Sokal and his colleagues has gone on to be accepted as the first meaningful and significant examination of CML prognosis. [For individual patients, the Sokal score can be calculated by accessing a web site developed by the Northern Regional Hematologists Group in the United Kingdom http://www.nrhg.ncl.ac.uk/cgi-bin/cml/sokal.pl. The Sokal prognostic score is calculated using the hazard ratio function published by Sokal (1984): 45 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. EXP 0.0116(age-43.4) + 0.0345(spleen size-7.51) + 0.188((platelets/700)2 - 0.563) + 0.0887(blasts-2.10).] The Hasford (Euro) Score: Prognosis -Interferon-a Treatment During the early 1980’s, there was significant improvement in our understanding of immune function. Shortly thereafter various immunological approaches to CML treatment were studied. O f the many cytokines investigated, the cytokine interferon-a (interferon-alpha), either alone or in combination with conventional chemotherapy, was found to improve both the clinical course and overall survival of many CML patients (Talpaz et al. 1983; Talpaz et al. 1987). (Cytokines are hormone-like proteins that are secreted by many different cell types to regulate the intensity and duration of immune responses and are involved in cell-to-cell communication (Damjanov 2000).) One limitation of interferon therapy was (and still is) its toxicity. Because of the adverse events experienced by some patients, interferon treatment was often discontinued even though a positive effect on the patient’s leukemia could be observed. Despite these drawbacks, because interferon was shown to significantly improve overall survival and suppress the re-emergence of disease for a period of time, in 1986, interferon based treatment was accepted as the best available (conservative) treatment for patients with CP CML (Hasford et al. 1998), supplanting busulfan/hydroxyurea based treatment as front line therapy. While hematologic and cytogenetic remissions were not uncommon, like those patients treated with busulfan/hydroxyurea, individual responses and overall survival were shown to vary considerably. (The concept of hematologic/cytogenetic remission and role of residual disease is described in the next section.) 46 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. In an effort to better understand (characterize) the variability seen in patients treated with interferon, factors previously shown to influence overall survival were studied (e.g., age, spleen size, platelet count and %blasts in the blood). The result of this investigation proved that although the Sokal Score was found to be a good discriminator of survival for patients treated with conventional chemotherapy, the generalizability of this score to patients treated with interferon was poor (Ozer et al. 1993; Ohnishi et al. 1995; Hasford et al. 1996). Hence, there was a need to assess the prognosis of patients treated with interferon. In 1998, Hasford and colleagues organized an international group of investigators to study this issue. What went on to be called the ‘Hasford (or Euro) Score’, was based on 1573 patients constructed from a meta-analysis of 14 studies across 12 different treating institutions. The objective of this meta-analysis was to ‘extract’ and validate a prognostic scoring system for CP CML patients treated with interferon. O f the 22 patient and disease features analyzed by univariate Cox regression, six factors were found to be of primary prognostic significance by multivariable analysis (significantly correlated with/predictive of survival): age, spleen size (cm), platelet count, % blasts, % basophils, and % eosinophils. The Hasford score was found to work well as a prognostic discriminator for survival of three distinct risk groups: low risk (<780), intermediate risk (781-1480), and high risk (>1480). Confirmation of its prognostic validity has occurred in many studies since the paper was published in 1998. [For individual patients, the Hasford score can be calculated by accessing a web site developed by Pharmacoepidemiology Research Group www.pharmacoeDi.de/cmlscore.html ] The Evolution of Treatment Goals The 1980’s and 90’s were an exciting time for CML physicians and researchers. As investigators in the area of cancer immunology were making scientific advances, the areas of 47 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. cancer cytogenetics and molecular genetics were making significant advances as well. In the 1980’s molecular genetic techniques became available to study the specific genes associated with the underlying cytogenetic abnormality in CML patients, the Philadelphia chromosome (Ph+). Groffen et al found that the molecular consequence of this aberration, t(9;22), is the creation of two new hybrid genes (two genes that flank the translocation breakpoint): the BCR/ABL chimeric fusion gene on the 22q- or Philadelphia (Ph+) chromosome, and the reciprocal ABL/BCR on the derivative 9q+ (Groffen et al. 1984). The protein derived from the BCR/ABL chimeric fusion gene has elevated tyrosine kinase activity, which correlates with its ability to transform normal cells to a malignant phenotype (Lugo et al. 1990). For scientists and clinicians, these findings were of great importance in the study of leukemogenesis (molecular biology of CML) because it proved that BCR/ABL is the causative event for this form of leukemia and not just a marker of disease. In many ways CML now serves as a paradigm for the utility of cytogenetic and molecular methods in the diagnosis and monitoring of disease following treatment. Response to treatment is expressed at three levels: hematologic/clinical (defined as the normalization of the peripheral blood values and spleen size), cytogenetic (defined as the proportion of residual Ph+ cells), and molecular/sub-clinical (defined as the proportion of residual BCR-ABL gene, transcript, or protein). Laboratory tests capable of detecting residual disease, based on level of tumor burden, include FISH, PCR and Q-PCR; the sensitivity associated with each tests’ ability to detect disease increases from hematologic to molecular (increases with increasing tumor burden) (Figure 4). Because the ultimate measure of treatment efficacy is survival, the association between the level of suppression of Ph+ cells [or related molecular events (e.g., clonal/disease evolution)] and improved survival, made minimal residual disease monitoring essential to the process of assessing effectiveness of treatment (Guilhot et al. 1997; Italian 48 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Cooperative Group 1994, 1998; Silver et al. 1999; Kantarjian et al. 1995; Kantarjian et al. 2003). Figure 4: Sensitivity of Laboratory Tests /v 4--------Treatment / \ 4-------- Hematologic Remission Assessment of Blood Target: Blood Counts \ 4-------- Cytogenetic Remission Assessment of Bone Marrow oells in mitosis Target: Philadelphia Chromosome Tumor Burden \ 4-------- FISH Remission Assessment of Blood or Bone Marrow interphas^m etaphase nudei Target: BCR-ABL fusion gene \ 4-------- Molecular Remission \ PCR/Q-PCR Assessment of Blood or Bone Marrow Target BCR-ABL mRNA Mdectiar Relapse Time *: Nashed AL Rao KW, and Gulley ML Clinical applications of BCR-ABL molecular testing in acute leukemia. Journal cif Molecular Diagnostics 5(2): 63-72,2003. * : HochhausA Minimum residual disease in chronic myeloid leukaemia patients. Best Practioe and Research Clinical Hematology 15(1): 159-178,2002. *: Laboratory-based assessments o f disease include: blood counts (panel), conventional cytogenetics, interphase and hypermetaphase fluorescence in situ hybridization (FISH), and qualitative/quantitative polymerase chain reaction (PCR/Q-PCR). Conventional cytogenetics is the recommended test for detecting the Philadelphia chromosome in newly diagnosed leukemia patients; FISH is also used at diagnosis to detect the BCR-ABL (gene) translocation and has become a complementary method to conventional cytogenetics. Because there are various biologic and genetic indicators o f CML, from morphologic to genetic, each test was designed to assess a different manifestation (component/expression) o f the disease, each test is able to detect the disease at different levels of ‘tumor resolution’ and sensitivity (e.g., hematologic cell morphology and counts, chromosome, DNA, gene, mRNA etc.). The ‘target’ disease marker or associated biological pattern under evaluation differs by test. The Gratwohl Score: Prognosis -Alio BMT In the late-1970’s bone marrow transplantation came into use for CML treatment for those patients with an appropriately matched donor. Although the first successful allogeneic bone 49 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. marrow transplant (Allo-BMT) from an HLA matched sibling was reported in 1979 (Fefer et al. 1979), it took several decades before graft-versus-host reactions were sufficiently controlled to make this a feasible therapeutic option (Thomas et al. 1986). [HLA matched unrelated allogeneic bone marrow transplantation was introduced later in 1990 (McGlave et al. 1990).] There are positive and negative aspects to allogeneic transplantation. Because the patient is subjected to massive doses of chemotherapy and radiation, in an attempt to eliminate the leukemic cells before transplant, this very aggressive ‘ablative’ treatment limits the patients who are considered appropriate for such treatment. As a result, during the 1980’s and early 90’s many older patients (55 years of age is the most common upper limit for eligibility in clinical trials of Allo-BMT) with an appropriately matched HLA sibling donor were often not eligible for the procedure because of coincident disease or poor organ function (Djulbegovic et al. 2003). [Clinical trials have demonstrated that this patient population is more likely to experience adverse events as a result of regimen-related toxicity.] Preparative treatments that were able to maintain the high efficacy of myeloablative Allo-BMT, with reduced toxicity, were needed. For these patients, a non- myeloablative preparative regimen followed by infusion of allogeneic stem cells was proposed in the mid-1990’s to decrease the treatment-related morbidity associated with myeloablative chemotherapy while attempting to improve disease free survival. Since then reduced intensity (or non-myeloablative) conditioning regimens have proved to reduce short term toxicity without sacrificing the beneficial graft-versus-leukemia effect; the short-term disease free survival results for this older patient population appear comparable to ablative Allo-BMT patients. Both forms of allogeneic transplantation have been shown to generate graft-versus-leukemia reactions, which studies have shown help eliminate residual cancer 50 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. cells in the patient. As a result of this effect, eradication of CML (defined by failure to detect BCR/ABL transcripts by molecular methods) is possible only with Allo-BMT. Since the late-1970’s, transplantation has been used with increasing frequency and success but remains associated with considerable risks of morbidity and mortality. Because of the short term results achieved with interferon based regimens, for patients with an available donor, assessments of personal risk for individual patients by simple methods based on standardized and fixed variables are needed so that patients can be counseled appropriately (Hasford et al. 1998). To that end, data reported to the Chronic Leukemia Working Party were used to generate a risk score based on main pretransplant risk factors identified in previous studies and defined by the patient (e.g., age, stage of disease, time from diagnosis to transplantation) and type of donor (e.g., sibling vs. unrelated, patient-donor gender combination) (Hasford et al. 1998). A major limitation of this study is that treatment dependent risk factors, such as conditioning and graft-versus-host disease prophylaxis methods, were not taken into consideration in the modeling. What went on to be called the ‘Gratwohl Score’, was constructed from a retrospective analysis of 3142 CML patients, from 172 institutions. The result of the risk-factor analysis showed that all five risk factors had a significant impact on overall survival. For the analysis, risk scores were calculated based on the ‘sum’ of the risk factors donor type (0 for HLA- identical sibling donor, 1 for a matched unrelated donor), disease stage (0 for 1CP, 1 for AP and 2 for BC or >1CP), age of patient (0 for <20 years, 1 for 20-40 years, and 2 for >40 years), patient-donor gender combination (0 for all, except 1 for male recipient/female 51 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. donor) and time from diagnosis to transplantation (0 for <12 months and 1 for >12 months). The data confirmed the predictive value of the selected risk factors and derived score. Targeting the Source of CML: Gleevec Although effective therapeutic techniques for CML were developed and/or improved during the 1990’s, none of them, as a primary treatment, were directed specifically at the abnormal gene product in Ph+ cells. This all changed with the introduction of a drug called Imatinib Mesylate (Gleevec). Gleevec, an Abl specific tyrosine kinase inhibitor, was shown to competitively block the ATP-binding site of the Abl kinase (the kinase activity of the stem- cell-receptor factor (c-KIT)) thereby inhibiting the proliferation of CML-derived cell-lines and the clonal growth of cells from the bone marrow of patients with CML (Druker, Talpaz, et al. 2001). The drug has been found to be well tolerated, and thus far has a manageable side-effect profile. The first presentation of clinical data using STI571, an investigational drug then, was made at the annual meeting of the American Society of Hematology in December of 1999. The preliminary results of the Phase I trial demonstrated that Gleevec induced hematologic remission in all 31 patients with interferon-resistant CP CML; of the 20 patients on treatment for 5 months or longer, 45% showed some degree of cytogenetic response. Since then, updates from the randomized Phase III trial conducted by the IRIS study group (International Randomized IFN vs. STI571) (presented in December 2003 with 31 months of follow-up) continue to support the remarkable clinical effectiveness and safety of Gleevec. As a result, the treatment guidelines and process for evaluating prognosis are undergoing substantial change (Goldman and Druker 2001; Cervantes 2003). In particular, the indications for and timing of Allo-BMT are being re-evaluated in the post-Gleevec era. While no major toxic effects involving other cells have yet been reported, an acquired 52 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. resistance to Gleevec has been discovered. Scientists now studying this issue have shown that the mechanisms of resistance are heterogeneous (Hochhaus et al. 2002) making it unlikely to find a common new inhibitor with broad utility to overcome resistance. In response to this scientists are now exploring the efficacy of Gleevec in combination with other agents (La Rosee, O’Dwyer, and Druker 2002). This may become less of an issue if resistance to Gleevec manifests as a slow and orderly relapse into chronic phase. However, because many questions remain, there is a real concern that patients may relapse abruptly into an advanced stage of the disease, a stage in which transplantation cannot be safely or effectively done. The other major concern has to do with delayed transplantation. Because delaying transplantation beyond one-year post diagnosis is associated with inferior outcome, the inevitable postponement associated with a lengthy Gleevec treatment period may compromise the efficacy of the only proven therapy available for patients with CML. It seems therefore necessary to retain Allo-BMT as an important upfront therapy in younger patients with a suitable donor, for now. Advice to the contrary is based on limited experience/follow up with Gleevec and could be judged to be overly optimistic in years to come (Craddock, Augustson, and Basu 2003). In the next few years, an improved understanding of the effect of Gleevec on survival/response rates, and an updated assessment of reduced intensity Allo-BMT should allow for more definite recommendations. The Future of Outcome Prediction The improvements in long-term survival and prognosis seen over the last two decades is a result of significant advances in treatment and new technologies that have allowed physicians and scientists to more effectively characterize the disease at presentation and monitor the disease post treatment. Studies of patient and tumor characteristics have helped 53 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. in understanding disease heterogeneity and in developing somewhat useful clinical prediction rules, or prognostic models, that categorize patients into different risk groups based on pretreatment or therapy related features. Today we have an enormous amount of new knowledge related to the underlying neoplastic process of CML and those factors that predict an altered disease course (outcome) in the presence of effective treatment. However, we also face the frustrating reality (limitation) that additional progress in area of risk determination is dependent on our ability to further distinguish between patients who are likely to have long-term disease free survival and those who are not. Recently, more sophisticated laboratory techniques/parameters have been applied to address this issue. Because differences in genetic alterations and expressions seen among CML patients have been shown to generate different malignant behaviors (manifestations) as it relates to treatment response (resistance) and survival, the presence of derivative 9q deletions, telomere length, and gene expression profiling are now being studied to assess their predictive value. The following is a brief summary of what is known about these techniques/parameters to date. The presence of deletions adjacent to the translocation break points on the derivative chromosome 9 has been described in between 10-15% of patients with CML (Dewald, Wyatt, and Silver 1999; Grand et al. 1999; Herens et al. 2000; Sinclair et al. 2000; Huntly et al. 2001; Kolomietz et al. 2001). These deletions span the translocation breakpoint, often involve both chromosome 9 and 22 sequences, are large, sometimes measuring many megabases, and occur at the same time as the formation of the Philadelphia translocation (Huntly et al. 2003). Studies have shown that these deletions are associated with an extremely poor prognosis, with those patients who carry them having shorter length of 54 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. chronic phase, earlier disease transformation, and shorter survival (Huntly et al. 2001; Kolomietz et al. 2001). [Gleevec improves but may not fully reverse the poor prognosis of CML patients with derivative chromosome 9 deletions (Huntly et al. 2003).] Hematopoietic stem cells express telomerase and contain long telomeres, which become shorter as cells differentiate and mature. Telomeres are protein DNA structures present at the ends of chromosomes and are essential for genetic stability and cell replication. Telomerase is the enzyme complex that maintains telomere integrity. The extent of telomere shortening and level of telomerase activity often correlate with the presence of severity of some hematopoietic disease, CML is one of them (Elwood 2004). While this issue has been investigated, unlike derivative 9q deletions, the role of telomerase and telomeres within hematopoietic stem cells needs further clarification. Some scientists believe that advances in our knowledge in this field may improve clinical outcomes for the treatment of hematologic disease. Experts agree that further improvement in outcome prediction for CML patients is dependent on in our ability to reliably predict progression through the use of new diagnostic genetic markers. Because little is known about the molecular changes that accompany the transition of CML from chronic phase to the more advanced phases, historically it has been difficult to stratify patients according to their potential outcome and response to therapy. This is all changing now with the recent advances in gene expression profiling using DNA microarray technology. [Gene expression profiling is a molecular strategy that is used for disease classification and the identification of disease mechanisms.] Despite the tremendous potential of microarray technology, concrete insights and advances that translate to the 55 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. clinical care of the patient are only recently beginning to be tapped (Dudda-Subramanya 2003). With the introduction of this technology, investigators are now hopeful that their ability to tailor treatment strategies for individual patients through the identification of genetic changes that occur as the disease progresses is within reach. 56 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. CHAPTER 4 IDENTIFYING PREDICTORS OF CYTOGENETIC RELAPSE AND DEATH FOR PATIENTS UNDERGOING ALLOGENEIC BLOOD OR MARROW TRANSPLANTATION FOR TREATMENT OF CHRONIC MYELOID LEUKEMIA IN CHRONIC PHASE: THE CITY OF HOPE EXPERIENCE Introduction The clinical course, for patients diagnosed with chronic myeloid leukemia (CML) in chronic phase (CP), is heterogeneous. Prognosis varies widely depending on the risk profile of patients. Risk profiles are usually based on patient characteristics, clinical/disease features at presentation and prior therapy (type, amount and duration). Multivariable risk classifications and scoring systems based on pretreatment features have been the subject of numerous prognostic studies (Tura, Baccarani, and Corbelli 1981; Cervantes and Rozman 1982; Sokal et al. 1984; Sokal et al. 1985; Kantarjian, Smith, et al. 1985; Kantarjian et al. 1990; Italian Cooperative Group 1991, 1994; Thiele et al. 1991; Thiele et al. 1993; Hehlmann et al. 1992; Cortes 1997; Hasford et al. 1998). In most cases, these earlier studies were limited to evaluating the relative impact of pretreatment features on overall survival. As a result, several models have been developed that categorize patients into different groups with distinctive survival characteristics (Sokal et al. 1984; Hasford et al. 1998). However, the reproducibility and generalizability of most of these scoring systems have been questioned 57 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. because these systems were restricted to certain therapeutic regimens. Application of the various risk models and scoring systems to cohorts with other treatment modalities, in particular allogeneic blood or marrow transplantation (Allo-BMT), frequently demonstrate a significant lack of prognostic efficiency with overlapping risk discrimination (Gratwohl et al. 1998; Clark et al. 2001; Michallet et al. 2001; Radich et al. 2001; Gratwohl 2003). While a number of prognostic models for non-BMT patients have been developed and are well documented in the literature, a useful scoring system/prognostic model has not been developed for CML-CP patients that undergo Allo-BMT. The overall objective of this analysis was to examine factors that may serve as prognostic indicators of cytogenetic relapse and/or death in patients who have undergone Allo-BMT for treatment of CML-CP. An examination of the role of patient, disease and treatment factors collected both at the time of diagnosis and Allo-BMT was completed to assess the predictive value of these factors on a patient’s risk for disease recurrence and/or death following Allo- BMT. (As part of the background for the data collection effort and statistical analysis, a review of the medical literature [from ®1980 to 2003] was completed to identify those factors that should be included in the analysis.) The proposed study design is a retrospective descriptive case-series study. An ongoing case-series of 234 CML-CP patients treated at City of Hope National Medical Center (COH) with Allo-BMT from 1982-2002 was used for this analysis. This study also explored the predictive value of three generally accepted prognostic scoring systems (Sokal, Hasford and Gratwohl) in this large single center Allo-BMT population. The result of the literature review suggests that this analysis is the first to examine the prognostic reproducibility of these scoring systems in a large single institution Allo-BMT population and the first to conduct a ‘head-to-head’ comparison of the three 58 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. scoring systems. The literature shows that the selection of optimal treatment depends on many factors. It is our hope that the results of this study will contribute to the overall understanding of CML-CP prognosis in the Allo-BMT setting and will serve as the catalyst for building a guide that could assist clinicians with treatment decisions related to Allo- BMT. Based on an identified case-series of Allo-BMT CML-CP patients, the specific aims of this analysis were to: 1. To collect and summarize data on: a) significant patient, disease, and clinical features recorded at diagnosis and Allo-BMT; b) initial treatment following diagnosis; c) cytogenetic studies performed at diagnosis and Allo-BMT; and d) complications and clinical outcomes following Allo-BMT, including evidence of cytogenetic relapse and/or death. 2. To examine the predictive value of molecular and cytogenetic features on survival following Allo-BMT after adjusting for patient and disease characteristics recorded at diagnosis and Allo-BMT. 3. To, based on each patient’s disease and clinical characteristics, assign weighted risk scores for the three most widely accepted scoring systems (Sokal, Hasford and Gratwohl) and test the prognostic significance in this independent patient population. 4. To assess the predictive value of disease and clinical features recorded at diagnosis and Allo- BMT, thereby identifying through statistical analysis potentially new disease and clinical features at Allo-BMT that are predictors of disease recurrence and/or death post Allo-BMT. 59 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Methods Protocol Submission and Patient Consent. A retrospective chart review protocol was submitted for this study to COH’s Institutional Review Board (IRB) and is approved through September 2005 (COH IRB# 00120). IRB approval was obtained to abstract information from the medical records of all patients with a ‘general-use’ consent on file. (The information abstracted from each patient’s medical record is described in the subsequent section [data collection and processing] of this chapter.) The PI of this study confirmed that all 234 patients had an institutional ‘general use’ consent form on file at the start of this study. Patient Population. Between June 1982 and December 2002, 234 consecutive patients with CML in first CP were treated at COH with Allo-BMT using histocompatible sibling donors. (The December 2002 date was selected to have a minimum of 12 months of follow-up for patients surviving to the December 2003 analysis start date.) All patients underwent diagnostic and disease phase confirmation just prior to the start of their preparative regimen for Allo-BMT. The initial diagnosis of CML-CP was based on pathology (biopsy), blood counts and cytogenetic tests done at the time of diagnosis. All ‘at diagnosis’ biopsy specimens originally collected and studied at an outside institution were re-reviewed and confirmed by an expert hematopathologist at COH prior to Allo-BMT. The results of the cytogenetic tests conducted at diagnosis and prior to Allo-BMT were available at both time points for all 234 patients. Of the 234 patients, 226 (97%) patients had the standard Philadelphia chromosome (Ph+), t(9;22), as their only cytogenetic abnormality (one patient was Ph-, but was positive for bcr-abl mRNA by polymerase chain reaction 60 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. [PCR] before BMT). O f the eight patients with additional cytogenetic abnormalities detected at diagnosis, four patients had a variant complex of the Ph+ with no other criteria for accelerated phase (Table 2), one patient had an additional cytogenetic abnormality (deletion 6) that is of unknown significance, and the remaining three patients had cytogenetic abnormalities that are considered inconsequential to the pathogenesis of CML [e.g., constitutional t(13; 16), non-clonal -13, and -X (loss of a sex chromosome which is an age related phenomena)]. The cytogenetic results for these eight patients were reviewed by an expert cytogeneticist and hematologist at COH for disease phase (stage) confirmation. Given the composition of the abnormalities detected in these eight patients, the experts decided that the cytogenetic and morphologic features of these patients were consistent with CML-CP and therefore could be included in this study. The date of analysis for this study was December 31, 2003, which was 12 months after the last patient in this case-series was transplanted. The ‘at diagnosis’ and ‘at transplant’ patient characteristics are summarized in Tables 4 and 5. There were 131 males and 103 females ranging in age from 8.6 to 71.5 years (median age, 36.4 years). Ninety patients (38%) were >40 years old at the time of BMT and nine patients were less than 18 years old. Chemotherapy was administered to 233 patients before BMT in a nonuniform manner. The majority of patients (78%) initially received hydroxyurea-based treatment following diagnosis. The median follow up for all 234 patients was 49.9 months (range, 1.5 to 227.4 months), and for the 153 patients surviving to the date of last contact, the median follow-up was 78.4 months (range, 10.3 to 227.4 months). R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Table 4: Allogeneic Blood or Marrow Transplantation (Allo-BMT) for Treatment of Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) Patients transplanted from 6/1982 to 12/2002 (N=234) Summary of Patient Characteristics at Diagnosis Variable Mean ± SD or n (%) Median (Range) N(%) with missing data Age at Diagnosis (years) 35.5+10.3 34.7(6.5-71.1) 0 Gender, proportion male 131 (56) 0 Race-Ethnicity White Non-Hispanic Hispanic Asian Black Non-Hispanic American Indian 114 (49) 84 (36) 25(11) 10 ( 4) 1 (<D 0 Occupation at Diagnosis High Risk Low Risk Unemployed Age < 18.0 years 64 (28) 124 (55) 29(13) 9 ( 4) 8(3) White blood cell count at Diagnosis (xl09 /liter) 159.7 ± 118.3 131 (13.9-730.0) 3(1) Eosinophils at Diagnosis (%, blood) 2.4 ±2.5 2(0-14) 32(14) Basophils at Diagnosis (%, blood) 3.2 ±2.9 3 (0-17) 32(14) Platelets at Diagnosis (xl09 /liter) 526.4 ± 382.2 423 (21-3500) 13(6) Blasts at Diagnosis (%, blood) 2.0 ±2.6 1 (0-12) 27(12) Splenomegaly at Diagnosis 137(62) 12(5) Spleen Size, cm below costal margin 8.8 ±5.5 8 (2-30) 121 (52) Initial Therapy Type Busulfan Hydroxyurea IFN-aa Allo-BMT (Sibling/Syngenic) Gleevec Other 18 ( 8) 183 (78) 8 ( 3) 1(d) i ( d ) 23 (10) 0 Interferon-alpha. 62 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Table 5: Allogeneic Blood or Marrow Transplantation (Allo-BMT) for Treatment of Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) Patients transplanted from 6/1982 to 12/2002 (N=234) Summary of Patient Characteristics at Transplant Variable Mean ± SD or n (%) Median (Range) N(%) with missing data Year of Transplant < 1985 1986-1990 1991-1995 1996-2000 2001-2002 22 ( 9) 45 (19) 76 (33) 78 (33) 13 ( 6) 0 Duration of CP: Time from Diagnosis to Transplant (years) 1.0+ 1.1 0.6 (0.1-8.2) 0 Age at Transplant (years) 36.5 + 10.2 36.4 (8.6-71.5) 0 < 40 Years > 40 Years 144 (62) 90 (38) Donor Match-Mismatch (Patient-Donor) Match (Male-Male) Match (Female-Female) Mismatch (Male-Female) Mismatch (Female-Male) 87 (37) 49 (21) 44(19) 54 (23) 0 Transplant Source Material Type Bone Marrow (BM) Peripheral Stem Cells (PSC) 206 (88) 28(12) 0 Preparative Regimen Busulfan/Cytoxan FTBIVCytoxan FTBI/VP-16b Other 70 (30) 25(11) 133 (57) 6 ( 3) 0 Graft vs. Plost Disease (GVHD) Prophylaxis Cyelosporine/PSEc Cyclosporine/MTXd Cyclosporine/MTX/PSE Other None-Twin 50 (21) 70 (30) 91 (39) 18 ( 8) 5( 2) 0 a Fractionated Total Body Irradiation b Etoposide 0 Prendisone d Methotrexate 63 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Data Collection and Processing. The majority of the data used for this analysis were collected manually after reviewing each patient’s paper and electronic medical record and all available outside correspondence. At the start of this study, approximately 40% of the data had been previously collected by protocol data managers (n ~90 patients); these data were re-reviewed and verified by the Principle Investigator (PI) of this study. The remaining 144 patients with incomplete data were collected by the PI of this study. For those patients who are no longer actively followed at COH or who have expired, medical records were requested and obtained from COH’s remote warehouse site. In addition to the patient’s medical record, there were two electronic sources of data. An electronic feed of cytogenetic/FISH data (extracted from a vendor-based application) and molecular data (obtained from an Access 97© application that was developed by the PI of this study and the COH CML disease committee chair -Appendix A) was established and these data were incorporated into the final data set. When available, the following information from these identified sources was retrieved on each patient: patient/donor gender, age at diagnosis/transplant, race-ethnicity, marital status at diagnosis, occupation at diagnosis, white blood cell/platelet count at diagnosis, % eosinophils/basophils/blasts in blood at diagnosis, spleen size at diagnosis (measured as centimeters below the costal margin -costal margin: the lower edge of the chest/thorax formed by the bottom edge of the rib cage), initial therapy type, time from diagnosis to transplant, Kamofsky performance status at transplant, material used for transplant (blood vs. bone marrow), preparative regimen, graft versus host disease (GvHD) prophylaxis and acute/chronic GvHD incidence. Finally, the date of last follow-up (or death) and disease status (by molecular and cytogenetic methods) were recorded. 64 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. For data that were not already stored in an electronic source/centralized database, one was either built or this information was transmitted to the clinical research database on case report forms developed by the PI for this study (Appendix B). Data that were entered into the clinical research database via case report forms were subjected to automated checks for consistency and reasonableness. The content of the automated checks was based on input provided by the COH quality assurance coordinator, COH Hematology/BMT clinical trials administrator, and COH CML disease committee chair. A program was written (using SAS® version 8.2) to execute the automated checks and generate printouts of all data items for each patient; these printouts were examined for each patient at the conclusion of the data collection and data entry process. These checks resulted in the identification of some data errors that occurred during the data collection process. The majority of errors identified (>75%) could be attributed to changes in the patient’s planned therapy, incomplete data, interpretation of cytogenetic reports, and missed review of outside correspondence. In most cases the quality assurance coordinator or CML disease committee chair provided the clarification necessary to rectify all questionable cases. Delinquencies in patient follow-up were also easily identified by the program and a print out of delinquent patients was generated for resolution. (This process was designed, organized and executed by the PI of this study.) For patients who remained lost to follow-up (n=17 (7%)), information was obtained regarding disease status when last seen. For patients that were alive as of last contact and are currently being followed by a non-COH physician, the patient’s outside clinician was contacted to obtain follow-up information (e.g., GvHD, disease status, vital status, last contact date). The Social Security Death Index, COH Cancer Registry database and COH (BMT) Long Term Follow-up database were also used to assist with the update of 65 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. disease status and vital status information for patients that are no longer actively followed at COH. Completeness o f Data. Data used for this analysis were collected at three distinct time points: at diagnosis, transplant and last contact. These data collection time points were selected to 1) cover the major milestones in the patient’s disease-treatment course and 2) satisfy the analysis requirements. Unlike those data collected at transplant and last contact, data generated at diagnosis were more difficult to obtain. While demographic and initial treatment information (e.g., age, gender, race-ethnicity, occupation and initial therapy) were readily available in the patient’s history and physical record, blood cell counts and spleen size were not (Table 4). Because a diagnosis of CML is based on pathology (bone marrow biopsy) and cytogenetic studies, the original laboratory reports containing the results of the patient’s blood counts at presentation were not always provided to COH by the referring institution/clinician. (The majority of patients [n=213 (91%)] were diagnosed at a non-COH facility.) In an attempt to collect this critical information, referring hospitals and clinicians were contacted. As a result of this additional effort, the proportion of patients with missing blood counts was reduced from -30% to 6-14% (Table 4). Unfortunately these attempts did not have the same effect in reducing the number of patients with missing spleen measurements. The reason for this had less to do with our ability to retrieve this data and more to do with the fact that these data were not recorded by the diagnosing physician. Although the literature and most hematologists/oncologists support the predictive value of this parameter on survival (increasing spleen size at presentation is associated with poorer outcome), of the 66 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. 121 patients with missing data in this case-series, >75% had spleen measurements recorded after the first course of treatment had been administered. A thorough investigation of these 121 patients revealed that an arbitrary missing data pattern exists. Contrary to what the literature (published data) asserts, in practice, it appears as though a significant number of clinicians place greater prognostic importance on spleen size reduction (from some imprecise baseline) rather than the patient’s actual spleen size (cm) at presentation. Prior to the start of this project, an early feasibility study that included 20 of the 234 patients was designed to examine our ability to collect data at presentation. The results of this feasibility study did not detect any major issues related to our ability to collect spleen size measurements; therefore, the final proportion of patients with missing spleen measurements was not expected. At the time of analysis 52% of the spleen size data were missing [n=121 patients]. Data Analysis and Statistical Methods Statistical Approach to Missing Data. In an ideal data collection/analysis project, complete data would exist for all variables across all patients. Unfortunately, a known limitation of retrospective studies is the potential for missing data. Given that 35% [n=82] of the patients in this sample were diagnosed and treated 10-20 years prior to the start date of data collection, the PI of this study appreciated that some values may not have been collected/reported, would have become lost, or would be unusable. A larger than expected amount of laboratory and physical exam data recorded at diagnosis were missing in this patient population (e.g., %eosinophils [14% missing], %basophils [14% missing], %blasts [12% missing], platelet count [6% missing] and spleen size [52% missing]). Therefore, in addition to analyzing only those patients with complete data, two statistical methods, an 67 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. imputation procedure and a prediction model, were applied to estimate values for each patient missing these data. While analyzing only those patients with complete data is the most simplistic statistical approach, information can be lost when the incomplete cases are removed. This approach may also ignore possible systematic differences between the complete cases and incomplete cases, and the resulting inference may not be applicable to the population of all cases, especially with a smaller number of cases. To maintain the integrity of this analysis, possible differences between complete and incomplete cases were explored. To that end, the final analysis (modeling) approach applied to these missing data included an examination of the predictive value of these parameters (%eosinophils/ basophils/ blasts, platelet count and spleen size) on the primary endpoints (survival and cytogenetic relapse) for the observed data (patient’s with complete data), imputed data and predicted data. Multiple imputation, the first of two methods used to estimate the missing data for this patient population, is a simulation-based approach where a user-specified number of complete data sets are created by filling in alternative values for the missing data (Rubin, 1987). In this analysis the multiple imputation procedure was executed to generate five complete data sets using the ‘PROC MI’ (SAS® version 8.2) procedure. Within each data set, the multiple imputation procedure replaced each missing value with a set of plausible values that represent the uncertainty about the right value to impute. This process results in hypothetical statistical inferences (parameter estimates and confidence limits) that reflect the uncertainty due to missing values; for example, confidence intervals with the correct probability coverage. The imputation method specified in this stored procedure depends on the type of missing data pattern. An ‘arbitrary missing data pattern’ that uses a Markov chain 68 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Monte Carlo (MCMC) method (Schafer 1997) that assumes multivariable normality was used. After the data sets were generated, the multiple imputed data sets were then analyzed by applying standard procedures for complete data using the combined results from these analyses. (Data for each patient were combined by adding the imputed values for each patient across the generated data sets and then dividing by the number of data sets specified). As a contrast to the multiple imputation method, another more basic statistical approach, linear regression analysis (the second of two methods) was applied to these data and used to estimate values for each patient with missing spleen data. Under the fixed regression line method, records with complete data were used to ‘fit a regression line’, from which, a patient’s missing spleen size could then be predicted from their non-missing white blood cell count (WBC), for example. In predicting an actual observed Y (spleen size) for a given individual, there are two sources of error operating: 1) the deviation of the individual’s Y from the true mean at X0 (observed WBC), and 2) the deviation of the estimated YX o from the true mean at X0 (Kleinbaum et al. 1998). This representation allows us to calculate the variance of the predicted responses given the observed Xo: Var Y + Var Yxo = a2 [1 + l/n + ((X0 - X ) 2 / ((n-l)Sx 2))] (Kleinbaum et al. 1998) Calculation of Weighted Risk Scores (Sokal, Hasford, and Gratwohl). The outcome used to construct the Sokal and Hasford prognostic scores was time to death following diagnosis of CML. The outcome used to construct the Gratwohl prognostic score was time to death following Allo- BMT. The Sokal score was calculated for each patient in this sample using the hazard rate ratio function published by Sokal et al. in 1984: EXP [0.0116(age-43.4) + 0.0345(spleen size-7.51) + 69 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. 0.188((platelets/700)2 - 0.563) + 0.0887(%blasts-2.10)]. Based on a risk schema proposed by Sokal et al. (1984), individual patient scores were then used to classify each patient into one of three risk groups (risk associated with death): low-risk (relative risk < 0.8), intermediate-risk (relative risk 0.8-1.2), or high-risk (relative risk >1.2). The Hasford prognostic score was also calculated for each patient using the formula published by Hasford et al in 1998: [(0.6666*age) + (0.0420*spleen size-cm) + (0.0584*blasts%) + (0.0413*eosinophils%) + (0.2039*basophils) + (1.0956*platelet count)] * 1000. [Recoded data. Age: if the patient’s age at diagnosis was <50 years then a value of 0 was assigned, otherwise a value of 1 was assigned. Basophils: if the patient’s % of basophils was <3% at diagnosis then a value of 0 was assigned, otherwise a value of 1 was assigned. Platelets: if the patient’s platelet count was <1500 at diagnosis then a value of 0 was assigned, otherwise a value of 1 was assigned.] Like Sokal et al. (1984) a risk schema was proposed by Hasford et al. (1998). For this analysis, the Hasford risk schema was also used to classify each patient into one of three risk groups (risk associated with death): low-risk (< 780), intermediate-risk (781-1480), or high-risk (>1480). Because both prognostic scores include spleen size in the calculation, Sokal and Hasford scores were calculated for each patient using the observed spleen size (when these data were present), the predicted spleen size (applying the linear regression method for patients with missing spleen data) and the imputed spleen size (applying the multiple imputation procedure for patients with missing spleen data) separately. 70 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. The Gratwohl prognostic score was calculated for each patient using the summary score published by Gratwohl et al in 1998. The risk score for an individual patient was calculated by taking the sum of the identified risk factors: donor type (0 for HLA-identical sibling donor) + disease stage (0 for first CP) + age of patient at Allo-BMT (0 for <20 years, 1 for 20-40 years, and 2 for >40 years) + patient/donor gender combination (0 for all, except for male-patient female-donor) + time from diagnosis to Allo-BMT (0 for <12 months, 1 for >12 months). The lowest possible score on this scale is 0 (lowest risk), which applies to a patient who undergoes a sibling Allo-BMT within 12 months following diagnosis, in first CP, under the age of 20, and is not male with a female donor. The highest possible score on this scale is 4 (highest risk), which applies to a male patient in first CP, over the age of 40, who undergoes a sibling Allo-BMT from his sister, beyond 12 months from diagnosis. Because these data were present for all 234 patients in the sample, the observed Gratwohl score was used for all relevant analyses. Statistical Analysis. Demographic, disease, and treatment characteristics were summarized for all patients using descriptive statistics. Survival estimates were calculated based on the product-limit method (Kaplan and Meier 1958), and 95% confidence intervals were calculated using the logit transformation and the Greenwood variance estimate (Breslow and Day 1980). Differences between survival curves were assessed by the Log Rank test. The significance of features collected at diagnosis and Allo-BMT was assessed using survival analysis and univariate/multivariable Cox regression analysis (Cox 1972). The list of features included in this analysis was determined from a literature review that identified factors found to be associated with overall survival in CML-CP patients treated with conventional chemotherapy or Allo-BMT. The values/levels of each variable whether continuous or categorical were based on findings published by large cooperative group and multi-centered studies. 71 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. In addition, a subset of these factors were used to create and test the ‘prognostic reproducibility’ of three generally accepted prognostic scores for CML (Sokal, Hasford and Gratwohl) in this patient population. The list of features examined in the statistical analysis is contained in Table 6. Table 6: Summary of Prognostic Features Collected at Diagnosis and Transplantation Features at Diagnosis Prognostic Factors Analyzed Age (years)a ’ b Continuous and Median Split Spleen size (cm)a ,b Continuous and Median Split White blood cell count (109 /liter) Continuous Platelet count (109 /liter)a ,b Continuous and Median Split Eosinophils in blood (%)b Continuous and Median Split Basophils in blood (%)b Continuous and Median Split Blasts in blood (%)a ,b Continuous and Median Split Initial therapy type 0 Hydroxyurea 1 All Other Therapies Features at Transplant Prognostic Factors Analyzed Time from diagnosis to transplantc 0 <12 Months (months) 1 >12 Months Year of Transplant 0 <1985 1 1986-1990 2 1991-1995 3 1996-2000 4 2001-2002 Age patientc 0 <40 Years (years) 1 >40 Years Patient-Donor gender combinationc 0 Male-Female 1 All Other Combinations Donor typec (syngeneic-sibling vs. related-unrelated) Syngeneic/Sibling only Material type 0 Bone Marrow (bone marrow vs. peripheral blood stem cells) 1 Peripheral Blood Stem Cells Preparative regimen 0 Busulfan/Cytoxan 1 FTBId /VP-16e 2 FTBI/Cytoxan 3 All Other Preparative Regimens Graft vs. Host Disease (GvHD) prophylaxis 0 CSAf /MTX8 /PSEh 1 CSA/MTX 2 CSA/PSE 3 Other 72 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Table 6: Continued Features at Transplant Prognostic Factors Analyzed Acute GvHD Chronic GvHD Molecular data: Qualitative PCR' results Molecular data: Quantitative PCR results Cytogenetic data (clonal evolution from baseline) 0 Grade 0-1 1 Grade 2 2 Grade 3 3 Grade 4 0 No Evidence 1 Limited 2 Extensive 0 Negative 1 Positive Continuous (# of copies of BCR-ABL oncogene/pg RNA) 0 No 1 Yes a Parameter used in Sokal Score b Parameter used in Hasford Score c Parameter used in Gratwohl Score d Fractionated total body irradiation e Etoposide fCyclosporine 8 Methotrexate h Prendisone 1 Polymerase Chain Reaction For each categorical variable, the proportional-hazards assumption was checked using two methods, 1) the log-log cumulative hazards plots check for parallelism and 2) the method of adding a time-dependent covariate for each covariate. The log-log survival curve is simply a transformation of an estimated survival curve that results from taking the natural log of an estimated survival probability twice. The parallelism of log-log survival plots for the Cox proportional hazards model provides a graphical approach for assessing the proportional hazards assumption. When time-dependent variables were used to assess the proportional hazards assumption for a time-independent variable, the Cox model was extended to contain product terms involving the time-independent variable being assessed and some function of time. For each endpoint a Cox regression model with a proportional-hazards analysis was applied using the factors listed above. (Cytogenetic relapse and death [overall and disease-free] post Allo-BMT are 73 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. the primary endpoints for the regression analysis.) The hazard rate ratio was calculated for each significant variable, along with the 95% confidence limits. To develop a multivariable model, stepwise Cox regression analysis was performed to determine the independent predictors of survival and cytogenetic relapse collected at diagnosis and Allo-BMT. All variables with a p- value < 0.10 by univariate analysis were included as candidates in this analysis. All calculations were done using the SAS® software version 8.2. Results Features at Diagnosis. The pre-transplant (at diagnosis) patient characteristics are summarized in Table 4. The disease features (e.g., white blood cell count, platelet count, % eosinophils/ basophils/ blasts) recorded at presentation meet the COH clinical diagnostic criterion (Table 2) and are compatible with those data reported by large CML cooperative group/multi-centered studies. Information regarding white blood cell count, platelet count, % eosinophils/basophils/blasts and initial therapy were available for almost all (86-99%) patients in this study; spleen size was known in only half of the cases. Overall the demographic characteristics seen in this patient population are fairly consistent with the Surveillance, Epidemiology and End Results Program’s (SEER) reported demographic statistics (e.g., age at diagnosis, gender, and race-ethnicity) (Ries et al. 2001). The following table (Table 7) provides a qualitative comparison between the demographic characteristics for the patient population and national statistics reported by SEER. The purpose of this exercise was to examine how representative the study population is relative to CML national statistics. 74 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Table 7: Comparison of Patient Characteristics Reported at Diagnosis City of Hope Chronic Myeloid Leukemia-Chronic Phase (CML-CP) Allogeneic Blood or Marrow Transplant (Allo- BMT) Patient Population Chronic Myeloid Leukemia (CML) National Statistics Reported by SEER* (1997-2001) Gender 56% Male Age adjusted incidence rate for men is 1.7 times higher than women Median Age at Diagnosis (years) 34.7(6.5-71.1) 66.0 (range not reported) Race-Ethnicity 49% White Age adjusted incidence rate for whites is 1.1 times higher than all other races * Source: Ries LAG, Eisner MP, Kossary CL, Hankey BF, Miller BA, Clegg L, Edwards BK eds. 1998/2001. Surveillance, Epidemiology, and End Results (SEER) Cancer Statistics Review, 1973-1998. National Cancer Institute. National Cancer Institute, Bethesda, MD. httD://seer.cancer.gov/Publications/CSR1973 1998. As expected, based on SEER data, a slight male predominance (56%) can be seen in the COH patient population. The number of cases rises slowly with age until the early-forties when it starts to rise more rapidly; very few cases (n=9) were diagnosed < 18.0 years of age. While this increasing trend with age is consistent with what has been reported by other groups, the median age at diagnosis for the COH case-series is 34.7 years, which is 15 to (approximately) 22 years below the national median of 66 years. This difference in median age is likely due to a selection process. Because elevated relapse and death events are seen among patients who undergo Allo- BMT over the age of 40, for safety purposes (in light of this known poor risk feature), the majority of the patients selected for transplantation are between the ages of 25 and 45. This younger patient population is purposely selected for Allo-BMT because they have been shown to tolerate the transplant procedure well with good long-term disease free survival. As for the race-ethnicity comparison, national statistics report a slight non-Hispanic white predominance; this finding is not seen in our data. The reason for this difference is again, likely 75 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. due to the transplant selection criteria. Historically, COH data suggest that the probability of identifying a suitably matched sibling donor is higher among certain minority groups, particularly the Hispanic population. Given that there is an increased number of Hispanics in our service area with HLA-matured sibling donors, the race-ethnicity distribution for our patient population is skewed slightly away from the non-Hispanic white predominance seen in the general population. Features at Transplant. The transplant characteristics for this patient population are summarized in Table 5. The average time from diagnosis to transplant for this patient population is one year (+/- 1.1 years), and the majority of patients (62%) were 40 years of age or younger when undergoing this procedure. Because an early engraftment benefit has only recently been associated with receiving peripheral blood stem cells (PBSC) (as the material source for the transplant procedure), a limited number of patients have received PBSC to date (n=28 [12%]). Since the first Allo-BMT was conducted for CML-CP in June of 1982, the proportion of transplant cases had been steadily increasing until the introduction of Gleevec in 2001 -2002 when a dramatic drop in the number of patients undergoing Allo- BMT is seen (Table 5). Preparative Regimen. A review of the past 20 years reveals noticeable changes in the preparative regimen therapies used to condition patients for transplant (conditioning patients for the infusion of healthy bone marrow or peripheral blood stem cells). The modifications seen over the years were in response to information acquired from maturing Allo-BMT data. These data were collected to assess the short- and long-term impact of the preparative regimen on 1) co-morbid conditions present at the time of conditioning, 2) an aging patient 76 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. population, and 3) the risk associated with the development of secondary malignancies (result of high doses of radiation). The early CML-CP patients were conditioned with fractionated total-body irradiation (FTBI) and Cyclophosphamide (CY). This treatment approach was based on positive findings seen in the acute leukemia setting at City of Hope and other large transplant centers. This approach was considered ‘standard of care’ until the mid-1980’s when a novel preparative regimen was developed by the clinicians at COH for the treatment of hematologic malignancies; the regimen consisted of FTBI followed by high-dose etoposide (VP-16) at 60mg/kg of actual body weight. This regimen was first used to treat patients with advanced stages of leukemia (i.e., acute leukemia beyond first complete remission and CML beyond first CP) (Blume et al. 1987; Schmitz et al. 1988; Blume et al. 1993). Because of the encouraging results seen among patients with more advanced forms of leukemia, in the mid-1980’s FTBI/VP-16 was applied to CML-CP and acute leukemia in first complete remission. Even though no studies were designed to compare the efficacy of the FTBI/VP-16 regimen to the more traditional regimen of FTBI/CY, the results reported by Blume et al. (1987, 1993) and Schmitz et al. (1988) showed improvements in survival and relapse rates among FTBI/VP-16 patients relative to FTBI/CY patients. Shortly thereafter, in *1987, FTBI/VP-16 was adopted as the new standard of care at COH for CML- CP Allo-BMT patients. It wasn’t until the late 1990’s that the next significant shift was seen. Since its introduction in the early 1980’s a preparative regimen consisting of Busulfan (BU) and CY (no radiation) was limited to 1) older patients (>40 years), 2) patients with 77 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. potentially life threatening co-morbid conditions/diseases, and/or 3) heavily pretreated patients (especially with radiation). By the late 1990’s, experience and outcome data were mounting in favor of patients conditioned with BU/CY (relative to those patients conditioned with FTBI based regimens) as a result, since mid-1998 >98% of CML-CP patients have been prepared with BU/CY. Graft Versus Host Disease (GvHD) Prophylaxis. All patients who were transplanted between December 1986 and December 1991 were included on a randomized, prospective study of GVHD prophylaxis that compared a two-drug regimen of cyclosporine (CSA) and methylprednisolone (PSE) to a three-drug regimen consisting of the same schedule of CSA and PSE, with three doses of methotrexate (MTX). The details and results of this randomized study have been published (Chao et al. 1993). Patients transplanted before December 1986 routinely received the two-drug regimen, whereas patients transplanted after December 1991 received the three-drug regimen. Thus, among the 234 patients in this case- series, the majority of patients received either the two-drug regimen (n=50 [21%]) or the three-drug regimen (n=91 [39%]) (Table 5). Summary o f Complications and Clinical Outcomes Following Allo-BMT (Specific Aim #1). A summary of the complications and outcomes experienced by this case-series following Allo-BMT are presented in Table 8. Engraftment data were available for all 234 patients. Of the 234 patients, 232 engrafted successfully with recovery of > 500 neutrophils/pL at a median of 19 days (range, 10-90). The majority of patients (n=172 [74%]) experienced some 78 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. form of mild Acute GvHD (< grade 1). All 15 patients that experienced the most severe form of Acute GvHD (grade 4) eventually died as a result of this complication. For the 212 patients surviving beyond 100 days post transplant, 57 (27%) patients did not experience chronic GvHD, the remaining two-thirds did experience either limited or extensive chronic GvHD. At the time of this analysis 153 patients were alive; 10 of these were alive with relapsed disease. The majority of expired patients (n=69 (85%)) died as a result of transplant-related complications (Table 8); the leading causes of death among these 69 patients were sepsis, pneumonia and chronic graft-versus-host disease (Table 9). The cumulative probabilities of overall survival (OS) and disease-free survival (DFS) for the 234 patients at 5 years were 68% (95% Cl, 62% to 74%) and 62% (95% Cl, 55% to 69%) respectively (Figures 5 and 6). The risk of cytogenetic relapse at 5 years was 12% (95% Cl, 8% to 18%) (Figure 7). An estimate of the hematologic relapse rate for this patient population was not possible given that all patients were treated following evidence of disease recurrence by classic cytogenetics and prior to hematological evidence of disease. For most of the 23 relapsed patients, their immunosuppressive therapy was reduced or stopped completely in an effort to induce a graft-versus-leukemia effect. 79 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Table 8: Allogeneic Blood or Marrow Transplantation (Allo-BMT) for Treatment of Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) Patients transplanted from 6/1982 to 12/2002 (N=234) Summary of Complications ant Outcomes post Transplant Variable Mean ± SD or n (% ) Median (Range) N (% ) with missing data Time to Engraftment (Days) Absolute Neutrophil Count >500 xl03 /pL Untransfused Platelet Count >25 x l03 /p.L 20.3 ±8.4 23.1 ± 14.9 19(10-90) 21 (3-146) 2 (<l)a 8 ( 3)b Acute GVHDC (Clinical Grade) 0-1 2 3 4 172 (74) 33 (14) 14 ( 6) 15 ( 6) 0 Chronic GVHD (Maximum Grade) Yes, Limited Yes, Extensive No Twin Unknown 72 (34) 77 (36) 57 (27) 5(2) 1 (<1) 22 (9)d # of Cytogenetic Relapse Events (post Allo-BMT) Yes No 23(10) 211 (90) 0 # of Death Events (post Allo-BMT) Alive Dead # of patients lost to follow-up 153 (65) 81 (35) 17 ( 7) 0 Cause of Death (Transplant Related) Yes No Unknown 69 (85) 10(12) 2 ( 3) 0 a Two patients expired prior to reaching milestone b Eight patients expired prior to reaching milestone c Graft vs Host Disease d Twenty-two patients died too early to assess chronic GvHD 80 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Table 9: Allogeneic Blood or Marrow Transplantation (Allo-BMT) for Treatment of Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) Patients transplanted from 6/1982 to 12/2002 (N=234) Summary of Death Information and Survival/Relapse Probabilities Variable Number of Events N (%) with missing data Primary Cause of Death 0 Graft failure 2 Sepsis 20 Bacterial sepsis 2 Fungal Infection 3 ARDSa and multiorgan failure 12 Brain abscess 3 Pneumonia 13 CMVb -IPc 12 Idiopathic-IP 1 CMV and PCPd 0 VODe and multiorgan failure 0 Acute Graft vs. Host Disease (GVHD) 11 Chronic GVHD 21 Suicide/Car Accident 2 Relapsed Leukemia 10 Secondary Malignancy 2 Unknown 2 Survival Probability Survival/Relapse 95% C f for Survival/ Estimate Replapse Estimate 1-Year 81% 75% to 85% 5-Year 68% 62% to 74% 10-Year 60% 52% to 68% Relapse Rate 1-Year 5% 3% to 10% 5-Year 12% 8% to 18% 10-Year Disease-Free Survival Probability 1-Year 77% 71% to 82% 5-Year 62% 55% to 69% 10-Year 57% 50% to 64% a Acute Respiratory Distress Syndrome b Cytomegolovirus 0 Interstital Pneumonitis d Pneumosistis Camii Pneumonia ' Veno-occlusive Disease f Confidence Interval 8 Unable to estimate, last event at 9 years. 81 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission. Figure 5: Allogeneic Blood or Marrow Transplantation (Allo-BMT) for Treatment of Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) Patients transplanted from 6/1982 to 12/2002 (N=234) Cumulative Probability of Overall Survival o 0 0 o < o C L < 0 > '£ w < D > 8 9 10 2 3 4 5 6 7 0 1 Time Post-BMT (Years) Tick Marks ( | ) R ep resen t C ensoring O O Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission. Figure 6: Allogeneic Blood or Marrow Transplantation (Allo-BMT) for Treatment of Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) Patients transplanted from 6/1982 to 12/2002 (N=234) Cumulative Probability of Disease-Free Survival O 00 O C L CD O ■ s f o c 0 ) > L U <D > J 2 3 E 3 o CM d o o 5 6 7 8 9 10 0 1 2 3 4 Time Post-BMT (Years) Tick Marks ( | ) R ep resen t C ensoring oo u > Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission. Figure 7: Allogeneic Blood or Marrow Transplantation (Allo-BMT) for Treatment of Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) Patients transplanted from 6/1982 to 12/2002 (N=234) Cumulative Probability of Cytogenetic Relapse O CO O CO O o CM d — g U t r t l t l r o o 5 6 10 0 1 2 3 4 7 8 9 Relapse Time (Years) Tick Marks ( | ) R ep resen t C ensoring 00 Limited Cytogenetic and Molecular Data Following Allo-BMT (Specific Aim #2). Samples of blood and/or bone marrow were collected before Allo-BMT from all patients to confirm the CML diagnosis and ‘chronic’ disease phase. In addition, following Allo-BMT, patients were to have samples collected for routine microscopic examination, karyotypic evaluation and molecular analysis at pre-defined intervals (Day +30, +100, +180, +365, and yearly thereafter). (This testing schedule is considered standard of care at COH.) The assumption was that these data could then be used to assess the impact of molecular and cytogenetic features on survival following Allo-BMT (Specific Aim #2). Surprisingly this sampling/testing schedule was rarely followed, resulting in few patients with complete data (-40% compliance). This discovery was further complicated by operational and database issues related to the introduction/viability of these techniques and accessibility of these data. For example, before 1989 cytogenetic analyses were performed less successfully and thus, it was not uncommon to have less than 20 (the minimum) metaphases to analyze, making the results of these tests inconclusive. (After 1989, cells were co-cultured with one or more myeloid growth factor supplemented media to increase the yield of metaphases.) Due to very limited data, the PI of this study was unable to explore the original study objective aimed at assessing the predictive value of molecular and cytogenetic features on survival (Specific Aim #2). Predictive Value o f Weighted Risk Scores (Specific Aim #3): Sokal, Hasford and Gratwohl. The Sokal and Hasford scoring systems use data recorded at diagnosis to calculate weighted risk scores for patients diagnosed with CML. Because a fair amount of the data recorded at diagnosis were missing (e.g., %eosinophils [14% missing], %basophils [14% missing], 85 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. “ /oblasts [12% missing], platelet count [6% missing] and spleen size [52% missing]), in addition to analyzing only those patients with complete data, two statistical methods (an imputation procedure and a prediction model), were applied to estimate values for each patient missing these data. The modeling approach applied to missing data included an examination of the predictive value of these parameters (%eosinophils/ basophils/ blasts, platelet count and spleen size) on the primary endpoints (survival and cytogenetic relapse) for the observed data (on patient’s with complete data), imputed data and predicted data. Table 10 summarizes the results of these analyses. Table 10: Results of Modeling Approaches for Missing Data Complete Sample Across All 3 Scores (A) All Available Observed Data (B) Imputation Method for Missing Data (C) Linear Regression Method for Missing D ata* (D) Sokal (Survival) N=95 N=99 N=231 N=206 Low Risk (RRb : <0.8) Intermediate Risk (RR: 0.8-1.2) High Risk (RR: >1.2) Median (Range) 25 (26%) 43 (45%) 27 (29%) 1.0 (0.48-4.84) 26 (26%) 44 (45%) 29 (29%) 1.0 (0.48-4.84) 81 (35%) 97 (42%) 53 (23%) 0.9 (0.48-4.84) 76 (37%) 87 (42%) 43 (21%) 0.9 (0.48-4.84) Hasford (Survival) N=95 N=95 N=231 N=199 Low Risk (< 780) Intermediate Risk (781-1480) High Risk (>1480) Median (Range) 51 (54%) 35 (37%) 9 (9%) 722.2 (126-2494) 51 (54%) 35 (37%) 9 (9%) 722.2(126-2494) 134 (58%) 79 (34%) 18(8%) 691.4(126-2496.7) 128 (64%) 57 (29%) 14 (7%) 630.1 (126-2494) R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Table 10: Continued Complete Sample Across All 3 Scores (A) All Available Observed Data (B) Imputation Method for Missing Data (Q Linear Regression Method for Missing Data* (D) Gratwohl (Survival) N=95 N=234 Not Applicable Not Applicable 0 1 2 3 4 Median (Range) 4 ( 4%) 29 (31%) 45 (47%) 17(18%) 0 ( 0%) 2( 0-3) . 6 ( 3%) 73 (31%) 116(50%) 36(15%) 3 ( 1%) 2 ( 0-4) a The regression line produced from the observed data is as follows: spleen size = 4.4 + (White Blood Cell * 0.02) b Relative Risk The median Sokal score for the observed data (n=99 [42%]) was 1.0 (range, 0.5-4.8), and the proportion of patients classified as low, intermediate and high risk (for death following diagnosis) were 26%, 45% and 29% respectively (see Table 10, Sokal: Column B). The distribution of patients across the three Sokal risk categories was consistent with those data that included imputed spleen size values (see Table 10, Sokal: Column C) or predicted spleen size values (see Table 10, Sokal: Column D). Using the observed data, no significant difference in survival across the three Sokal-defined risk categories was seen in this case- series (Log Rank p-value =0.46) (Figure 8). As an alternative approach, median cut points were applied to each variable in the model (age at diagnosis, spleen size, platelet count and blast percentage) to examine the prognostic significance of these categorical variables. The result of this analysis was also non-significant. 87 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission. Figure 8: Allogeneic Blood or Marrow Transplantation (Allo-BMT) for Treatment of Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) Patients transplanted from 6/1982 to 12/2002 Overall Survival by Sokal Risk Category Patients with Classifiable Sokal Data (N=99) O Low Risk: Relative Risk (RR) < 0.8 High Risk: (RR)>1.2 (Nf 29) CO o •-H- -M- Intermediate Risk: RR 0.8- (N=44) to o c i o o o ' 5 6 7 8 9 10 1 2 3 4 0 Time Post-BMT (Years) Tick Marks ( | ) Represent Censoring Log Rank Test p-value = 0.46 O O OO The median Hasford score for the observed data (n=95 [41%]) was 722 (range, 126-2494) and the proportion of patients classified as low, intermediate and high risk (for death following diagnosis) were 54%, 37% and 9% respectively (see Table 10, Hasford: Column B). The distribution of patients across the three Hasford risk categories was fairly consistent with those data that included imputed spleen size values (see Table 10, Hasford: Column C) or predicted spleen size values (see Table 10, Hasford: Column D). Using the observed data, no significant difference in survival across the three Hasford-defined risk categories was seen in this case-series (Log Rank p-value =0.91)(Figure 9). Median cut points were applied to each of the six variables in the model to examine the prognostic significance of these categorical variables. The result of this analysis was also non-significant. The median Gratwohl score for the observed data (n=234 [100%]) was 2 (range, 0-4). Based on the Gratwohl risk classification schema, patients with an increasing number of risk factors are at increased risk for death post Allo-BMT. Following the method used by Gratwohl et al. (1998), the risk categories used to compare survival were levels 0-4 (or five categories). A significant difference in survival across the five Gratwohl-defined risk categories was seen in the case-series (Log Rank p-value =0.03)(Figure 10). As expected, the overall survival probabilities decrease with the addition of poor risk features (the only exception is level 4). [Please note: the 5-year survival probability for levels 0, 1,2, and 3 are 83%, 80%, 63%, and 57% respectively. The 5-year survival probability (of 100%) for the highest risk group, level 4, is based on only 3 patients.] 89 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission. Figure 9: Allogeneic Blood or Marrow Transplantation (Allo-BMT) for Treatment of Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) Patients transplanted from 6/1982 to 12/2002 Overall Survival by Hasford Risk Category Patients with Classifiable Hasford Data (N=95) Low Risk: <780 (N=51) O CO o CL 7 6 > £ 3 C O 0 ) > JO 3 E 3 o Intermediate Risk: =781-1480 (N=35) High Risk: >1480 (N=9) 7 8 2 3 4 5 6 9 10 0 1 Time Post-BMT (Years) Tick Marks ( | ) Represent Censoring Log Rank Test p-value = 0.91 V O O Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission. Figure 10: Allogeneic Blood or Marrow Transplantation (Allo-BMT) for Treatment of Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) Patients transplanted from 6/1982 to 12/2002 Overall Survival by Gratwohl Risk Levels (N=234) I V , Gratwohl Level 4 (high risk) A (N=3) I n 1 1 > -H 1- Gratwohl Level 0 (no risk factors present) (N=6) j 00 o co o • * * o CM d X I C D J O o £ 3 CO C D ,> T O 3 E 3 o 1 — | ---1 - ........ " " I n n r~i Gratwohl Level 3 (medium/high risk) (N=36) : - H - -I- -I I--H -----------h - H— I - ................. H—H------ 1 ----- -• m m i i " I V-.+, Gratwohl Level 2 (low/medium risk) (N=116) — H-H--- H h - -# — i ------- r Gratwohl Level 1 (low risk) (N=73) O o 10 Tick Marks ( | ) R ep resen t C ensoring Time Post-BMT (Years) Log Rank T est p -value = 0.0 3 When the patient sample was held constant for all three scoring systems (Table 10, Column A), the distribution seen for the complete sample (across all three scores) was consistent with the observed data (see Table 10, Sokal, Hasford and Gratwohl: Column A and B). (Please note: The complete patient sample in Column A was defined to include only those patients with complete data across all three scores.) When assessing/comparing the predictive value/outcome (using) of the observed, imputed and predicted data individually for the three scoring systems, the results were non-significant across all three methods. As expected the direction and significance of the effect remained non-significant with improved/narrowed confidence limits around the point estimate as a result of incorporating additional data. Because the strength of the predicted and imputed data was not significantly different from the predictive value of the observed data, the observed data was used for all univariate and multivariable modeling exercises. Testing of Proportional Hazards Assumption The validity of the proportional hazards (PH) assumption was evaluated using two methods, 1) the log-log cumulative hazards plots check for parallelism and 2) the method of adding a time-dependent covariate for each covariate. The parallelism of the log-log survival plots for the Cox proportional hazards model provides a graphical approach for assessing the proportional hazards assumption. The proportional hazards assumption tests for hazard equivalency between two or more groups. This assumption is the basis for the Cox PH Model, where the “model” assumes that the hazard ratio comparing any two specifications of predictors is constant over time. If a proportional hazards model is appropriate for a given set of predictors, we could expect that plots of the log-log survival curves for different individuals will be approximately parallel. Using the time-dependent method, the 92 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. proportional hazards assumption was examined by testing for the significance of the product term. The test was carried out using the likelihood ratio statistic. All categorical variables that were used in the univariate (and multivariable) modeling process were tested using both methods, the results of these analyses are listed in Table 11. Table 11: Testing of Proportional Hazards Assumption Features at Diagnosis Prognostic Factors Analyzed Log-Log Survival Curves Check for Parallelism * Time Dependent Method* Outcome b — > OS DFS R OS DFS R Initial therapy type 0 Hydroxyurea 1 All Other Therapies ND ND ND ND ND ND Sokal Prognostic Risk Category 0 Low Risk (RRC : <0.8) 1 Intermediate Risk (RR: 0.8-1.2) 2 High Risk (RR: >1.2) D D D D D D Hasford Prognostic Risk Category 0 Low Risk (< 780) 1 Intermediate Risk (781-1480) 2 High Risk (>1480) D D D D D D Gratwohl Prognostic Risk Score/Level 0 Level 1 1 Level 2 2 Level 3 3 Level 4 4 Level 5 ND ND ND ND ND ND Features at Transplant Prognostic Factors Analyzed Log-Log Survival Curves Check for Parallelism1 Time Dependent M ethod* Outcomeb -> OS DFS R OS DFS R Time from diagnosis to transplant (months) 0 <12 Months 1 >12 Months ND ND ND ND ND ND Year of Transplant 0 <1985 1 1986-1990 2 1991-1995 3 1996-2000 4 2001-2002 ND ND D ND ND D Age patient (years) 0 <40 Years 1 >40 Years ND ND ND ND ND ND Patient-Donor gender combination 0 Male-Female 1 All Other Combinations ND ND ND ND ND ND 93 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Table 11: Continued Features at Transplant Prognostic Factors Analyzed Log-Log Survival Curves Check for Parallelism * Time Dependent M ethod" Outcome/Endpointb -» OS DFS R OS DFS R Material type (bone marrow vs. peripheral blood stem cells) 0 Bone Marrow 1 Peripheral Blood Stem Cells ND ND ND ND ND ND D D D D D D D D D D D D ND ND ND ND ND ND ND ND ND ND ND ND Preparative regimen 0 Busulfan/Cytoxan 1 FTBId /VP-16e 2 FTBI/Cytoxan 3 All Other Preparative Regimens Graft vs. Host Disease (GvHD) prophylaxis 0 CSAf /MTX8 /PSEh 1 CSA/MTX 2 CSA/PSE 3 Other Acute GvHD 0 Grade 0-1 1 Grade 2 2 Grade 3 3 Grade 4 Chronic GvHD 0 No Evidence 1 Limited 2 Extensive a D = Departure from underlying proportional hazards assumption; ND = No departure from underlying proportional hazards assumption b OS = Overall Survival, DFS = Disease-Free Survival and R = Cytogenetic Relapse c Relative Risk d Fractionated Total Body Irradiation e Etoposide f Cyclosporine 8 Prendisone h Methotrexate The results of these analyses showed no departure from the underlying proportional hazards assumption for eight of the thirteen features tested. There were, however, five features that showed a departure from the proportional hazards assumption; these features were the Sokal and Hasford prognostic risk categories, year of transplant, preparative regimen and GvHD prophylaxis. Based on these results, a closer examination of the number of patients and events for each level, within each of these features, was conducted. Transplant year was the only feature shown to violate the proportional hazards assumption for just one of the three 94 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. outcomes studied. Given that a limited number of patients (n=23) experienced a cytogenetic relapse event following transplant and that the concentration of these events was within the first 1.5 years following Allo-BMT, considerable overlap and variability was seen across the survival curves for the five-levels of transplant year. Although unsuccessful, attempts were made to correct for this departure by combining categories -levels of transplant year. Ultimately the collapsing of the <1985 and 1986-1990 categories and the merging of the 1996-2000 with the 2001-2002 category had no impact on correcting for the departure seen in the data. Because there were very few patients (n=6) in the ‘other’ preparative regimen treatment category these six patients were combined with the FTBI/Cytoxan treatment category and the proportional hazards assumption was re-tested. Similarly because there were very few patients (n=18) in the ‘other’ GvHD prophylaxis treatment category these eighteen patients were combined with the CSA/PSE treatment category and the proportional hazards assumption was re-tested. The results of the reclassified treatment categories (preparative regimen and GvHD prophylaxis) showed no departure from the underlying proportional hazards assumption. As for the other two features (the Hasford and Sokal prognostic risk categories) a closer examination of the number of patients and events within each level of these categories was also conducted. Hasford Score: The result of this examination showed that the Hasford risk score suffers from the same sample size issue seen among the treatment features, with the highest Hasford risk category comprised of nine patients. A second test of the proportional hazards assumption was conducted for the Hasford score using two levels: a low-risk group 95 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. and a re-classified ‘intermediate’ risk group that included the nine patients previously classified as high risk. Unfortunately, the reclassification of the Hasford score did not resolve the departure from the underlying proportional hazards assumption seen prior to the reclassification. (More details on how this deviation was handled can be found in the ‘Univariate Cox Regression Analysis’ section of this chapter.) Sokal Score: Unlike the other three features, a closer examination of the Sokal risk score did not reveal the same ‘disproportionate’ sample sizes across categories, in light of this, a reclassification or collapsing of Sokal risk categories did not seem beneficial. Unlike the Hasford risk score, a fairly normal Sokal score-distribution was seen in this case-series. (More details on how this deviation was handled can be found in the ‘Univariate Cox Regression Analysis’ section of this chapter.) The appropriateness of the proportional hazards regression method and the validity of the results depend on the correctness of the proportional hazards assumption. When this assumption is not upheld, data transformations can be used to correct for this departure. An adjustment of the underlying distribution allows for a more appropriate application of the regression method. For variables that violate the proportional hazards assumption the underlying distribution of the failure times for each group must be studied. The ‘distributional’ differences seen in the data can then be corrected using for example, lognormal or exponential transformations to obtain a normal distribution of failure times across the strata. The transformed data then (now following a uniform distribution) could be appropriately assessed using the Cox regression method. 96 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Predictive Value o f Disease and Clinical Features at Diagnosis/Transplant on OS, DFS and Cytogenetic Relapse (Specific Aim #4): Univariate Cox Regression analysis. Following the proportional hazards assessment, a univariate Cox regression analysis was conducted to evaluate the impact of ‘at diagnosis’ and ‘at transplant’ features on overall survival (OS), disease-free survival (DFS), and cytogenetic relapse. (As part of the background for the statistical analysis, a review of the medical literature [from «1980 to 2003] was completed to identify those factors that should be included in the analysis.) The values/levels of each categorical variable were based on findings published by large cooperative group/multi centered studies. Every attempt was made to maintain the ‘integrity’ of these categories given that a major objective of this analysis was to ‘validate’ these factors in this case-series. Contrary to previously reported studies, features recorded about the patient at diagnosis did not have a significant impact on the outcomes (OS, DFS, and cytogenetic relapse) studied in this patient population. Although the direction of the hazard ratio point estimates for the ‘at diagnosis’ features (white blood cell/platelet count, % eosinophils/basophils/blasts in blood, spleen size, and initial therapy type) were consistent with previously reported data, all were found to be non-significant by univariate analysis p>0.05 (Table 12). In an attempt to further explore the predictive value of spleen size at diagnosis, a qualitative assessment of spleen enlargement (classified as: no enlargement, small, medium, large and unknown) was conducted. The result of this assessment was consistent with the assessment of the continuous form of this variable, neither was found to be predictive of the outcomes under investigation. 97 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission. Table 12: Results of Univariate Cox Regression Analysis for Three Endpoints: ______ Overall Survival, Disease-Free Survival, and Relapse______ O verall Survival D isease-Free Survival Relapse Variable Values N # o f Hazard Rate P # o f Hazard Rate P # o f Hazard Rate Ratio P deaths Ratio (95% Cl*) Value deaths/ relapse events Ratio (95% Cl) Value relapse events (95% Cl) Value Features at Diagnosis Spleen Size Continuous 113 40 1.0(0.97, 1.08) 0.45 44 1.0 (0.95, 1.06) 0.98 8 0.83 (0.67, 1.0) 0.08 (observed) White Continuous 231 80 1.0 (0.99, 1.00) 0.40 89 0.99 (0.97, 1.00) 0.24 22 0.996(0.991, 1.000) 0.07 Blood Cell Count Initial Hydroxyurea 183 57 Baseline 66 Baseline 16 Baseline Therapy Type Other 51 24 1.5 (0.96,2.49) 0.08 25 1.4 (0.90, 2.26) 0.13 7 1.73 (0.71,4.21) 0.22 Features at Transplant Year o f < 1985 22 15 Baseline 15 Baseline Proportional Hazard Transplant 1986-1990 1991-1995 45 76 23 28 0.64(0.33, 1.23) 0.44 (0.23, 0.83) 0.18 0.01 24 36 0.67 (0.35, 1.28) 0.60(0.32, 1.10) 0.23 0.10 (PH) Departure PH Departure PH Departure 1996-2000 78 14 0.26 (0.12, 0.55) <0.01 15 0.25 (0.12, 0.52) <0.01 PH Departure Months 2001-2002 < 12 Months 13 165 1 50 0.14(0.02, 1.05) Baseline 0.06 1 59 0.12(0.02, 0.93) Baseline 0.04 17 PH Departure Baseline from Dx* to BMT* > 12 Months 69 31 1.6(1.01,2.49) 0.04 32 1.38 (0.90,2.12) 0.15 6 0.91 (0.36, 2.30) 0.84 Age at < 40 Years 144 46 Baseline 56 Baseline 15 Baseline BMT > 40 Years 90 35 1.5 (0.95, 2.33) 0.08 35 1.13 (0.74, 1.74) 0.57 8 0.95 (0.40, 2.25) 0.91 00 Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission. Table 12: Continued Overall Survival Disease-Free Survival Relapse Variable Values N # o f Hazard Rate P H of Hazard Rate P # o f Hazard Rate Ratio P deaths Ratio (95% Cl) Value deaths/ relapse events Ratio (95% Cl) Value relapse events (95% Cl) Value Preparative Busulfan / 70 12 Baseline 13 Baseline 3 Baseline Regimen Cytoxan FTBI/VP-16* 133 50 1.76 (0.93,3.34) 0.08 58 2.15(1.17,3.93) 0.01 17 2.81 (0.82, 9.65) 0.10 FTBI/Cytoxan 31 19 3.40(1.62, 7.13) <0.01 20 3.79(1.86, 7.71) <0.01 3 2.72 (0.54, 13.59) 0.22 + Other GvHD* CSA/MTX* / 96 33 Baseline 40 Baseline 11 Baseline Prophylaxis PSE* CSA/MTX 70 8 0.41 (0.19, 0.88) 0.02 11 0.43 (0.22, 0.84) 0.01 5 0.70 (0.24, 2.03) 0.51 CSA/PSE + 68 40 1.90(1.19, 3.02) 0.01 40 1.60(1.03, 2.49) 0.04 7 1.09 (0.42, 2.81) 0.87 Other Acute Grade 0-1 172 45 Baseline 55 Baseline 21 Baseline GvHD Grade Grade 2 33 14 1.98(1.08,3.60) 0.03 14 1.54 (0.85, 2.77) 0.15 1 0.30 (0.04, 2.24) 0.24 Grade 3 14 7 2.69(1.21,5.97) 0.02 7 2.14(0.97,4.71) 0.06 1 0.82(0.11,6.08) 0.84 Grade 4 15 15 27.76 (13.68, 56.33) <0.01 15 19.79 (10.16,38.55) <0.01 0 Unable to estimate * Chronic None 62 32 Baseline 37 Baseline 10 Baseline GvHD Grade Limited 72 14 0.36 (0.19, 0.68) <0.01 17 0.37(0.21,0.66) <0.01 7 0.57(0.22, 1.51) 0.57 Extensive 77 35 1.11 (0.69, 1.80) 0.66 37 0.96 (0.61, 1.51) 0.86 6 0.59(0.21, 1.61) 0.59 Gratwohl Level 0 6 1 Baseline 1 Baseline 0 Baseline Risk Score Level 1 73 17 1.47 (0.19, 11.16) 0.71 24 2.17(0.29, 16.16) 0.45 9 Unable to Estimate * Level 2 116 47 2.94(0.40,21.56) 0.29 49 3.03 (0.42, 22.12) 0.27 11 Unable to Estimate * Level 3 36 16 3.66 (0.48, 27.92) 0.21 17 3.87(0.51,29.39) 0.19 3 Unable to Estimate * Level 4 3 0 Unable to Estimate * 0 Unable to Estimate * 0 Unable to Estimate * * Notes: CI=Confidence Interval; Dx=Diagnosis; BMT=Blood or Marrow Transplant; FTBI=Fractionated Total Body Irradiation; VP-16 Etoposide; GvFID=Graft- versus-Host Disease; CSA=Cyclosporine; MTX=Methotrexate; PSE=Prendisone Because the Sokal and Hasford scores are summary risk measures constructed from features recorded at diagnosis, it was not surprising to find that these ‘risk scores’ did not significantly predict OS (Log Rank p=0.46 and 0.91 respectively). (The Log Rank p-values for the imputed/predicted Sokal and Hasford scores also showed no difference in OS.) Because the Sokal and Hasford risk scores did not satisfy the proportional hazards assumption, a stratified Cox regression procedure was considered for both scoring systems. However, due to small numbers in each group (Sokal N=99, Hasford N=95), and even smaller numbers within each strata, this was not feasible. As a result of this finding we were unable to explore the predictive value of the Sokal and Hasford risk measures on OS beyond the log rank test statistic. Following the assessment of ‘at diagnosis’ features, an assessment of ‘at transplant’ features was conducted. Interestingly, none of the ‘at transplant’ features were found to significantly predict cytogenetic relapse. Given the limited number of patients (N=23) in this case-series that experienced a cytogenetic relapse event following Allo-BMT, the majority of the ‘at transplant’ features either 1) could not be estimated or 2) the direction of the hazard ratio point estimates were clinically not interpretable/meaningful (Table 12). The ‘at transplant’ features found to be significantly predictive of survival (by univariate analysis) did not differ much between the endpoints, OS and DFS. With the exception of months from diagnosis to Allo-BMT, the variables found to be of prognostic significance for both OS and DFS were: year of transplant, preparative regimen, grafit-versus-host disease (GvHD) prophylaxis, acute GvHD grade and chronic GvHD grade (p< 0.05 for at least one level of the covariate) (Table 12). These findings are consistent with the published data, in that it is generally accepted that, patients transplanted within the last decade with radiation based regimens more than 12 100 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. months following diagnosis, who receive a non-methotrexate (MTX) based GvHD prophylaxis regimen, and experience severe acute GvHD within the first 100 days following transplant (and therefore are unable to benefit from the graft versus leukemia reaction) tend to do more poorly. Even though age at transplant (< 40, >40 years of age) was not found to be significantly predictive of OS or DFS by univariate analysis, the literature suggests that age at transplant does influence survival and the type of preparative regimen/prophylaxis treatment used to prevent GvHD. To that end the possible effect of (or interaction between) age on each of these two treatments was examined. The result of the analyses for both comparisons showed no significant interaction effect, meaning the type of preparative regimen or GvHD prophylaxis selected is not modified by (or interacting with) the patient’s age at transplant in this case-series. Because the type and amount of conditioning used to prepare patients for transplant has varied over time along with supportive care strategies following transplant, a test for interaction between year of transplant and these factors was conducted. The result of these analyses showed that the effect of year of transplant was not modified/effected by the inclusion of conditioning regimen and/or GvHD prophylaxis in the model. Predictive Value o f Disease and Clinical Features at Diagnosis/Transplant on OS, DFS and Cytogenetic Relapse (Specific Aim #4): Multivariable Cox Regression analysis. To determine whether a Cox regression model could provide a useful representation of risk status, a multivariable model was constructed for each of the survival endpoints using the variables found to have a p-value <0.10 by univariate analysis (Table 12). Table 13 is a summary of those features that met the p<0.10 criteria for inclusion in the multivariable model: 101 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Table 13: Summary of Features Included in the Multivariable Model Feature/V ariable Multivariable Model for Outcome of: Initial Therapy Type Year of Transplant Months for Diagnosis to Allo-BMTa Age at BMT Preparative Regimen GvHDb Prophylaxis Acute GvHD Grade Chronic GvHD Grade Overall Survival Overall Survival and Disease-Free Survival Overall Survival Overall Survival Overall Survival and Disease-Free Survival Overall Survival and Disease-Free Survival Overall Survival and Disease-Free Survival Overall Survival and Disease-Free Survival a Allogeneic Blood or Marrow Transplantation b Graft vs. Host Disease Based on the results of the multivariable stepwise analysis, the variables found to be significantly associated with OS were acute GvHD, chronic GvHD, GvHD prophylaxis, months from diagnosis to Allo-BMT, and age at Allo-BMT. The significant variables for DFS were acute GvHD, chronic GvHD, and GvHD prophylaxis. Detailed results for the two survival endpoints are presented in Table 14. The covariates included in the final model and the direction of the effects seen for each variable are consistent with the literature and support the clinical observations reported by the ‘expert’ CML Allo-BMT transplant physicians. For both survival outcomes, the trends are generally the same. These data show that with increasing severity of acute GvHD (from grade 0-1 to 4) comes increasing ‘hazard’ or risk for death/relapse events. Patients experiencing grade 4 acute GvHD have 27 times the ‘hazard’ for death as those that do not experience (or experience a mild form of) acute GvHD (p<0.01). (The trend is the same for disease-free survival.) Patients who experience limited (or mild) chronic GvHD appear to be at a decreased hazard (HR =0.28) for death or going out of remission when compared to those patients that do not experience chronic GvHD (p<0.01). For patients that did not receive a methotrexate (MTX) based regimen, these data suggest that this group of patients is at almost two times the ‘hazard’ (HR = 1.83) for death when compared to those that did receive a MTX based regimen (p =0.03). 102 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Table 14: Final Model for Multivariable Cox Regression Analysis Variable P Value Hazard Ratio (95% CT) Overall Survival Acute GvHDb Grade 0-1 Baseline Grade 2 <0.01 2.57(1.32,4.97) Grade 3 <0.01 4.06(1.73,9.54) Grade 4(1) <0.01 27.38(12.72, 58.96) No Evidence of Chronic GvHD Baseline Limited Chronic GvHD (2) <0.01 0.28 (0.14, 0.55) Extensive Chronic GvHD 0.72 0.90 (0.50, 1.61) GvHD Prophylaxis: CSA7MTXd /PSEe Baseline GvHD Prophylaxis: CSA/MTX 0.06 0.41 (0.16, 1.04) GvHD Prophylaxis: CSA/PSE + Other (3) 0.03 1.83 (1.07,3.15) <12 months from Dxf to BMTh Baseline >12 months from Dx to BMT (4) <0.01 1.98(1.19,3.31) < 40 Years of age at BMT Baseline >40 years of age at BMT (5) <0.01 2.32 (1.38,3.88) Disease-Free Survival Acute GvHD Grade 0-1 Baseline Grade 2 0.05 1.86 (0.99,3.46) Grade 3 0.03 2.50(1.10,5.68) Grade 4(1) <0.01 17.97 (8.92, 36.21) No Evidence of Chronic GvHD Baseline Limited Chronic GvHD (2) <0.01 0.26 (0.14, 0.49) Extensive Chronic GvHD 0.20 0.71 (0.42, 1.20) GvHD Prophylaxis: CSA/MTX/PSE Baseline GvHD Prophylaxis: CSA/MTX <0.29 0.39 (0.20, 0.77) GvHD Prophylaxis: CSA/PSE + Other (3) 0.048 1.67(1.003,2.77) a Confidence Interval b Graft versus. Host Disease 0 Cyclosporine d Methotrexate e Prendisone f Diagnosis h Blood or Marrow Transplantation When patients are transplanted over the age of 40 (HR =2.32) or beyond one year following diagnosis (HR =1.98) these data suggest that patients falling into either category are at (roughly) two times the risk for death following Allo-BMT as those patients who undergo Allo-BMT less than one year following diagnosis or are under the age of 41 at transplant (p<0.01). 103 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Because the Gratwohl score was found to be significantly associated with overall survival (p =0.03) (Figure 10), even though the univariate Cox analysis did not carry this earlier finding forward, the investigators of this project were interested in examining whether or not the addition of the Gratwohl score would improve the ‘fit’ of final multivariable models. The likelihood ratio statistic that compared the final multivariable models (+/- Gratwohl score) for the OS and DFS endpoints revealed no significant improvement with the addition of the Gratwohl score as a covariate in the model. Discussion: CML-CP Prognosis in the Allo-BMT Setting The importance of predicting the likely long-term outcome of treatment for CML-CP is seen throughout the literature. While a number of prognostic models for non-transplant patients have been developed and are well documented (Sokal et al. 1984; Hasford et al. 1998), a useful scoring system/prognostic model has not been developed for CML-CP patients treated with Allo-BMT. To address the limitation seen in published medical literature, an analysis was conducted to examine factors that may serve as prognostic indicators of cytogenetic relapse and/or death in patients who have undergone Allo-BMT for treatment of CML-CP. A case-series of 234 CML-CP patients treated at COH with Allo-BMT from 1982-2002 was used for this analysis. An examination of the role of patient, disease and treatment factors collected both at the time of diagnosis and Allo-BMT was completed to assess the predictive value of these factors on a patient’s risk for disease recurrence and/or death following Allo- BMT. In addition, this study also explored the predictive value of three generally accepted prognostic scoring systems (Sokal, Hasford and Gratwohl) in this large single center Allo- BMT population. 104 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. The patients that made up this case-series were generally younger (median age: 34.7) (and in a more controlled phase of their disease) at presentation when compared to the national case- population/statistics reported by SEER (Ries et al. 2001). This tells us that the inherent Allo- BMT patient referral patterns/treatment recommendations that were in operation during the study period (1982-2002) were being followed and were having the desired effect of referring younger patients diagnosed early in their disease. Although rare, national and international data report that CML-CP is a disease that is more common among white men, the demographics collected on our patient population support this finding. The disease features (e.g., white blood cell count, platelet count, % eosinophils/ basophils/ blasts) recorded at presentation meet the COH clinical diagnostic criterion (Table 2) and are compatible with those data reported by large CML cooperative group/multi-centered studies. Overall, with the exception of age, the patient, disease and clinical features of this patient population are consistent with previously reported data/characterizations of patients with CML-CP. Of the demographic and clinical factors studied, the patient and treatment characteristics found to be predictive of survival (overall and disease-free) were factors present at the time of transplantation. Although the importance of ‘at diagnosis’ features have been reported in non-transplant patient populations, (Tura, Baccarani, and Corbelli 1981; Cervantes and Rozman 1982; Sokal et al. 1984; Sokal et al. 1985; Kantarjian, Smith, et al. 1985; Kantarjian et al. 1990; Italian Cooperative Group 1991; Thiele et al. 1991; Hehlmann et al 1992; Thiele et al. 1993; Italian Cooperative Group 1994; Cortes, 1997; Hasford et al- 1998) the significance of these features was not seen in this case-series. Because two of the three prognostic scoring systems (Sokal and Hasford) studied are based on features recorded at 105 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. presentation, their predictive value was not seen. Likewise, after additional transplant factors (e.g., GvHD -incidence and prophylaxis, months from diagnosis to transplant, and age at Allo-BMT) were included in the multivariable model, the Gratwohl score did not provide additional predictability. These data suggest that the prognostic scores examined in this study have little predictive value (on survival and relapse endpoints) when applied to this case-series of 234 transplant patients. To gain a better understanding of how our data compare to the published Sokal and Hasford data, a contrast of the risk index distributions for this case-series with the published data was made. The result of this comparison is outlined in Table 15. Table 15: Comparison of City of Hope (COH) Results Publised by Sokal and Hasford Risk Categories for Outcome of Survival COH Observed Data (1982-2002) N=99 Published Results (Sokal Score, 1984*) N=361 Low Risk (Relative Risk [RR]: <0.8) Intermediate Risk (RR: 0.8-1.2) High Risk (RR:>1.2) Median (Range) 26 (26%) 44 (45%) 29 (29%) 1.0 (0.48-4.84) 114(32%) 145 (40%) 102 (28%) Not Reported COH Observed Data (1982-2002) N=95 Published Results (Hasford Score, 1998b ) N=908 Low Risk (< 780) Intermediate Risk (781-1480) High Risk (>1480) Median (Range) 51 (54%) 35 (37%) 9 ( 9%) 722.2(126-2494) 369(41%) 406 (45%) 133 (14%) 913 (0-2697) Sources: a Sokal JE, Cox EB, Baccarani M, Tura S, Gomez GA, Robertson JE, Tso CY, Braun TJ, Clarkson BD, Cervnates F 1984. Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood 63(4): 789-99. b Hasford J, Pfirrmann M, Hehlmann R, Allan NC, Baccarani M, Kluin-Nelemans JC, Alimena G, Steegmann JL, and Ansari H. 1998. A new prognostic score for survival o f patients with chronic myeloid leukemia treated with interferon-alpha: Writing Committee for the Collaborative CML Prognostic Factors Project Group. Journal o f the National Cancer Institute 90(11):850-858. 106 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Even though there is a clear difference in the total number of patients included in each study, the distribution of patients (proportion of patients falling into each risk category) across the prognostic scores for the COH sample appears to be fairly consistent with those data published by Sokal et al. (1984) and Hasford et al. (1998). The most notable difference can be seen when comparing the proportion of high-risk patients under the Hasford score across the two studies. The PI of this project attributes this difference to the fact that the Hasford study included patients that were technically beyond CP. As a result, a larger proportion of patients are showing more high-risk features at presentation in the Hasford population. While this comparison shows that the proportion of patients in each category are fairly compatible, the underlying survival pattern seen across these studies is quite different, suggesting that the effect of transplantation overwhelms the prognostic importance of the presentation features. A closer examination of the Sokal and Hasford survival curves for the COH case-series shows considerable overlap (without clear risk discrimination) across the risk categories (Figure 8 and 9), making the prognostic utility of these scoring systems questionable. When patients (and their physicians) are confronted with the choice of Allo-BMT, these data suggest that the factors that have the greatest impact on long-term survival (and therefore should be considered carefully) are the patients’ age at transplant, the time from diagnosis to transplant, the transplanting physician’s ability to manage acute GvHD within the first 100 days following transplant, and the physician’s ability to optimize the graft-vs-leukemia reaction post Allo-BMT. This study has shown that disease and treatment related variables recorded at diagnosis have little impact on survival or cytogenetic relapse in CML-CP patients that underwent Allo-BMT from 1982 to 2002. Prior to the introduction of Gleevec 107 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. in 2002, the interpretation and practical implementation of these findings would have been less controversial. However, since the introduction of Gleevec, updates from the randomized Phase III trial conducted by the IRIS study group (International Randomized IFN vs. STI571) (presented in December 2003 with 31 months of follow-up) continue to support the remarkable clinical effectiveness and safety of Gleevec (Cervantes 2003). As a result, the treatment guidelines and process for evaluating prognosis are undergoing substantial change (Goldman and Druker 2001; Cervantes 2003). In particular, the indications for and timing of Allo-BMT are being re-evaluated in the post-Gleevec era. While no major toxic effects involving other cells have yet been reported, an acquired resistance to Gleevec has been discovered. Scientists now studying this issue have shown that the mechanisms of resistance are heterogeneous (Hochhaus et al. 2002) making it unlikely to find a common new inhibitor with broad utility to overcome resistance. In response to this scientists are now exploring the efficacy of Gleevec in combination with other agents (La Rosee, O ’Dwyer, and Druker 2002). This may become less of an issue if resistance to Gleevec manifests as a slow and orderly relapse into chronic phase. However, because many questions remain, there is a real concern that patients may relapse abruptly into an advanced stage of the disease, a stage in which Allo-BMT cannot be safely or effectively done. The other major concern has to do with delayed transplantation. Because this study and others (Gratwohl et al. 1998) suggest that delaying transplantation beyond one-year post diagnosis is associated with inferior outcome, the inevitable postponement associated with a lengthy Gleevec treatment period may compromise the efficacy of the only proven therapy 108 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. available for patients with CML. It seems therefore necessary to retain Allo-BMT as an important upfront therapy in younger patients with a suitable donor, for now. Advice to the contrary is based on limited experience/follow up with Gleevec and could be judged to be overly optimistic in years to come. In the next few years, an improved understanding of the effect of Gleevec on survival/response rates, and an updated assessment of reduced intensity Allo-BMT should allow for more definite recommendations. The data from our study will now serve as a ‘baseline or historical control’ for those patients that ultimately do not respond favorably to Gleevec or become resistant to Gleevec and eventually seek an Allo- BMT after prolonged Gleevec treatment in a more advanced phase of the disease. Future Studies As the Gleevec data continue to mature, validation of the significant transplant factors reported by our study (factors found to influence survival following Allo-BMT) will need to occur in parallel. To that end, the PI of this study and the COH CML disease committee chair are already exploring a possible collaboration with two other transplant centers (Stanford Medical Center and the Fred Hutchinson Cancer Center), centers with whom a clinical research partnership already exists. In addition to this ‘external’ validation study, the PI of this study has drafted a grant proposal (R03) that extends the COH CML-CP patient population (analyzed here) to include patients that have undergone Allogeneic MUD/MRD transplantation as well. The PI of this study is planning to submit this R03 in the fall of 2004. R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. CHAPTER 5 LEUKEMIA: INVESTIGATING CAUSES OF DEATH AND DISEASE RECURRENCE Research Plan Specific Aims The overall objective of this proposal is to examine factors that may serve as prognostic indicators of cytogenetic relapse and/or death in patients who have undergone allogeneic blood or marrow transplantation (Allo-BMT) for treatment of chronic myeloid leukemia in chronic phase (CML- CP). The clinical course for patients diagnosed with CML-CP is heterogeneous. Previous studies have demonstrated that prognosis varies widely depending on the risk profiles of patients; historically risk profiles were based on demographic characteristics, clinical features at presentation and prior therapy (type, amount and duration). Multivariable risk classifications and scoring systems based on pretreatment features have been the subject of numerous prognostic studies (Tura, Baccarani, and Corbelli 1981; Cervantes and Rozman 1982; Sokal et al. 1984; Sokal et al. 1985; Kantaijian, Smith, et al. 1985; Kantaijian et al. 1990; Italian Cooperative Group 1991; Thiele et al. 1991; Hehlmann et al. 1992; Ozer et al. 1993; Thiele et al. 1993; Italian Cooperative Group 1994; Cortes, 1997; Hasford et al. 1998). [In most cases, these earlier studies were limited to evaluating the relative impact of pretreatment features on overall survival.] As a result, several models have been established that categorize patients into different groups with distinctive survival characteristics (Sokal et al.l 984; Hasford et al. 1998), however, the 110 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. reproducibility and generalizability of most of these staging systems have been repeatedly questioned because these systems were generally restricted to certain therapeutic regimens. Application of the various risk models and scoring systems to cohorts with other treatment modalities, in particular Allo-BMT, frequently demonstrate a significant lack of prognostic efficiency with overlapping risk discrimination (Gratwohl et al. 1998; Clark et al. 2001; Michallet et al. 2001; Radich et al. 2001; Gratwohl 2003). While a number of prognostic models for non- BMT patients have been developed and are well documented in the literature, a useful scoring system/prognostic model has not been developed for CML-CP patients that undergo Allo-BMT. The purpose of this analysis is to evaluate the prognostic significance of patient, disease, and treatment characteristics for patients who have undergone Allo-BMT for treatment of CML- CP. An examination of the role of patient, clinical and treatment factors collected both at the time of diagnosis and Allo-BMT will be done to assess the predictive value of these factors on a patient’s risk for disease recurrence and/or death following Allo-BMT. An ongoing case-series of 393 CML-CP patients treated at the City of Hope National Medical Center with Allo-BMT from 1981-2002 will be used for this analysis. As part of the background for the statistical analysis, an extensive review of the medical literature (from 1980 to 2003) has been completed. This review has revealed the historically significant patient, disease and treatment factors that will be used in this analysis. This study will also explore the predictive value of three generally accepted scoring systems (Sokal, Hasford and Gratwohl) in this large single center Allo-BMT population. The question and selection of optimal treatment depends on many factors, which include disease characteristics, previous treatment, and individual patient considerations. The results of this study will contribute to the overall 111 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. understanding of CML-CP prognosis in the Allo-BMT setting and could assist clinicians with treatment decisions related to Allo-BMT. Our specific aims are: 1: To, based on an identified case-series of Allo-BMT CML-CP patients, collect and summarize data on: 1) significant disease and patient characteristics (recorded at diagnosis and Allo- BMT); 2) patient’s treatment history (recorded from diagnosis to Allo-BMT); 3) potentially relevant molecular, cytogenetic and clinical features (at diagnosis and Allo-BMT); and 4) cytogenetic relapse events and/or death post Allo-BMT (if applicable). 2: To use the updated database to assign weighted risk scores for the three most widely accepted scoring systems (Sokal, Hasford and Gratwohl) and test the prognostic reproducibility in this independent patient population. 3: To use the updated database to examine the predictive value of molecular, cytogenetic and clinical features on survival and cytogenetic relapse post Allo-BMT [after adjusting for ‘at diagnosis’ disease and patient characteristics] (developing a prognostic model). 4: To compare the prognostic factors seen at diagnosis with those at Allo-BMT, thereby identifying through statistical analysis (potentially) new disease and clinical features at Allo- BMT that are predictors of disease recurrence and/or death post Allo-BMT. Background and Significance Why the Study o f CML-CP Requires a Non-Traditional Approach. Overall, the study of CML-CP does not follow the standard ‘population-based’ research approach that has been applied to the majority of chronic diseases that undergo epidemiologic investigation. This departure is due in large part to the limited number of patients diagnosed annually with 112 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. CML1 . As a result, epidemiologic efforts focused on preventing CML by revealing the underlying cause/s of disease through case-control, cohort, or ecologic studies are less viable for this patient population. For more than 50 years, ‘classic’ epidemiologic investigation has studied the more inclusive leukemia disease construct. (Leukemia is made up of four major subtypes: chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML).) Consistently, the results of these studies have implicated environmental and occupational exposures (e.g. ionizing radiation, non-ionizing electromagnetic fields, benzene, agricultural exposures related to poultry and dairy farming, livestock production and certain crops) in the etiology and pathogenesis of this hematologic malignancy (Schottenfeld and Fraumeni 1996). However, most experts would agree that occupational and environmental exposure to radiation or chemicals are responsible for only a small number of leukemia cases, and are more relevant to acute leukemia than chronic leukemia. For the past 20 years, the goals of CML epidemiologic research have been to: 1) identify and understand appropriate disease measures/indicators, 2) study the strength of evidence regarding the benefits and risks of available treatment options, 3) help identify the optimal timing of the intervention and monitoring of disease based on disease and patient characteristics, and 4) identify prognostic indicators of disease relapse and death. In an effort to improve the long-term survival for CML-CP patients, this research proposal seeks to study remaining questions in the area of prognosis for patients that undergo allogeneic blood or marrow transplantation. This project 1 Annually CML constitutes about 0.3% (.0033) o f all incident cancers in the United States, accounting for 13- 20% o f all cases o f leukemia (Perkins, 2000; Ries, 2001). CML has an annual incidence of 1-2 cases per 100,000 per year and affects about 4,500 Americans each year (465 annually in California) (American Cancer Society, 2001). Although CML occurs in all decades o f life, it is mainly a disease o f adults. Incidence rises slowly with age until the mid-forties when it starts to rise more rapidly, resulting in a median age o f onset between 50 and 60 years o f age. Age-adjusted incidence rates reported by SEER (Surveillance, Epidemiology and End Results) for all races from 1994-1998 were 0.7 and 7.2 per 100,000 for persons diagnosed <65 years and >65 years respectively (Ries, 2001). Males have a rate 1.7 times as high as females. 113 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. will build on the current body of literature related to risk modeling (prediction) of relapse and/or death events following treatment. Current Limitations o f CML Risk Classification. Because of the highly variable clinical course of CML-CP, methods were developed to predict the biological behavior of individual cases based on clinical features at diagnosis. Studies of patient and tumor characteristics by univariate and multivariable analysis have helped in understanding disease heterogeneity and in developing clinical prediction rules (or prognostic models) that categorize patients into different risk groups based on pretreatment prognostic factors (Tura, Baccarani, and Corbelli 1981; Cervantes and Rozman 1982; Sokal et al. 1984; Sokal et al. 1985; Kantarjian, Smith, et al. 1985; Kantarjian et al. 1990; Italian Cooperative Group 1991; Thiele et al. 1991; Hehlmann et al. 1992; Thiele et al. 1993; Italian Cooperative Group 1994; Cortes 1997; Hasford et al. 1998). Over the past 20 years several distinct scoring systems have been developed, and numerous predictive models have been derived based on one or more clinical parameters at presentation. The most generally accepted prognostic scores are the Sokal (Sokal et al. 1984), Hasford (or European) (Hasford et al. 1998), and Gratwohl (Gratwohl et al. 1998) risk scores (Deininger et al. 2003). These scoring systems are based on parameters with an established unfavorable effect on survival, the parameters include: (at diagnosis) age, spleen size, platelet count, blast %, basophil %, eosinophil %, (at transplant) disease phase, time from diagnosis to transplant, and patient-donor gender combination. An evaluation of the literature shows that the diversity in relevant factors found by investigators can be linked to heterogeneous patient samples, differences in front line treatment, and differences in disease management strategies. The fact that these differences 114 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. exist has been an enormous impediment to their application. Although these scores are capable of identifying patients in low, intermediate and high-risk groups, they are relatively crude indicators that have limited value in outcome prediction for individual patients (Deininger et al. 2003). Moreover, it is not clear that any of these scoring systems retain their predictive value through the patient’s treatment course, especially in patients that receive therapies known to alter the underlying natural course of the disease (e.g., blood or marrow transplantation and Imatinib Mesylate). Given that the majority of these studies modeled characteristics recorded at diagnosis and did not include significant patient, disease and clinical features at Allo-BMT patients, scientific questions remain related to the validation of these risk-scores in Allo-BMT patients. Because the scientific community acknowledges the limitations of the existing scoring systems and prognostic models, research is focused on the development of a revised risk score/risk model that is expanded to include treatment history and cytogenetic/molecular features for Allo-BMT patients. Experts agree that the analysis and validation of an expanded list of prognostic factors is necessary for the development and application of risk-adjusted therapies, improved disease/patient management, and improved survival (outcome). Literature Review. As part of the background for the data collection effort and statistical analysis, a review of the medical literature (from 1980 to 2003) was completed to identify the appropriate patient, disease and treatment factors that were either shown to be meaningful by univariate analysis or used in a multivariable prognostic scoring system/model for patients diagnosed with CML-CP. This review of the literature included an assessment of the patient population (e.g., diagnosis period, prior therapy), statistical methods, study design (e.g., observational studies, sample size, duration of follow-up), and method used to define modeling factors. The result of this 115 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. evaluation shows that not all of these papers deal with the actual development of a prognostic model. Some focus on new factors that are of independent prognostic importance without specifying an actual model. Others use prognostic factors to define subgroups of patients with good or bad (low, medium, high-risk) prognosis. (Models presented in the literature are often a compromise between the extremes of the statistical ideal and the clinical ideal.) Generally, covariate information was either used by defining a prognostic index as a weighted mean of the prognostic variables or by defining some rules for grouping of patients. Strangely enough, the concept of a prognostic model is far from well defined. Some authors use the term to indicate the selection of prognostic factors included in the model, while others are satisfied to report that factor X is of independent prognostic value, suggesting that it can be added to an already long list of relevant and generalizable prognostic factors. Interestingly enough many studies do not report basic data on their patient population, such as age, disease phase, disease characteristics, and duration of follow-up. Some long-term survival data were based on the observations of vety few patients. In other cases, the inclusion criteria were vague and sample sizes were small, providing inadequate statistical power to evaluate differences in outcomes, and wide 95% confidence intervals for the estimate of relative risk. These deficiencies pose a serious problem as health care providers attempt to decipher and apply the outcome of these studies to the medical decisions about their patients. These initial findings are a call to researchers and clinicians to use rigorous study designs and statistical methodology when developing or applying these prognostic scoring systems and to observe greater scientific diligence in the evaluation of these data. These findings help explain the variation in the reported risk factors between studies and will guide the analysis proposed here. 116 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Preliminary Results Identified Allo-BMT CML-CP Patient Population. In 2002, Leukemia continued to be the second leading cancer diagnosis for newly diagnosed cases or treated cancers at the City of Hope National Medical Center, breast cancer was first (City of Hope Cancer Registry Report 2002). City of Hope is the world’s 3rd largest provider of blood or marrow transplantation; since the first transplant in May of 1981 through the end of 2002, a total of 393 patients have undergone Allo-BMT for treatment of CML-CP. The patient population used for this retrospective analysis will be drawn from this identified case-series. Results o f the Literature Review. As part of the background for the data collection effort and statistical analysis, a review of the medical literature (from 1980 to 2003) was conducted to identify the relevant patient, disease and treatment factors that will be collected and analyzed for this research proposal. The final list of ‘at diagnosis’ and ‘at transplant’ features that will be used for this analysis are outlined in Table 16 and was constructed from factors that were shown in the Table 16: Factors Shown to be Predictive of Overall Survival Features at Diagnosis Features at Transplant Age (years)a ,b Spleen size (cm)a ,b White blood cell count (109 /liter) Platelet count (109 /liter)a ,b Eosinophils in blood (%)b Basophils in blood (%)b Blasts in blood (%)a ,b Initial therapy type Time from diagnosis to transplant (months)c Age patient (years)0 Patient-Donor gender combinationc Donor type (syngeneic-sibling vs. related-unrelated)0 Material type (bone marrow vs. peripheral blood stem cells) Preparative regimen Graft vs. Host Disease (GvHD) prophylaxis Acute - Chronic GvHD (yes/no) Molecular data (qualitative and quantitative PCRd results) Cytogenetic data (clonal evolution from baseline) a Parameter used in Sokal Score b Parameter used in Hasford Score c Parameter used in Gratwohl Score d Polymerase Chain Reaction 117 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. literature to be either 1) significantly predictive of overall survival by univariate analysis or 2) used in a multivariable prognostic scoring system/model. Special consideration was given to those prognostic factors that were identified or corroborated by the National Comprehensive Cancer Network (NCCN) Expert Panel for CML in lieu of formal research studies. (The panel’s evaluation of existing treatment options and factors believed to influence response/outcome are summarized in the NCCN Clinical Practice Guidelines for CML -version 01.2004.) Summary of Data Collection Efforts and Initial Results. Patient characteristics recorded ‘at diagnosis’ are summarized in Table 17. Patient demographics have been collected and summarized for all patients and are considered complete. As expected, a slight male predominance (55%) can be seen in this patient population, which is consistent with statistics Table 17: Allogeneic Blood or Marrow Transplantation for Treatment of Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) Summary of Patient Characteristics Pre-Transplant Patients Transplanted 05.May.1981 to 31 .December.2002 TOTAL PATIENTS3 (N=393) SIBLING/ SYNGENEIC3 (n=266) MUD3 - 1 5 / MRD3 , C (n=127) P* Year of Diagnosis < 1985 47(12.0) 46(17.3) 1 ( 0.8) < .0001 1986-1990 70(17.8) 54 (20.3) 16(12.6) 1991-1995 128 (32.6) 72 (27.1) 56(44.1) 1996-2000 133 (33.8) 84 (31.6) 49 (38.6) 2001-2002 15 ( 3.8) 10 ( 3.8) 5 ( 3.9) Patient Gender Male 216(55.0) 153 (57.5) 63 (49.6) .16 Female 177 (45.0) 113(42.5) 64 (50.4) Age at Diagnosis (Years) Mean ± Std 35.3 ± 10.4 35.1 ± 10.2 35.8+10.7 .55 Median (Range) 35.4 (4.9-71.1) 34.3 (6.5-71.1) 36.7 (4.9-55.6) 118 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Table 17: Continued TOTAL PATIENTS (N=393) SIBLING/ SYNGENEIC2 (n=266) MUD^V MRD (n=127) P* Race-Ethnicity American Indian 1 ( 0.3) 1 ( 0.4) 0 ( 0) <.0001 Asian 40(10.2) 29(10.9) 1 1 ( 8.7) Black Non-Hispanic 15 ( 3.8) 13 ( 4.9) 2 ( 1.6) Hispanic 113(28.8) 96 (36.1) 17(13.4) White Non-Hispanic 222 (56.5) 125 (47.0) 97 (76.4) Other/Unknown 2 ( 0.5) 2 ( 0.8) 0 ( 0) Marital Status at Diagnosis Single 104 (26.5) 71 (26.7) 33 (26.0) .48 Married 241 (61.3) 167 (62.8) 74 (58.3) Separated 1 1 ( 2.8) 7 ( 2.6) 4 ( 3.2) Divorced 29 ( 7.4) 15 ( 5.6) 14(11.0) Widowed 6 ( 1.5) 4 ( 1.5) 2 ( 1.6) Unknown 2 ( 0.5) 2 ( 0.8) 0 ( 0) Occupation at Diagnosis Data Available | Classification 359 (91.3) 245 114 Descriptive Age <18.0 years 19 ( 4.8) 12 7 Data Not Reported 15 ( 3.8) 9 6 a Descriptive results are mean ± std/median (range) or number (percent) b Matched Unrelated Donar c Matched Related Donar d p-value obtained from Fisher’s exact test, Student t-test, or Wilcoxon Rank Sum Test when appropriate published by Surveillance, Epidemiology and End Results Program (SEER) (Ries et al. 2001). Age trends also follow national statistics with very few children/adolescents (age<18.0 years) diagnosed with this disease. The number of cases rises slowly with age until the early-forties when it starts to rise more rapidly. While the age trends are consistent with what has been reported, the median age of onset for this case-series is 35, which is fifteen years below the national median of 50-60 years of age. The meaning/possible impact of this finding will be explored as part of the analysis. As for the disease features at diagnosis and treatment history prior to transplant (Table 18) (e.g., white blood cell/platelet count, % eosinophils, % basophils, % blasts, spleen size and initial therapy), data for the sibling and syngenic patients has been collected and is considered 119 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. complete. As for the matched unrelated and related donors (not listed in table 3), over 50% of these data are missing and will be collected as part of this research proposal. The same is true for the ‘at transplant’ characteristics (Table 19) and outcomes (Table 20). While the sources of these data have been identified and access has been granted, a substantial data collection effort will be needed to complete this project. Table 18: Allogeneic Blood or Marrow Transplantation (Allo-BMT) for Treatment of Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) Summary of Patient Characteristics Pre-Transplant Sibling and Syngenic Transplant Patients Only Patients Transplanted 05.May. 1981 to 31 .December.2002 Variable Mean ± SD or n (%) Median (Range) N (%) with missing data White blood cell count at Diagnosis (xl09 /liter) 159.7 ± 118.3 131 (13.9-730.0) 3(1) Eosinophils at Diagnosis (%, blood) 2.4 ± 2.5 2(0-14) 32(14) Basophils at Diagnosis (%, blood) 3.212.9 3 (0-17) 32(14) Platelets at Diagnosis (xl09 /liter) 526.4 ± 382.2 423 (21-3500) 13(6) Blasts at Diagnosis (%, blood) 2.012.6 1 (0-12) 27(12) Splenomegaly at Diagnosis 137(62) 12(5) Spleen Size, cm below costal margin 8.815.5 8 (2-30) 121 (52) Initial Therapy Type Busulfan Hydroxyurea IFN-aa Allo-BMT (Sibling/Syngenic) Gleevec Other 18 ( 8) 183 (78) 8 ( 3) 1 ( <1) 1 (<1) 23 (10) 0 a: Interferon-alpha 120 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Table 19: Allogeneic Blood or Marrow Transplantation (Allo-BMT) for Treatment of Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) Summary of Patient Characteristics at Transplant Sibling and Syngenic Transplant Patients Only Patients Transplanted 05.May.1981 to 31 ■December.2002 Variable Mean ± SD or n (%) Median (Range) N (%) with missing data Year of Transplant < 1985 1986-1990 1991-1995 1996-2000 2001-2002 22 ( 9) 45 (19) 76 (33) 78 (33) 13 ( 6) 0 Duration of CP: Time from Diagnosis to Transplant (years) 1.0 ± 1.1 0.6 (0.1-8.2) 0 Age at Transplant (years) 36.5 ± 10.2 36.4 (8.6-71.5) 0 < 40 Years > 40 Years 144 (62) 90 (38) Donor Match-Mismatch (Patient-Donor) Match (Male-Male) Match (Female-Female) Mismatch (Male-Female) Mismatch (Female-Male) 87 (37) 49 (21) 44(19) 54 (23) 0 Transplant Source Material Type Bone Marrow (BM) Peripheral Stem Cells (PSC) 206 (88) 28(12) 0 Preparative Regimen Busulfan/Cytoxan FTBP/Cytoxan FTBWP-16b Other 70 (30) 25(11) 133 (57) 6 ( 3) 0 Graft vs. Host Disease (GvHD) Prophylaxis Cyelosporine/PSEc Cyclosporine/MTXd Cyclosporine/MTX/PSE Other None-Twin 50 (21) 70 (30) 91 (39) 18 ( 8) 5( 2) 0 a Fracturiated Total Body Irradiation b Etoposide c Prendisone d Methotrexate 121 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Table 20: Allogeneic Blood or Marrow Transplantation (Allo-BMT) for Treatment of Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) Summary of Complications and Outcomes post Transplant Sibling and Syngenic Transplant Patients Only Patients Transplanted 05.May.1981 to 31 .December.2002 Variable Mean ± SD or n (%) Median (Range) N (%) with missing data Time to Engraftment (Days) Absolute Neutrophil Count >500 xl03 /pL Untransfused Platelet Count >25 xl03 /pL 20.3 ± 8.4 23.1 ± 14.9 19(10-90) 21 (3-146) 2 (<l)a 8 ( 3)b Acute GVHD0 (Clinical Grade) 0-1 2 3 4 172 (74) 33(14) 14 ( 6) 15 ( 6) 0 Chronic GVHD (Maximum Grade) Yes, Limited Yes, Extensive No Twin Unknown 72 (34) 77 (36) 57 (27) 5(2) 1 (<1) 22 (9)d # of Cytogenetic Relapse Events (post Allo- BMT) Yes No 23(10) 211 (90) 0 # of Death Events (post Allo-BMT) Alive Dead # of patients lost to follow-up 153 (65) 81 (35) 17 ( 7) 0 Cause of Death (Transplant Related) Yes No Unknown 69 (85) 10(12) 2( 3) 0 a Two patients expired prior to reaching milestone b Eight patients expired prior to reaching milestone c Graft vs Host Disease d Twenty-two patients died too early to assess chronic GvHD 122 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Table 20: (continued) Allogeneic Blood or Marrow Transplantation for Treatment of Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) Summary of Death Information and Survival/Relapse Probabilities Sibling and Syngenic Transplant Patients Only Patients Transplanted 05.May.1981 to 31.December.2002 Variable Number of Events N (%) with missing data Primary Cause of Death 0 Graft failure 2 Sepsis 20 Bacterial sepsis 2 Fungal Infection 3 ARDSa and multiorgan failure 12 Brain abscess 3 Pneumonia 13 CMVb -IPc 12 Idiopathic-IP 1 CMV and PCPd 0 VODe and multiorgan failure 0 Acute Graft vs Host Disease (GVHD) 1 1 Chronic GVHD 21 Suicide/Car Accident 2 Relapsed Leukemia 10 Secondary Malignancy 2 Unknown 2 Survival Probability Survival/Relapse 95% CT for Survival/ Estimate Replapse Estimate 1-Year 81% 75% to 85% 5-Year 68% 62% to 74% 10-Year 60% 52% to 68% Relapse Rate 1-Year 5% 3% to 10% 5-Year 12% 8% to 18% 10-Year* Disease-Free Survival Probability 1-Year 77% 71% to 82% 5-Year 62% 55% to 69% 10-Year 57% 50% to 64% a Acute Respiratory Distress Syndrome b Cytomegolovirus 0 Interstital Pneumonitis d Pneumosistis Camii Pneumonia e Veno-occlusive Disease f Confidence Interval g Unable to estimate, last event at 9 years. 123 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Research Design and Methods Patient Population. The patient population has been identified as a case-series of patients that have undergone Allo-BMT for treatment of CML-CP at the City of Hope National Medical Center. Between May 1981 and December 2002, 393 consecutive CML-CP patients received an Allo-BMT from either a histocompatible sibling donor or unrelated donor identified through the National Marrow Donor Program. All patients who were otherwise eligible were included in the study regardless of their gender or ethnic identity. Eligibility criteria for patients include year of transplant, diagnosis at transplant, phase of disease at transplant, and type of transplant. The dates of inclusion for selection of the patient population was projected to ensure that each patient would have a minimum of 12 months of follow-up (for patients surviving to the date of analysis). The diagnosis of CML was based on biopsy; all biopsy specimens were reviewed and confirmed by an expert hematopathologist at City of Hope. Written informed consent was obtained from each patient and the City of Hope Institutional Review Board has approved this study (protocol #00120). For all patients registered onto this study, data on eligibility status, informed consent date, diagnosis, dates of treatment, follow-up interval, last contact date, relapse and survival status are computerized in BITS (see database management section of the research proposal). The case report forms for this study have been drafted and include the study specific data (all of the necessary elements required to conduct this study). Two data entry clerks within the Division of Information Sciences will enter the data into BITS, and the Quality Assurance Analyst will run computerized logic checks and distribute error reports to the data manager for rectification. At the time of analysis, the data will be exported from BITS to SAS (a statistical software package) for programming by the Biostatistician. 124 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Updating the Database, Data Collection. An initial draft of the case report forms have developed. All data collected will undergo a periodic audit by the physician on this study and the quality assurance committee (the cost associated with the quality assurance committee will be provided by City of Hope). The primary goal of the audit procedure is to assure accurate data collection and interpretation. In addition to collecting the information about the patients disease and treatment history, follow up will be conducted on all patients from diagnosis to last contact or death, to determine their cancer status and vital status; complete death information including date and cause of death will be captured for all expired patients. City of Hope Institutional Review Board approval has been obtained to review the medical records for these patients to abstract tumor, treatment, genetic, clinical/transplant characteristics, relapse and vital status data. Database Management and Data Management. At City of Hope all cancer center study data are entered into the Biostatistics Information Tracking System (BITS), a centralized relational research database developed within the Division of Information Sciences over 15 years ago using the Advanced Revelation (AREV) software system. BITS is deployed on an NT server and is maintained within the Division of Information Sciences. The system is password protected to restrict access to research staff and investigators. Security can be set to “read only” or “write” privileges based on the user’s permission to view, enter and/or edit data. BITS incorporates all data required for study administration, statistical analysis, and has electronic interfaces for importing demographic, disease, laboratory and treatment data from other institutional systems. The key personnel for this study (with the exception of the off-site consultant) have gained access to this database and the appropriate permissions have been set based on study role. 125 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Statistical Methods. Demographic and disease characteristics will be summarized for all patients using descriptive statistics. The Wilcoxon rank-sum test will be used when comparing medians for continuous data, and Fisher’s exact test to compare categorical data. Survival estimates will be calculated based on the product-limit method (Kaplan and Meier 1958), and 95% confidence intervals will be calculated using the logit transformation with Greenwood’s variance estimate (Breslow and Day 1980). Three endpoints will be studied: overall survival (OS), disease free survival (DFS) and relapse. Factors associated with overall survival, disease free survival and relapse will be examined separately by univariate Cox regression analysis (Cox 1972). The assumption of proportionality of the hazard ratio will first be tested on each variable. The proportional hazards assumption will be checked using a formal test procedure described by Marubini and Valsecchi (1994). The variables to be tested were determined from the literature review. The risk ratio will be calculated for each variable along with the 95% confidence limits. To develop a multivariable model, stepwise Cox regression will be performed to determine independent predictors of survival and relapse; all variables with a p-value <0.10 by univariate analysis will be included as candidates in this analysis. All calculations will be done using SAS version 8.2. Power Justification for Survival Analysis. Focusing on the primary endpoint (survival), this analysis was aimed at evaluating the minimum hazard rate ratios that can be detected given the expected number of events under three different scenarios. The scenarios included in this analysis were selected to show the range of power given a set of meaningful hazard ratios (1.4, 1.6 and 1.8). (When survival is the outcome of interest it appears to be common practice to compare the survival time between groups; this is what was done here.) This power analysis was conducted to test for an association between overall survival time and 126 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. covariates in a retrospective cohort of 393 BMT patients. Power results for a two-group ‘survival time’ comparison are presented in Table 21. For example, when the sample sizes in age groups >40 and <40 are 156 and 237, respectively, a .05 level two-sided log-rank test will have 91% power to detect the survival time difference for a hazard ratio (HR) of 1.8, which is much lower than the HR of 2.9 in the observed data. Table 21: Results of Power Analysis -Comparing survival time between two groups; two-sided log-rank test, a-level .05, total sample size 393 patients Scenarios Sample Size by Comparison Group3 Hazard Ratiob between groups Power3 Age group: >40 vs. <40 years 156 vs. 237 1.4 42 1.6 73 1.8 91 2.9* 99 Transplant Type: MUDd /MRDe vs. 127 vs. 266 1.4* 52 Sibling/Syngeneic 1.6 83 1.8 96 2.0 99 Time from Diagnosis to Allo- BMTf: 196 vs. 197 1.4 49 >12 months vs. <12 months 1.6 80 1.8 95 1.9* 98 a Sample sizes in groups o f high vs. low survival risks. b Hazard ratio in observed data was marked with an asterisk (*). c Power estimated by nQuery Advisor 5.0 software using 2000 simulations. d Matched Unrelated Donar ' Matched Related Donar f Allogeneic Blood or Marrow Transplantation These data show that, under the scenarios tested, a .05 level two-sided log-rank test will have >80% power to detect the survival difference that corresponds to a hazard ratio (HR) of 1.6- 2.9. With the exception of parameters with more heavily unbalanced sample size splits (e.g., 127 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. transplant type) this analysis shows that the range of hazard ratios that are detectable given the data is generally good. 3-Year Project Schedule The following project schedule itemizes the major tasks and grant deliverables by fiscal year. Fiscal Year 01 (7/1/02-6/30/03) 1. Draft review paper, manuscript # 1 2. Gain access to identified sources of molecular and cytogenetic data 3. Begin data collection and finalize the analysis strategy 4. Submit manuscript #1 for publication The first 3 months of the funding period will be devoted to finalizing a draft of the review paper on CML-CP prognosis (manuscript #1). The remaining nine months of fiscal year 01 will be devoted to the data collection effort and finalizing the analysis strategy. Fiscal Year 02 (7/1/03-6/30/04) 1. Continue data collection and begin programming of statistical programs 2. Draft results of statistical analysis (manuscript #2) Fiscal Year 03 (7/1/04-6/30/05) 1. Finalize data collection and complete statistical analysis 2. Submit results of statistical analysis, manuscript #2 128 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Collecting the required data will be a labor-intensive process that is projected to take 2 years to complete. Because not all patients were initially diagnosed or treated at City of Hope and may have been diagnosed 15-25 years ago, obtaining source documentation on these patients will take some time to retrieve and is dependent on the cooperation of outside hospitals and clinics. Please note: A full copy of the grant can be found in Appendix C. 129 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. REFERENCES Abeloff MD, Armitage JO, Lichter AS, and Niederhuber J E. 2000. Clinical Oncology, Second Edition. Philadelphia, PA: Churchill Livingstone. Allan NC, Richards SM, and Shepherd PCA. 1995. UK medical research council randomized, multi-centered trial of interferon-alpha for chronic myeloid leukemia: improved survival irrespective of cytogenetic response. Lancet 345:1392-1397 American Cancer Society 2001. Cancer reference information: Adult Chronic Leukemia. American Cancer Society http://www.cancer.org American Cancer Society, California Division, and Public Health Institute, California Cancer Registry. California Cancer Facts and Figures 2002. Oakland, CA: American Cancer Society, California Division, September 2001. Andreeff M, and Pinkel D. 1999. Introduction to Fluorescence In Situ Hybridization, Principles and Clinical Applications. New York, NY: John Wiley & Sons, Inc. Berman E, Clift RA, Copelan EA, Emanuel PD, Erba HP, Glenn MJ, Greenberg PL, Jones RJ, O’Brien S, Saba HI, Schilder R, Snyder DS, Soiffer RJ, Tallman MS, Wetzler M, Ravandi-Kashani F, Kantarjian H, and Talpaz M. 2000. National Comprehensive Cancer Network practice guidelines for chronic myelogenous leukemia. Oncology 14(1 lA):229-240 Blume KG, Forman SJ, O’Donnell MR, Doroshow JH, Krance RA, Nademanee AP, Snyder DS, Schmidt GM, Fahey JL, and Metter GE. 1987. Total body irradiation and high- dose etoposide: A new preparatory regimen for bone marrow transplantation in patients with advanced hematologic malignancies. Blood 69(4): 1015-1020. Blume KG, Kopecky KJ, Henslee-Downey JP, Forman SJ, Stiff PJ, LeMaistre CF, and Appelbaum FR. 1993. A prospective randomized comparison of total body irradiation-etoposide versus busulfan-cyclophosphamide as preparatory regimens for bone marrow transplantation in patients with leukemia who were not in first remission: a Southwest Oncology Group study. Blood 81(8):2187-2193. Boice JD, Day NE, Andersen A, Brinton LA, Brown R, Choi NW, Clarke EA, Coleman MP, Curtis RE, Flannery JT, Hakama M, Hakulinen T, Howe GR, Jensen OM, Kleinerman RA, Magnin D, Magnus K, Makela K, Malker B, Miller AB, Nelson N, Skeet RG, Skjerven JE, Smith PG, Sok M, Spengler RF, Strom HH, Stovall M, Tomkins GWO, and Wall C. 1985. Second cancers following radiation treatment for cervical cancer: An international collaboration among cancer registries. Journal o f the National Cancer Institute 74(5):955-75. Bolin RW, Robinson WA, Sutherland J, and Hamman RF. 1982. Busulfan versus hydroxyurea in long-term therapy of chronic myelogenous leukemia. Cancer 50(9):1683-1686. 130 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Breslow NE and Day NE. 1980. Statistical methods in cancer research, vol 1: The analysis of case-control studies. Lyon, France, WHO International Agency fo r Research in Cancer. Scientific Pulications No. 32: 5-338. Byar DP. 1984. Identification of prognostic factors. In: Buyse ME, Staquet MJ, Sylvester RS, editors. Cancer Clinical Trials, Methods and Practice. Oxford, England: Oxford University Press: 423-443. CancerNet: Leukemia. National Cancer Institute, 2001. http://cancemet.nci.nih.gov/Cancer Tvpes/Leukemia.shtml Cervantes F, and Rozman C. 1982. A multivariate analysis of prognostic factors in chronic myeloid leukemia. Blood 60:1298-1304 Cervantes F, on behalf of the IRIS (International Randomized IFN vs. STI571) study group 2003. Durability of responses to Imatinib in newly diagnosed chronic phase chronic myeloid leukemia (CML): 24-month update from the IRIS study. Blood 102:181a, abstract 633. Chao NJ, Schmidt GM, Niland JC, Amylon MD, Dagis AC, Long GD, Nademanee AP, Negrin RS, O ’Donnell MR, Parker PM, Smith EP, Snyder DS, Stein AS, Wong RM, Blume KG, and Forman SJ. 1993. Cyclosporine, methotrexate, and prednisone compared with cyclosporine and prednisone for prophylaxis of acute graft-versus- host disease. New England Journal o f Medicine 329: 1225-1230. Chronic Myeloid Leukemia Trialists’ Collaborative Group 1997. Interferon-alpha versus chemotherapy for chronic myeloid leukemia: a meta-analysis of seven randomized trials. Journal o f the National Cancer Institute 89(21): 1616-1620. Clark RE, Hermans J, Madrigal A, Nachbaur D, Kropshofer G, Gratwohl A, Apperley J, and Niederwieser D for the Chronic Leukaemia Working Party of the European Group of Blood and Bone Marrow Transplantation 2001. HLA-A3 increases and HLA- DR1 decreases the risk of acute graft-versus-host disease after HLA-matched sibling bone marrow transplantation for chronic myelogenous leukaemia. British Journal o f Haematology 114(1 ):36-41. Cohen BJ, and Wood DL. 2000. Memmler’ s Structure and Function o f the Human Body, 7th Edition. Philadelphia, PA: Lippincott Williams & Wilkins. Cortes J, Kantarjian HM, Giralt S, and Talpaz M. 1997. Natural history and staging of chronic myelogenous leukemia. Baillieres Clinical Hematology 10:277-290. Court-Brown WM, and Doll R. 1965. Mortality from cancer and other causes after radiotherapy for ankylosing spondylitis. British Journal o f Medicine 5474:1327-32. Cox DR. 1972. Regression models and life tables. Journal o f the Royal Statistical Soc. Ser. B. 34:187. 131 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Craddock C, Augustson B, and Basu S. 2003. Imatinib or transplant for chronic myeloid leukaemia? Lancet 362(9378): 173. Damjanov I. 2000. Pathology for the Health-Related Professions, Second Edition. Philadelphia, PA: W.B. Saunders Company. Deininger MW, Goldman JM, and Melo JV. 2000 The molecular biology of chronic myeloid leukemia. Blood 96:3343-3356. Deininger MW, O’Brien SG, Ford JM, and Druker BJ 2003. Practical management of patients with chronic myeloid leukemia receiving imatinib. Journal o f Clinical Oncology 21(8): 1637-1647. Deisseroth AB, Zu Z, Claxton D, Hanania EG, Fu S, Ellerson D, Goldberg L, Thomas M, Janicek K, and Anderson WF. 1994. Genetic marking shows that Ph+ cells present in autologous transplants of chronic myelogenous leukemia contribute to relapse after autologous bone marrow in CML. Blood 83(10):3068-3076. Dewald G, Wyatt W, and Silver R. 1999. Atypical BCR and ABL D-FISH patterns in chronic myeloid leukemia and their possible role in therapy. Leukemia Lymphoma 34:491-491. Djulbegovic B, Seidenfeld J, Bonnell C, and Kumar A. 2003. Nonmyeloablative allogeneic stem-cell transplantation for hematologic malignancies: A systematic review. Cancer Control 10(1): 17-41. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, and Sawyers CL. 2001. Efficacy and safety of a specific inhibitor of the bcr-abl tyrosine kinase in chronic myeloid leukemia. New England Journal o f Medicine 344( 14): 1031-1037. Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, Capdeville R, and Talpaz M. 2001. Activity of a specific inhibitor of the bcr-abl tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. New England Journal o f Medicine 344(14): 1038-1042. Dudda-Subramanya R, Lucchese G, Kanduc D, and Sinha A. 2003. Clinical applications of DNA microarray analysis. Journal o f Experimental Therapeutics and Oncology 3(6):297-304. Elwood, NJ. 2004. Telomere biology of human hematopoietic stem cells. Cancer Control 11(2):77-85. Faderl S, Talpaz M, Estrov Z, and Kantarjian HM. 1999. Chronic myelogenous leukemia: biology and therapy. Annals o f Internal Medicine 131 (3):207-219. 132 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Fefer A, Cheever MA, Thomas ED, Boyd C, Ramberg R, Glucksberg H, Buckner CD, and Storb R. 1979. Disappearance of Phl-pos cells in four patients with chronic granulocytic leukemia after chemotherapy, irradiation and marrow transplantation from an identical twin. New England Journal o f Medicine 300(7):333-337. Geary CG. 2000. Historical Review: The story of chronic myeloid leukemia. British Journal o f Haematology 110:2-11. Goldman JM and Lu DP. 1982. New approaches in chronic granulocytic leukaemia: Origin, prognosis, and treatment. Seminars in Hematology 19(4):241-256. Goldman JM, and Druker BJ. 2001. Chronic myeloid leukemia: current treatment options. Blood 98(7):2039-2042. Grand F, Kulkami S, Chase A, Goldman JM, and Cross NCP. 1999. Frequent deletion of hSNF5/INIl, a component of the SW1/SNF complex, in chronic myeloid leukaemia. Cancer Research 59:3870-3874. Gratwohl A, Hermans J, Goldman JM, Arcese W, Carreras E, Devergie A, Frassoni F, Gahrton G, Kolb HJ, Niederwieser D, Ruutu T, Vemant JP, de Witte T, and Apperley J. 1998. Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation. Lancet 352(9134):1087-1092. Gratwohl A. 2003. Prognostic factors in chronic myeloid leukemia: Allografting. Seminars in Hematology 40( 1): 13-21. Groffen J, Stephenson JR, Heisterkamp N, deKlein A, Bartram CR, and Grosveld G. 1984. Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell 36:93-99. Guilhot F, Chastang C, Michallet M, Guerci A, Harousseau JL, Maloisel F, Bouabdallah R, Guyotat D, Cheron N, Nicolini F, Abgrall JF, and Tanzar J. 1997. Interferon-alpha- 2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. French Myeloid Leukemia Study Group. New England Journal o f Medicine 337: 223-229. Hasford J, Ansari H, Pfirrmann M, and Hehlmann R. 1996. Analysis and validation of prognostic factors for CML: German CML Study Group. Bone Marrow Transplant 17:S49-S54. Hasford J, Pfirrmann M, Hehlmann R, Allan NC, Baccarani M, Kluin-Nelemans JC, Alimena G, Steegmann JL, and Ansari H. 1998. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon-alpha: Writing Committee for the Collaborative CML Prognostic Factors Project Group. Journal o f the National Cancer Institute 90(11):850-858. 133 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Haut A, Abbott WS, Wintrobe MM, and Cartwright GE. 1961. Busulfan in the treatment of chronic myelocytic leukemia: The effect of long term intermittent therapy. Blood 17:1-19. Hehlmann R, Heimpel H, Griesshammer M, Kolb HJ, Heinze B, Hossfeld DK, Wickramanayake PD, Essers U, Thiele J, Georgii A, Ansar H, Hochhau A, and Hasford J. 1992. Chronic myelogenous leukemia: recent developments in prognostic evaluation and chemotherapy. The German CML Study Group. Leukemia 6(Suppl 3): 110S-114S. Hehlmann R, Heimpel H, Hasford J, Kolb HJ, Pralle H, Hossfeld DK, Queisser W, Loffler H, Heinze B, and Georgii A. 1993. Randomized comparison of busulfan and hydroxyurea in chronic myelogenous leukemia: prolongation of survival by hydroxyurea. Blood 82:398-407. Hehlmann R, Heimpel H, Hasford J, Kolb HJ, Pralle H, Hossfeld DK, Queisser W, Loffler H, Hochhaus A, and Heinze B. 1994. Randomized comparison of interferon-alpha with busulfan and hydroxyurea in chronic myelogenous leukemia. Blood 84(12):4064-4077. Heim S. 1995. Cancer Cytogenetics, Second Edition. New York, NY: John Wiley & Sons, Inc. Herens C, Tassin F, Lemaire V, Beguin Y, Collard E, Lampertz S, Croisiau C, Lecomte M, De Prijk B, Longree L, Koulischer L. 2000. Deletion of the 5’-ABL region: A recurrent anomaly detected by fluorescence in situ hybridisation in about 10% of Philadelphia-positive chronic myeloid leukaemia patients. British Journal o f Haematology 110(1 ):214-216. Hochhaus A, Reiter A, Saussele S, Reichert A, Emig M, Kaeda J, Schultheis B, Berger U, Shepherd PC, Allan NC, Hehlmann R, Goldman JM, Cross NC. 2000. Molecular heterogeneity in complete cytogenetic responders after interferon-alpha therapy for chronic myelogenous leukemia: low levels of minimal residual disease are associated with continuing remission. Blood 95(l):62-66. Hochhaus A. 2002. Minimal residual disease in chronic myeloid leukemia patients. Best Practice and Research Clinical Haematology 15(1): 159-178. Hochhaus A, Kreil S, Corbin AS, La Rosee P, Muller MC, Lahaye T, Hanfstein B, Schoch C, Cross NC, Berger U, Gschaidmeier H, Druker BJ, Hehlmann R. 2002. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 16(11 ):2190-2196. R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Huntly BJP, Bench AJ, Delabesse E, Reid AG, Li J, Scott MA, Campbell L, Byme J, Pinto E, Brizard A, Niedermeiser D, Nacheva EP, Guilhot F, Deininger M, Green AR. 2002. Derivative chromosome 9 deletions in chronic myeloid leukemia: Poor prognosis is not associated with loss of abl-bcr expression, elevated BCR/ABL levels, or karyotypic instability. 5/ooc/99(12):4547-4553. Huntly BJP, Guilhot F, Reid AG, Vassiliou G, Hennig E, Franke C, Byme J, Brizard A, Niederwieser D, Freeman-Edward J, Cuthbert G, Bown N, Clark RE, Nacheva EP, Green AR, Deininger MW. 2003. Imatinib improves but may not fully reverse the poor prognosis of patients with CML with derivative chromosome 9 deletions. Blood 102(6):2205-2212. ISCN (1995): An international system for human cytogenetic nomenclature, Mitelman F (ed); S. Karger, Basel, 1995. Italian Cooperative Study Group on chronic myeloid leukemia 1991. Confirmation and improvement of Sokal’s prognostic classification of Ph+ chronic myeloid leukemia: The value of early evaluation in the course of the disease. Annals o f Hematology 63:307-314. Italian Cooperative Study Group on chronic myeloid leukemia 1994. Interferon-alpha as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia. New England Journal o f Medicine 330:820-825. Italian Cooperative Study Group on chronic myeloid leukemia 1998. Long-term follow-up of the Italian trial of interferon-alpha versus conventional chemotherapy in chronic myeloid leukemia. Blood 92(5): 1541 -1548. Kantarjian HM, Smith TL, McCredie KB, Keating MJ, Walters RS, Talpaz M, Hester JP, Bligham G, Gehan E, Freireich EJ. 1985. Chronic myelogenous leukemia: a multivariate analysis of the associations of patient characteristics and therapy with survival. Blood 66(6): 1326-1335. Kantarjian HM, Keating M, Smith TL, Talpaz M, McCredie KB. 1990. Proposal for a simple synthesis prognostic staging system in chronic myelogenous leukemia. American Journal o f Medicine 88(1): 1-8. Kantarjian HM, Smith TL, O’Brien S, Beran M, Pierce S, and Talpaz M. 1995. Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon- alpha therapy: the leukemia service. Annals o f Internal Medicine 122:254-261. Kantarjian H, Melo JV, Tura S, Giralt S, and Talpaz M. 2000. Chronic myelogenous leukemia: disease biology and current and future therapeutic strategies. American Society o f Hematology Annual Meeting Educational Proceedings: 90-109. 135 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Kantarjian HM, Talpaz M, Cortes J, O’Brien S, Faderl S, Thomas D, Giles F, Rios MB, Shan J, and Arlinghaus R. 2003. Quantitative polymerase chain reaction monitoring of BCR-ABL during therapy with Imatinib Mesylate (STI571; Gleevec) in chronic phase chronic myelogenous leukemia. Clinical Cancer Research 9: 160-166. Kaplan G, and Meier P. 1958. Non-parametric estimations from incomplete observations. Journal o f the American Statistical Association 53(282):457-481. Kato H, and Schull WJ. 1982. Studies on the mortality of A-bomb survivors 1950-1971. Radiation Research 90(2):395-432. Kennedy BJ. 1972. Hydroxyurea therapy in chronic myelogenous leukemia. Cancer 29(4): 1052-1056. Kennedy BJ. 1992. The evolution of hydroxyurea therapy in chronic myelogenous leukemia. Seminars in Oncology 19(Suppl 9):21 -26. Khoury MJ, Beaty TH, and Cohen BH. 1993. Fundamentals o f Genetic Epidemiology. New York, USA: Oxford University Press. Kleinbaum DG, Kupper LL, Muller KE, and Nizam A. 1998. Applied regression analysis and other multivariable methods, Third Edition. Pacific Grove, CA: Brooks/Cole Publishing Company. Kolomietz E, Al-Maghrabi J, Brennan S, Karaskova J, Minkin S, Lipton J, Squire JA. 2001. Primary chromosomal rearrangements of leukemia are frequently accompanied by extensive submicroscopic deletions and may lead to altered prognosis. Blood 97(11):3581-3588. La Rosee P, O’Dwyer ME and Druker BJ. 2002. Insights from pre-clinical studies for new combination treatment regimens with the BCR-ABL kinase inhibitor imatinib mesylate (Gleevec/Glivec) in chronic myelogenous leukemia: A translational perspective. Leukemia 16:1213-1219. Lugo TG, Pendergast AM, Muller AJ, Witte ON. 1990. Tyrosine kinase activity and transformation potency of BCR/ABL oncogene products. Science 247:1079-1082. Mahon F, Faberes C, Pueyo S, Cony-Makhoul P, Salmi R, Boiron JM, Marit G, Bilhou- Nabera C, Carrere A, Montastruc M, Pigneux A, Bernard P, Reiffers J. 1998. Response at three months is a good predictive factor for newly diagnosed chronic myeloid leukemia patients treated with recombinant interferon-alpha. Blood 92(11):4059-4065. Marubini E and Valsecchi MG. 1994. Analyzing survival data from clinical trials and observational studies. John Wiley and Sons. 136 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. McGlave PB, Beatty P, Ash R, and Hows JM. 1990. Therapy for chronic myelogenous leukemia with unrelated donor bone marrow transplantation: results in 102 cases. 5/ooJ75:1728-1732. Melo JV. 1996. The diversity of bcr-abl fusion proteins and their relationship to leukemia phenotype. Blood 88(7):2375-2384. Melo JV, Gordon DE, Cross NC, and Goldman JM. 1993. The ABL/BCR fusion gene is expressed in chronic myeloid leukemia. Blood 81(1):158-165. Michallet M, Bilger K, Garban Frederic, Attal M, Huyn A, Blaise D, Milpied N, Moreau P, Bordigoni P, Kuentz M, Sadoun A, Cahn JY, Socie G, Thomas X, Amaud P, Raus N, Lheritier V, Pigneux A, Boiron JM. 2001. Allogeneic hematopoietic stem cell transplantation after nonmyeloablative preparative regimens: Impact of pre transplantation and post-transplantation factors on outcome. Journal o f Clinical Oncology 19(14): 3340-3349. Minot GR, Buckman TE, and Isaacs R. 1924. Chronic myeloid leukemia. Journal o f the American Medical Association 82:1489-1494. Monfardini S, Gee T, Fried J, and Clarkson B. 1973. Survival in chronic myelogenous leukemia: Influence of treatment and extent of disease at diagnosis. Cancer 31(3):492-501. Mueller RF, and Young ID. 1998. Emery’ s Elements o f Medical Genetics, Tenth Edition. London, UK: Churchill Livingstone. Nowell PC, and Hungerford DA. 1960. A minute chromosome in human chronic granulocytic leukemia. Science 132(3438): 1497. Oda T, Tamura S, Matsuguchi T, Griffin JD, Druker BJ. 1995. The SH2 domain of Abl is not required for factor independent growth induced by bcr-abl in a murine myeloid cell line. Leukemia 9(2):295-301. Ohnishi K, Ohno R, Tomonaga M, Kamada N, Onozawa K, Kuramoto A, Dohy H, Mizoguchi H, Miyawaki S, Tsubaki K. 1995. A randomized trial comparing interferon-alpha with busulfan for newly diagnosed chronic myelogenous leukemia in chronic phase. Blood 86(3):906-916. Ozer H, George SL, Schiffer CA, Rao K, Rao PN, Wurster-Hill DH, Arthur DD, Powell B, Gottlieb A, and Peterson BA. 1993. Prolonged subcutaneous administration of recombinant alpha-2b interferon in patients previously untreated Philadelphia chromosome-positive chronic-phase chronic myelogenous leukemia. Effect on remission duration and survival: Cancer and Leukemia Group B Study 8593. Blood 82(10):2975-2984. 137 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Perkins Cl, Kwong SL, Morris CR, Cohen R, Allen M, Schalg R, and Wright WE. 2000. Cancer in California, 2001. Sacramento, CA: California Department of Health Services, Cancer Surveillance Section, December. Pinilla-Ibarz J, Cathcart K, Korontsvit T, Soignet S, Bocchia M, Caggiano J, Lai L, Jimenez J, Kolitz J, and Scheinberg DA. 2000. Vaccination of patients with chronic myelogenous leukemia with BCR/ABL oncogene breakpoint fusion peptides generates specific immune responses. Blood 95(5): 1781-1787. Radich JP, Gooley T, Bryant E, Chauncey T, Clift R, Beppu L, Edmands S, Flowers MED, Kerkof K, Nelson R, and Appelbaum FR. 2001. The significance of bcr-abl molecular detection in chronic myeloid leukemia patients ‘late’, 18 months or more after transplantation. Blood 98:1701-1707. Reiffers J, Goldman J, Meloni G, Cahn JY and Gratwohl A. 1994. Autologous stem cell transplantation in chronic myelogenous leukemia: a retrospective analysis of the European Group for Bone Marrow Transplantation. Chronic Leukemia Working Party of the EBMT. Bone Marrow Transplantation 14:407-410. Ries LAG, Eisner MP, Kosary CL, Hankey BF, Miller BA, Clegg L, Edwards BK. (eds). Surveillance, Epidemiology, and End Results (SEER) Cancer Statistics Review, 1973-1998, National Cancer Institute. National Cancer Institute, Bethesda, MD. http://seer.cancer.gov/Publications/CSR1973 1998/. 2001. Rowley JD. 1973. A new consistent chromosomal abnormality in chronic myelogenous leukemia identified by quinacrine fluorescence and giemsa staining. Nature 243(5405): 290-293. Rosenberg SA. 2000. Principles and Practice o f the Biologic Therapy o f Cancer, Third Edition. Philadelphia, PA: Lippincott Williams & Wilkins. Rubin DB. 1987. Multiple imputation fo r non-response in surveys. New York: John Wiley & Sons Inc. Rushing D, Goldman A, Gibbs G, Howe R, and Kennedy BJ. 1982. Hydroxyurea versus busulfan in the treatment of chronic myelogenous leukemia. American Journal o f Clinical Oncology 5(3):307-313. Schafer JL. 1997. Analysis o f Incomplete Multivariate Data. New York: Chapman and Hall. Schmitz N, Gassmann W, Rister M, Johannson W, Suttorp M, Brix F, Holthuis JJ, Heit W, Hertenstein B, Schaub J. 1988. Fractionated total body irradiation and high dose VP- 16-213 followed by allogeneic bone marrow transplantation in advanced leukemias. Blood 72(5): 1567-1573. Schottenfeld D, and Fraumeni JF. 1996. Cancer Epidemiology and Prevention, Second Edition. New York, NY: Oxford University Press, Inc. 138 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Silver RT, Woolf SH, Hehlmann R, Appelbaum FR, Anderson J, Bennett C, Goldman JM, Guilhot F, Kantarjian HM, Lichtin AE, Talpaz M, and Tura S. 1999. An evidence- based analysis of the effect of busulfan, hydroxyurea, interferon, and allogeneic bone marrow transplantation in treating the chronic phase of chronic myeloid leukemia: Developed for the American Society of Hematology. Blood 94:1517- 1536. Sinclair PB, Nacheva EP, Levasha M, Telford N, Chang J, Reid A, Bench A, Champion K, Huntly B, Green AR. 2000. Large deletions at the t(9;22) breakpoint are common and may identify a poor-prognosis sub-group of patients with chronic myeloid leukemia. Blood 95(3): 738-744. Sokal JE. 1976. Evaluation of survival data for chronic myelocytic leukemia. American Journal o f Hematology l(4):493-500. Sokal JE, Cox EB, Baccarani M, Tura S, Gomez GA, Robertson JE, Tso CY, Braun TJ, Clarkson BD, Cervantes F. 1984. Prognostic discrimination in ‘good-risk’ chronic granulocytic leukemia. Blood 63(4): 789-799. Sokal JE, Baccarani M, Tura S, Fiacchini M, Cervantes F, Rozman C, Gomez GA, Galton DA, Canellos GP, Braun TJ. 1985. Prognostic discrimination among younger patients with chronic granulocytic leukemia: Relevance to bone marrow transplantation. Blood 66(6): 1352-1357. Sokal JE, Baccarani M, Russo D, Tura S. 1988. Staging and prognosis in chronic myelogenous leukemia. Seminars in Hematology 25(1):49-61. Talpaz M, McCredie KB, Mavligit GM and Gutterman J. 1983. Leucocyte interferon- induced myeloid cyto-reduction in chronic myeloid leukemia. Blood 62:1052-1056. Talpaz M, Kantarjian HM, McCredie K, Trujillo JM, Keating MJ, and Gutterman JU. 1986. Hematologic remission and cytogenetic improvement induced by recombinant human interferon alpha in chronic myelogenous leukemia. New England Journal o f Medicine 314(17): 1065-1069. Talpaz M, Kantarjian HM, McCredie KB, Keating MJ, Trujillo J, and Gutterman J. 1987. Clinical investigation of human alpha interferon in chronic myelogenous leukemia. 5/ooc/69(5): 1280-1288. Talpaz M, Kantarjian H, Kurzrock R, Trujillo JM, Gutterman JU. 1991. Interferon-alpha produces sustained cytogenetic responses in chronic myelogenous leukemia. Annals o f Internal Medicine 114(7):532-538. Thiele J, Kvasnicka HM, Zankovich R, et al. 1991. Parameters of predictive value in chronic myeloid leukemia -the prognostic impact of histopathological variables in a multivariate regression analysis. Leukemia Lymphoma 4:63-74. 139 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Thiele J, Kvasnicka HM, Titius BR, Parpert U, Nebel R, Zankovich R, Dienemann D, Stein H, Diehl V, Fischer R. 1993. Histological features of prognostic significance in CML: an immunohistochemical and morphometric study (multivariate regression analysis) on trephine biopsies of the bone marrow. Annals o f Hematology 66(6):291- 302. Thomas ED, Clift RA, Fefer A, Appelbaum FR, Beatty P, Bensinger WI, Buckner Greenberg P, Hansen JA, Martin P, McGuffin R, Ramberg R, Sanders JE, Singer J, Stewart P, Storb R, Sullivan K, Weiden PL, Witherspoon R. 1986. Marrow transplantation for the treatment of chronic myelogenous leukemia. Annals o f Internal Medicine 104(2): 155-163. Thomas ED, Blume KG, and Forman SJ. 1999. Hematopoietic Cell Transplantation,Second Edition. Malden, MA: Blackwell Science, Inc. Thompson RB and Stainsby D. 1982. The clinical and haematological features of chronic granulocytic leukaemia in the chronic phase, in Shaw MT (ed): Chronic Granulocytic Leukaemia. New York, Praeger, 139-167. Tura S, Baccarani M, Corbelli G. 1981. Staging of chronic myeloid leukemia. British Journal o f Hematology 47(1): 105-119. Whitby LEH and Britton CJC. 1935. Disorders o f the Blood: Diagnosis, Pathology, Treatment and Technique, First Edition. London, UK: J and A Churchill. Woodruff RK. 1981. Chronic myeloid leukaemia. Australian NZ Journal o f Medicine 11(6): 678-686. R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix A Qualitative and Quantitative PCR Access 97® Research Database M icro soft A c c e s s 141 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix A: Continued M icro soft A c c e s s HBBEEB .Ei^rroHMed>c^^rdta^ , Ar... ■ ■ ■ ■ ■ - ? ■ . 142 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix A: Continued M icro soft A c c e s s m m COH M ED RECN O S E Q . NO DOT DX D O N O R TY PE TREATIN G D i.: DATE O F R EL A PSE PA T IE N T NAME SEX : STE M C E L ! SO U R C E: PSC TRA N SPL A N T T Y P E : jALLC D O N O R SEX : P R O T .U S T : 99053. 96081, 99061. 98075.01 OX D ATE O F D EA TH : DAYS P O S T BMT AT DEATH: S T U D Y N O. D O N O R : , D ATE O F U PD A TE: r 37/ 24/2002 DX IPCRJ: REG IM EN : D IS. S ta tu s IPCRJ: GVHD P R O P H : DAYS P O S T BMT AT U PO A T E : | 294 ) LA BO RATORY DATA S P E C ■Dayv “ L A B . S E O .N O i Singie j f l f o s g Single J j ^ g Q H Single 04/24/2001 2240000 I MfOS glS ^'jjE K T B sirfle 'M fU> 07/23/2001 Singte j j p o s g f o f r j j f € Q j | Shgle 09/04/2001 pos gjSr^e rtfio 09/24/2001 11/05)20011 |NEG § | S rg le j j j f i o |NEO j j S h f l f c J B e 2 H jShgle g f f C j i Single 12/18/2001 g p i I single" a | N E G ~ g S i ^ e B S in^e " H ^ O ^ POS 02/13/20/2 r r - r T w 143 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B Chronic Myeloid Leukemia (CML) Case Report Forms Chronic Myelogenous Leukemia Study: 01113 FORM SET CML Fax Cover Sheet COH1985 Accession Record COH1986 Diagnosis Record COH2002 Diagnosis Detail (CML) COH2252 Prior Drug Treatment - Single Agent (CML) COH2251 Prior Drug Treatment - Combination (CML) COH2253 Prior Treatment - Other Therapies (CML) COH2254 Prior Treatment - Radiation (CML) COH1995 Protocol Treatment - Drug Agent COH2012 Protocol Treatment - Radiation COH2003 Disease Assessment - On Study COH2014 Product Evaluation COH2013 Disease Assessment - Follow-up COH2011 Apheresis COH2004 Count Recovery COH1100 HCT Intake Module COH2005 Engraftment COH1993 Pre-Existing Conditions CO H1098 Common Toxicity Criteria COH1046 Follow-up Log COH1024 Follow-up After BMT (LTFU) U:\AdobePDF Forms\CML Table of Contents (Form Set) Last revision: 06/21/04 144 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued * 2 3 CML Fax Cover Sheet E 8 £ Jp e o f * Todays Date: Sender: □ j/m /L Sender's Fax Number: ( ) n F a x To: (626)256 - 8656 Number of Diagnosis Detail (COH2002) Forms: Number of Prior Drug Tx - Single Agent (COH2252) Forms: Number of Prior Drug Tx - Combination (COH2251) Forms: Number of Prior Tx - O ther (COH22S3) Forms: Number of Prior Tx - Radiation (COH2254) Forms: Number of D isease A ssessm ent - On Study (COH2003) Forms: Number of Product Evaluation (COH2014) Forms: Number of Protocol Tx - Drug Agent (COH1995) Forms: Number of Protocol Tx - Radiation (COH2012) Forms: Number of D isease A ssessm ent - Follow-up (COH2013) Forms: Number of Apheresis (COH2011) Forms: Number of Count Recovery (COH2004) Forms: Number of HCT Intake Module (COH1100) Forms: Number of Engraftment (COH2005) Forms: Number of Pre-Existing Conditions (COH1993) Forms: Number of Common Toxlcitles Criteria (COH1098) Forms: Number of Follow-up Log (COH1046) Forms: Number of Follow-up After BMT (COH1024) Forms: Comments: Total N um ber of Form * : ■ ■ R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued EjOityof M i (one ACCESSION/DIAGNOSIS RECORD R esearch Participant #: Medical Reoord #: P articipant Initials Accession S eq # □ □ Protocol ID: C a lifo rn ia C a n c e r C o n s o rtiu m : Consortium Participant ID: Consortium Protocol ID: B ecau se this Is a co m p u ter read form, please use BLACK Ink only. For data elem ents or questions requiring text responses, print In block letters avoiding contact with the edges of the boxes. Please solidly flN bubbles for choice responses, and submit only orlglnel form s for processing. Participant’s Name: 0 Last Date of Birth: CD' Race: O B*Black O O A elan/lndlan Sub-Continent O W *Caucaslan O A*Amertcan Indian/Alaskan Native O X*Other 0 Pe Paclfic Islander/Native Hawaiian Ethnicity: O 1 * Hispanic 0 2 * Non-Hispantc 0 3 * Unknown Gender: O Male O Female O Unk Referral Source: 0 1 * COH 0 6 * Transfer 0 4 = COH Affiliate O 1 3 * COH Branch Hospital ID #: S ee Form Instructions for codes FOR CDUS STUDIES ONLY Insurance Carrier at Start of Treatment: O 1 * Private Insurance 0 7 * Self Pay (No Insurance) 0 2 * Medicare 0 8 * No M eans of Paym ent (No Insurance) 0 3 * Medicare & Private Insurance 0 9 * HMO 0 4 * Medicaid 0 1 0 * P P O 0 5 » Medicaid & Medicare 0 9S • Other 0 6 * Military/Veterans Administration Sponsored ■ V Protocol, NCI Sub-group Code: V Patient Zip Code at on Study: J E lig ib ility Physician ID# Physician Name: Date Screened: /[ Patient Eligible? O Y e s O N o - If No, Why Not? O 1 * Value(s) Outside Range 0 4 * Other, S p ecify :_________ 0 2 * Results Outside Time Frame O 21 * 2nd Oplnon/Consult Only 0 3 * Does Not Match Other Criteria O 22 * KPS Too Low _ O 23 * Patient Not Interested O 24 * Life Expectancy O 25 * No Protocol For Patient C onsent Signed? O Yes O No - If No, Why Not? I I/I / 0 2 * Language Barrier 0 4 * Other, N/A mm dc yyyy O 5 * Not Eligible ©Copyright City of Hope. COH1966v01 Rev: 07/15/2003 P age 1 o f 2 146 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued R esearch Participant #: ACCESSION/DIAGNOSIS RECORD Medical Record #: Participant Initials A ccession S ea # m Eligibility C ontinued On Study? O Y e s O N o - if Yes, On Study Date; m / m / [ If No, Why Not? O 1 8 Patient Refused Rx O 2 8 Refused Randomized Arm O 3 s=Too III O 4 « Other O 6 8 Not Eligible dd yyyy IP PATIENT SCREENED, CONSENTED, AND ON STUDY, COMPLETE THIS SECTION; Treatment Arm: Description: D i a g n o s is NCI Diagnosis Code: NCI Description: CRA Signature Diagnosis Year: Diagnosis #: R e s p o n s i b l e P a r ti e s A c c e a a i o n ln g C R A FULL NAME (P lea se Pnnt) F o llo w -U p C R A FULL NAME (P lea ts Print) D a ta E n try FULL NAME (P lease Prtnt) Date Completed: C D ' H M Date Completed: [D'CD/I Date Entered: CE'CD/I C R A A p p r o v a l S e c ti o n Approval Date: [ | | / | | | / ecopyrtght City ot Hope, P a g e 2 o t2 COH198Sv01 Rev: 07/15/2003 S 3 ■ 147 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued DIAGNOSIS RECORD Research Participant #: Participant Initials: Dx Record Protocol ID: California Cancer Consortium: Consortium Participant ID: Consortium Protocol ID: B ecau se th is Is a co m p u ter read form , please use BLACK Ink only. For data elem ents or questions requiring text responses, print in block letters avoiding contact with the edges of the boxes. P lease solidly fill bubbles for choice responses, and submit only original form s for processing. D i a g n o s is : T o h o c o m p l e t e d b y C linical R e s e a r c h A s s o c ia t e Primary Site: Histology: _ ^ D _ * Behavior Code: Differentiation: □ □ r iH... / <r * / V w Diagnosis Confirmed By: O Radiology O Lab Panel O Pathology O Clinical Impression Diagnosis Date Based On: O Radiology O Lab Panel O Pathology O Clinical Impression D ia g n o s is : T o b e c o m p l e t e d b y C a n c e r R e g is tr a r Primary Site: Histology: Behavior Code: Differentiation: □ □ / Diagnosis Date: m e y y yy Diagnosis Confirmed By: O Radiology O Lab Panel O Pathology O Clinical Impression Diagnosis Date Based On: 0 Radiology O Lab Panel O Pathology O Clinical impression D i s e n s e C h a i a c t e r i s t i c s 1. IS THIS A NEW DISEASE (de novo)? O Y e s O N o O Unknown — ^ U If No, (complete both) Secondary to treatm ent? If Unknow n, R eason: O Medical record not available O Insufficient documentation within medical record Evolved or related to a prior diagnosis? - - ► O Y e s O N o ) Yes O No X' Relates to [ Diagnosis Record #:| If Yes, specify prior diagnosis and complete another Diagnosis Record: _ 2. DOES THIS DIAGNOSIS HAVE A CONCURRENT PRIMARY CANCER OIAGNOSIS (e.g., multiple active primaries)? O Yes O I ^ If Y es, Diagnosis Group #: I I (To be completed by Data Entry •teff) '------1 concurrent diagnosis (or diagnoses): _ S i g n a tu r e s FULL NAME (P leat* Print) FULL NAME (P letM Print) D ata E n try FULL NAME (P leat* Print) ■ ©Copyright City of Hope, COH1986vOO Rev: 06/17/2003 Date Completed: Date Completed: Date Entered: P age 1 of 1 I 'Q H ' ; / [ D ' Draft S B 148 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued DIAGNOSIS DETAIL Chronic Myelogenous Leukemia Fax completed study form to: (626) 256-6656 Research Participant# (Uae OS# for outside patlanta) Participant Initials Dx R ecord #[ 0 Protocol ID 0 1 1 1 3 California Cancer Consortium: Consortium Participant ID: Consortium Protocol ID: B ecau se th is Is s com puter read form, please use BLACK Ink only. For data elem ents or questions requiring text responses, print In block letters avoiding contact with the edges of the boxes. Please solidly fill bubbles for choice responses, and submit only original form s for processing. Clinical F i n d in g s a t D i a g n o s is CML Disease Phase: O Chronic O Accelerated O Blast Crisis Complete Blood Count with Leukocyte Differential and Platelet Count O Data collection complete Date of Hematologic Findings: ‘ C D ' C P m m d d / RBC m 1 Neutrophils j HO* WBC | | [ JQ xioV Bands HO* Hgb [ [ |.J jgm /100m l (only patlanta untranafuaed within 4 waaka) I — S ag s HO* Hot L i io% (only patienta untransfuaed within 4 waaka) Eosinophils l - l I* Platelets I I I | x 103/ mL (only patients untransfuaed within 1 week) Basophils N I* Promyelocytes f in blood: L I JO* Lymphocytes IJ I* Blasts in blood: ^ 1 JO* Monocytes l - l I* Myelocytes l - l I* Metamyelocytes n o * Bone Marrow Values Promyelocytes in marrow: Blasts in marrow: Date of bone marrow aspiration: (Date of diagnosis) ]'l O Data collection complete 60289 © Copyright City of Hope P age 1 o f 3 t T p j COH2002v00 Rev: 04X39/2004 rW m m 149 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued DIAGNOSIS DETAIL Chronic Myelogenous Leukemia R e se a rc h P articip an t # tun OS# for o ut»ld» pitlentM) P articipant Initials Dx R ecord # C lin ic a l F i n d in g s a t D i a g n o s is C ontinued Physical Examination Findings W hat is/was the patient's spleen size at presentation/diagnosis? O Normal O Enlarged ----------------------- if enlarged, size: [~ O Unknown O Data collection complete cm below costal margin Did the patient have his/her spleen removed (splenectomy)? O Yes ____ O N o -► Wyes, date: /[ W as extramedullary leukemia present? O Yes -------------------► If yes, complete the following: O N o - a a yyyy CNS leukemia O Y e s O No Chloroma O Yes O No Other, specify: O Yes O N o C y t o g e n e t i c s a t D i a g n o s is NOTE: Report BCR/ABL gene rearrangement below. O Data collection complete W ere cytogenetic tests performed at diagnosis (first cytogenetic test done prior to Initial/any treatment)’ O Yes, with evaluable mitoses — ► if yes, fax copy o f cytogenetic report to COH and com plete s e ctio n s 1-3 below: O Yes, but no mitoses evaluable —► If y es, fax copy of cytogenetic rep o rt to COH and com plete se ctio n 1 only: O No O Unknown .* — ■ -------- ■ ■ "■ " ■ ■ - ---------------------------- Date of sample collection: ]/| Source of cells: O Blood O Bone marrow W as the specimen adequate O Yes for cytogenetic analysis? Q No W as Ph-chromosome t(9;22) O Yes detected at diagnosis? q no Number of m itotic cells analyzed: O Unknown Number of m itotic cells positive for Philadelphia chromosome: % Ph positive: W ere other cytogenetic abnormalities detected? O Y e s . O N o If y es, Specify karyotype: O Copyright City of Hopo P ag e 2 of 3 CQH2002v00 Rev: 04/08/2004 150 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued DIAGNOSIS DETAIL Chronic Myelogenous Leukemia Research Participant # FISH Participant Initials Dx Record (U»9 OS# for outahfo pafiantt) • m M o le c u la r T e s tin g at D i a g n o s is O Data collection complete W as FISH analysis performed at diagnosis (first FISH analysis done prior to initial/any treatment)? Source of cells: O Y e s 1 O N o O Unknown O Blood O Bone marrow Number of Interphase nuclei screened for BCR/ABL fusion gene: Oate of sample collection: Number of cells positive for BCR/ABL fusion gene: BCR/ABL I positive: I PCR W as PCR analysis performed at diagnosis (first PCR analysis done prior to Inltlal/any treatment)? Source of cells: O Data collection complete O Y e s 1 O No O Unknown O Blood O Bone marrow Date of sample I 1 I / I [ ] / i collection: | { | ' | I | / | BCR/ABL positive: O Y e s ------ ^ 1 1 1 — I — I — I (Qualitative) O N o Quantitative PCR: | | | | I | # c o p les/n g RNA W as a p 2 l0 splice detected? O Yes ------- ^ f- 0 Splice 1 0 No [_ 0 Splice 2 O Unknown F o r m C o m p le t io n I n fo rm a tio n FULL NAM E (PIm m Print) Physician Date Completed: | | ""| / | | | / | Date Reviewed: I | I / | | | / | O Copyright City o f Hope COH2O02v00 Rev: 04/09/2004 P age 3 o f 3 60289 151 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission. L A t o PRIOR DRUG TREATMENT - SINGLE AGENT Chronic Myelogenous Leukemia Fax completed study form to: (626) 256*8656 R e s e a rc h P articip an t # P articip an t Initiate: A ccessio n S e q # -. m Form * □ P rotocol ID: California Cancer Consortium only: C onsortium P articip an t ID: C on so rtiu m P ro to co l ID: B e c a u se th is Is a co m p u ter rea d form , please use BLACK ink only. For data elem ents or questions requiring text respons e s , print in Mock letters avokfing contact with the e d g es of the boxes. P lease sofidly fin bubbles for choice responses, and submit only original fo rm s for processing. P rio r A g e n t s /D r u g s P rio r d ru g tre a tm e n t includes c h e m o , horm one, o r im m uno th era p y . A gent Agent Code: Total # of 'B e st Response: courses received: ^ Q Clinical I O C yto g en etic J I 1 I I O M olecular Start Date: (first date pt received drug) Date of Best Response: m / i O Data collection complete Stop Date: (last month pt received drug) Agent Agent Code: Total # of *Best R esponse: courses received: ^ o Clinical I I I I I I O C yto g en etic I I I I_1 __I O M olecular Start Date: (first date pt received drug) CD'I Date of Best R esponse: [ D ' l Stop Date: (last month pt received drug) A gent B T otal# of courses received: m O Clinical O C ytogenetic O M olecular Agent Code: S tart Date: (first d ate pt received drug) Stop O ste: (last month pt received drug) Date of Best Response: / *See re s p o n s e c o d e s O Copyright City of Hope COH2252vOO Rev: OSC1/2003 P a g e 1 of 2 Appendix B : Continued Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission. PRIOR DRUG TREATMENT - SINGLE AGENT Chronic Myelogenous Leukemia R e s e a rc h P articip an t # A gent P a rtic ip a n t initials: A c c e ssio n [ S e q # : j P r io r A g e n t s /D r u g s (C ontinued) Agent Code: Total # of ‘Best Response: courses received: < O Clinical I I O C ytogenetic ■ < I I___ 1 I O M olecular Start Oate: (first date pt received drug) Date o f B est R esponse: m/ F orm #: Stop Date: (last m onth pt received drug) 1 1 I / I mm yyyy Stop Date: (last m onth pt received drug) M Agent A gent Code: Start Date: (first date p t received drug) T otal# of courses received: i' [ m O Clinical O C ytogenetic O M olecular Date o f B est Response: CD'C Agent: Agent Code: Start Date: (first date p t received drug) Stop Date: (last m onth pt received drug) T otal# of courses received: ‘Best R esponse: O Clinical ] O C ytogenetic J O M olecular H U M Date of Best R esponse: CD' •See response codes S i g n a tu r e s E FULL NAME (P le as* Print) D ate Completed: Date Reviewed: P hysician O Copyright City o f Hope COH2252VOO Rev: 05/01/2003 Page 2 of 2 Appendix B : Continued Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission. RESPONSE CODES 0 m • Clinical I • Clinical I 0 | • Clinical (C o m p lete C linical R em issio n ) a. W 8C < 10.000/ul b. Hemoglobin > 11.0 gm/cfl c. P latelet count < 500,000/ul e . No palpable splenom egaly Rule: To m eet definition of Complete Clinical R esp o n se criteria a and b an d c and d and e m ust b e p rese n t R I Cytogenetic (C o m p lete C y to g en etic R em issio n ) 0% Ph+ m etap h ases (minimum # of c e ls 2 0) o r * 1% by FISH (minimun of 200 cells) R i Molecular (C o m p lete M olecular R em issio n ) No d etectable bcr-abl mRNA by RT- PCR (P artial C linical R em issio n ) a. WBC > 10.000/ul but < 50,000/u! a n d 50% below p retreatm ent value b. Hemoglobin > 9.0 but < 11.0 gm/dl c. Platelet C ount > 500,000/ul d. Differential > 1% precursor cells e. Palpable splenom egaly Rule: To m eet definition o f Partial Clinica! R esponse, criteria a o r b o r c o r d o r e m ust b e present. R I Cytogenetic (P artial C y to g en etic R em issio n ) Record actual p ercen tag e of Ph+ m etap h ases o r # of interphase cells that a re positive. R ) Molecular (PartialM ofecular R em ission) N/A for C M L (C linical R e la p se ) a. P ersistent leukocytosis with im m ature form s (prom yelocytes an d blasts) in the peripheral Mood b. Extra m edullary m anifestations of th e d ise a se with docum ented P h + cells Rule: To m eet definition o f Com plete Clinical R elap se, criteria a o r b m ust b e present. R I Cytogenetic (C y to g en etic R e la p se ) a . N o hem atologic abnorm alities b. N o extra m edullary abnorm alities (e.g. chlorom as p resent) c. H ave Ph+ cells ft blood o r bone marrow, on two o r m ore o ccasions I Molecular (M olecular R e la p se ) 10x o r g reater in crease in the relative expression o f the m arker g e n e detected and confirm ed by a minimum o f 3 consecutive quantitative PC R analysis. Sam ple c an b e either blood o r bone marrow Appendix B : Continued Appendix B: Continued PRIOR DRUG TREATMENT - COMBINATION Chronic Myelogenous Leukemia Fax completed study form to: (626) 256-8656 R esearch Participant # Participant Initials: Accession Seq #: Form #: >□ Protocol ID: California Cancer Consortium; Consortium Participant ID: C onsortium Protocol ID: B ecau se this Is a co m p u ter read form , please u se BLACK Ink only. For data elem ents or questions requiring text responses, print in block letters avoiding contact with the edges of the boxes. P lease solidly fill bubbles for choice responses, and submit only original form s for processing. P rio r C o m b in a t io n A g e n t s /D r u g s P rior drug tre a tm e n t Includes ch em o , ho rm o n e, o r im m uno therapy. Regimen: J j Agent: Agent code: 0 Data collection complete Start date: (first date pt received drug) Stop date: Total # of courses received: ED'! ] Q H ' [ Best response*: m O Clinical O Cytogenetic 0 Molecular y m Date of best response: J / | y y y y Regimen: □ Agent: Agent code: Start date: Stop date: (first date pt received drug) yyyy Total # of courses received: m Best response*: Date of best response: O Clinical 0 Cytogenetic O Molecular CD' * 8 » raap o n ae c o d es F o rm C o m p le tio n In fo rm atio n CRA FULL NAM E (PiMse Pmt) P hysician (Signature) O Copyright City of Hoptj COH2251vOO Rev: 05/01/2003 Date completed: Date reviewed: Page 1 of 1 LD'CLI'L m/m/rrm m v 12419 155 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued RESPONSE CODES R e s p o n s e C o d e s C R I Clinical (Complete Clinical Remission) a. W BC< 10,000/ul b. Hemoglobin > 11.0 gm/dl c. Platelet count < 500.000/ul e. No palpable splenomegaly Rule: To m eet definition of Complete Clinical Response criteria a and b and c and d and e must be present. R • Cytogenetic (Complete Cytogenetic Remission) 0% Ph+ m etaphases (minimum # of cells 20) or 1 % by FISH (mlnlmun of 200 cells) R I Molecular (Complete Molecular Remission) No detectable bcr-abl mRNA by RT- PCR • Clinical (Partial Clinical Remission) a. WBC > 10,000/ul but < 50.000/ul and 50% below pretreatment value b. Hemoglobin > 9.0 but < 11.0 gm/dl c. Platelet Count > 500,000/ul d. Differential >1% precursor cells e. Palpable splenomegaly Rule: To m eet definition of Partial Clinical Response, criteria a or b or c or d or e m ust b e present. • Cytogenetic (Partial Cytogenetic Remission) Record actual percentage of Ph+ m etaphases or # of Interphase cells that are positive. • Molecular (PartlalMolecular Remission) N/A for CML • Clinical (Clinical Relapse) a. Persistent leukocytosis with Immature forms (promyelocytes and blasts) in the peripheral blood b. Extramedullary m anifestations of the disease with documented Ph + cells Rule: To m eet definition of Complete Clinical Relapse, criteria a or b m ust be present. • Cytogenetic (Cytogenetic Relapse) 8. No hematologic abnormalities b. No extramedullary abnormalities (e.g. chioromas present) c. Have Ph+ cells In blood or bone marrow, on two or m ore occasions • Molecular (Molecular Relapse) 10x or greater Increase In the relative expression of the marker gene detected and oonfirmed by a minimum of 3 consecutive quantitative PCR analysis. Sam ple can be either blood or bone 156 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission. -J PRIOR TREATMENT- OTHER THERAPIES Chronic Myelogenous Leukemia Fax completed study form to: (626) 256-6656 Research Participant #: Participant Initials: Accession Seq #: Form « □ Protocol ID : California Cancer Consortium only: Consortium Participant ID : Consortium Protocol ID : B e c a u se th is is a co m p u ter read form , please u se BLACK ink only. For data elem ents o r questions requiring text responses, print in block letters avoiding contact with the ed g e s o f th e boxes. P lease so6dly fill bubbles for choice responses, and submit only o riginal fo rm s for processing. P rio r T h e r a p i e s Prior Bone Marrow Transplant (?nc/ud?ng stemcell rescue) O Data collection complete Date of Transplant 1. Transplant type: O Allogeneic O Autologous O Non-Myeloablative ---------- [ I I' 2. Transplant type: O Allogeneic O Autologous 0 Non-Myeloablative --------- ► | I I' 3. Transplant type: O Allogeneic O Autologous O Non-Myeloabiative ------ ---------- [ I I' Other Treatments Description 1. _______________________ Agent Code: Stop D ate {if applicable) m/r m / i CD'I m /[ m /[ O Data collection complete Best Response* m O Clinical O Cytogenetic O Molecular m O Clinical O Cytogenetic O Molecular m O Clinical O Cytogenetic O Molecular *See R esponse C odes Pg S i g n a t u r e s FULL NAME (P to a M Print) Date Completed: Date Reviewed: P hysician ©Copyright City of Hope, COH2253vOO Rev: 04/25/2003 P ag e 1 o f 1 Appendix B : Continued Appendix B: Continued *8 if 3 8 g 158 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission. R e se a rc h P articip an t #: PRIOR TREATMENT- RADIATION Chronic Myelogenous Leukemia Fax completed study form 1o: (626) 256-8656 Participant Initials A ccessio n S e q # Form P rotocol ID C a lifo rn ia C a n c e r C o n s o r tiu m o n ly : C on so rtiu m P articip an t ID: - C onsortium P ro to co l ID: 1 1 l - l B ecau se th is is a c o m p u te r read form , please u se BLACK Ink only. For data elem ents or questions requiring text responses, print in block letters avoiding contact with the e d g es o f the boxes. P lease sofidlyfifi bubbles for choice responses, and submit only original fo rm s for processing. 1. Start Date O Involved Reid OR O Extended field 2 . Start Date mm 33 O Involved field OR O Extendedfield Stop Date yyyy if Involved: Best R esponse * I — i — | O C linical J S ? 0* O C y to g en etic w '— 1 — 1 O M olecular O Data collection complete Date of b est response: CD'I J g B L O A0 diagnosis (except lymphoma) Specify Site: _ Site Code * O Lymphoma only O Mantle O Inverted Y O Total nodal O Periaortic nodes 6 spleen O W hole abdom en O O ther_____ Stop Date Radiation yyyy If Involved: Best R esponse * I — |— j O Clinical Radsof I I * O C y to g en etic cGy O M olecular yyyy O AH diagnosis (except lymphoma) Specify Site: Site C ode* O Lymphoma only O Mantle O Inverted Y O Tota) nodal O Periaortic nodes & spleen O WtxXe abdom en O O ther______ • See R esponse C odes Page * * Use ICP-0-3 tum or site codes S i g n a t u r e s s FULLNAfcG (Please Print) Date Completed: Date Reviewed: Physician 1 M/LL/L L U / [ T J 'L © Copyright City o f Hope COH22S4vOO Rev: 05/01/2003 Page 1 of 1 Appendix B : Continued Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission. O n O RESPONSE CODES 0 \ r _I • Cfinical I 0 0 I • Clinical I 00 I • Clinical (C om plete CKnicai R em ission) a. W BC < 10,000/ul b. Hemoglobin > 11.0 gm/dl c. Platelet count < 500,000/ul e. No palpable splenomegaly Rule: To m eet definition of Complete Clinical R esponse criteria a and b and c and d and e m ust be p resen t R I Cytogenetic (Com plete C ytogenetic R em ission) 0% Ph+ m etap h ases (minimum # of cells 20) or £ 1% by FISH (mmimun o f 2 0 0 ceils) l Molecular (Com plete M olecular R em ission) No detectable bcr-abl mRNA by RT- PCR (Partial C linical R em ission) a WBC > 10.000/ul but < 50.000/ut and 50% below pretreatm ent value b. Hemoglobin > 9.0 but < 11.0 gm/dl c. Platelet Count > 500,000/ul d. Differential > 1% precursor cells e. Palpable splenom egaly Rule: To m eet definition of Partial Clin tea) R esponse, criteria a o r b o r c o r d o r e m ust b e p rese n t R I Cytogenetic (Partial C y to g en etic R em ission) Record actual p ercentage of Ph+ m etaphases or # of interphase cells that are positive. R • Molecular (P artiaM o iecu tar R em ission) N/AforCML (Clinical R elapse) a. Persistent leukocytosis with immature forms (promyelocytes an d blasts) in the peripheral blood b. Extramedullary manifestations of the disease with docum ented P h + cells Rule: To m eet definition of C om plete Clinical R elapse, criteria a o r b m ust b e present. I Cytogenetic (C ytogenetic R elapse) a . No hematologic abnormalities b. No extramedullary abrxxmafities (e.g. chlorom as present) c. H ave Ph+ cells in blood o r bone marrow, on two o r m ore o ccasions R L • Molecular (M olecular R elapse) 1 0 x or greater increase in th e relative expression of th e marker g e n e d etected and confirmed by a minimum o f 3 consecutive quantitative PC R analysis. Sam ple can be either blood o r bone marrow Appendix B : Continued Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission. Research Participant # PROTOCOL TREATMENT-DRUG AGENT Fax completed study foort to: (626) 256-8656 Participant Initials Accession Seq# m C ourse # Protocol ID California Cancer Consortium only: Consortium Participant ID : Consortium Protocol ID: B e c a u se th is Is a c o m p u te r rea d form , please u se BLACK ink only. For data elem ents o r questions requiring text responses, print in block letters avoiding contact with the e d g es o f the boxes. P lease solidly fill bubbles for choice responses, and submit onty original fo rm s for processing.________________________ _________________________ _ A g e n t s /D r u g s Intent o f tre a tm e n t I O Induction O Consolidation O Prime/Purge O Conditioning O F I O Nonmyelobtafive condRioning O M aintenance O Salvage/Rescue O Data collection complete 1. Course status: O Not Started O Started / Not Completed O Started / Completed 2 . Start Date: 3. Was this course delayed due to earlier adverse events? O Y es ONo 5 . Agent C ode Name En^e: [ £ ] / □ □ / I mm dd If CDUS, NCI Treatm ent Assignment C ode for this course: yyyy Height inches Actual body weight Actual BSA: Ideal body weight: lm2 weight Actual BSA: O e I 1 1 * 1 I n Adjusted BSA: o - Planned Dose Units Hi CCopyrigtrt City of Hope, COH1995vOO Rev: 05/01/2003 S am e As Previous C o u se ? □ □ □ □ □ □ 9 Osdoee changed per protocol guidelines 1«first course or dose same as previous course 2>dose changed, not per guidelines Page 1 of 2 O m gfcg O g m /m z O mcg/kg O ml O m g/m 2 O mcg/m 3 O mg O mg/kg O gm/m 2 O mcg/kg O ml O mg/m2 O mcg/m 2 O mg O mg/kg O gm/m 2 O mcg/kg O ml O mg/hi2 O mcg/m 2 O mg O mg/kg O gnVm 2 O mcg/kg O ml O mg/m2 O m cg/m 2 O mg O mgAfl O gm/m 2 O mcg/kg O ml O mgAn2 O mcg/m 2 O mg O m g ftg O gm/m 2 O mcg/kg O m) O mgfrn2 O mcg/m 2 O mg O mgrtcg O gm/m 2 O mcg/kg O ml O mg/m2 O mcg/m 2 O m g Dose Moddted During C ourse? ModWedDose □ □ □ □ □ □ 9 Oadose was not modified course 1«dose modified per protocol guidelines 2«dose modified, not per guidelines Units O m g O mi O g m O meg O m g O ml O g m O meg O m g O ml O g m O meg O mg O ml O g m O meg O mg O mi O g m O meg O mg O ml . O gm O meg O mg O mi O ra n O meg Appendix B : Continued Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission. PROTOCOL TREATMENT-DRUG AGENT R e se a rc h P articipant # Agent Code Name P articipant Initials A ccessio n S e q # C o u rse/E v alu atio n # A g e n t s / D r u g s C on tin u ed Planned Dose Units Sam e As Previous Course? □ □ □ □ □ □ O=do«e chan g ed p e r protocot gu ideline s c o u rse o r d o se sa m e a s pre v io u s co u rse 2>dose ch anged, n o t p e r guidelines O mg/kg O gm/m 2 O mcg/kg O ml O mg/m2 O m og/m 2 O mg O mg/kg O gm/m 2 O mcg/kg O ml O mg/m2 O m c g /m 2 O m g O mg/kg O gmAn2 O n x g A g O m l O mg/m2 O mcg/m 2 O mg O mg/kg O gm/m 2 O mcgricg O ml O mgAn2 O mcg/m 2 O mg O m g A g O gm /m 2 O m o g A g O r rd O mgAn2 O m cg/m 2 O mg O mg/kg O gm /kn2 O m cg/kg O ml O mg/m2 O meg/tn 2 O mg O mg/kg O g m /m 2 O m cg/kg O m l O mg/m2 O mcg/m 2 O mg Oose Modified During Course? Modffied Dose □ □ □ □ □ □ 9 O^doso w a s n o t m odified co u rse 1 " d o s e modified p e r pro to co l guidelines 2« d o se wodW ed, n o t p e r guid elines Units O mg O m l O gm O meg O mg O m l O gm O meg O m g O ml O gm O meg O mg O ml O gm O meg O mg O ml O gm O meg O m g O ml O gm O meg O mg O ml O gm O meg 6 . Did a n A d v e rse E v e n t ( ex p e c ted o r u n e x p e cte d ) o ccu r? O Y e s O No If Y es, com plete CTC form S i g n a t u r e s FULL NAME (P le ase Print) . ■ | m Physician Date Completed: m ' E D ' i Date Reviewed: CD'CD'I m m <M ©Copyright City of Hope. COH1995vOO R ev: 05/01/2003 Page 2 of 2 Os Appendix B : Continued Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission. O n PROTOCOL TREATMENT- RADIATION Fax completed study fonm to: (626) 256-8656 P articip an t # P articip an t initials A c c e ssio n S e q # C o u rse # , # □ Protocol ID California Cancer Consortium only: Consortium Participant ID: - ^ C o n so rtiu m P ro to co l ID: -I I I B e c a u se th is Is a c o m p u te r read form , p lea se u s e BLACK Ink o nly a n d p rin t in b lock le tters avoiding c o n ta c t w ith th e e d g e s o f th e b o x e s fo r q u e stio n s requiring tex t re s p o n s e s . P le ase solidly fiH b u b b les fo r ch o ice r e s p o n s e s . P le ase su b m it on ly original fo rm s fo r p ro ce ssin g . O Data collection complete 1. Intent of treatm ent | O Induction O Consolidation O Prim e/Purge O Conditioning O Nonmyeloblative conditioning O M aintenance O S alvage/Rescue O P alfiative Start Date E E I ' C P ' mm oo O Involved field — ► O R O Extended field yyyy If involved: Stop Date i ' I R a d s o r cgy O All diagnosis (ex cep t lymphoma) Specify Site: _ Site C ode * O Lymphoma only O Mantle O Inverted Y O Total nodal O Periaortic nodes & spleen O W hole abdom en O O th e r______ 2. Intent of treatm en t | Q Induction Q Consolidation Q Prim e/Purge O CondMorfing O NonmyeloblatTve conditioning O M aintenance O Salvage/Rescue O Pafiiatrve j Start D ate Stop Date Radiation m/f I M / mm dd yyyy Rads or cgy O Involved field OR O Extended field If Involved: O All dtegnosis (except lymphoma) Specify Site: _ Site C ode * * O Lymphoma only O Mantle O Inverted Y O Total nodal O Periaortic nodes & spleen O W hole abdom en O O th e r______ * U se 1CD-0-3 tum or site c o d e s S i g n a t u r e s FULL NAME (Pleas* Pri nt ) Physician ©Copyright City of Hope. COH2012vOO Rov:06/24/2003 Date Completed: Date Reviewed: Page 1 of 1 Appendix B : Continued Appendix B: Continued f e 1 ' R e se a rc h P articipant # DISEASE ASSESSMENT - ON STUDY Chronic Myelogenous Leukemia P articip an t Initials A ccessio n S e q # m Fax completed 9tudy form to: (628) 256-6696 Protocol 10 0 1 1 1 3 California Cancer Consortium; C onsortium P articipant ID: C onsortium Protocol ID: B ecause this Is a com puter read form , please u se BLACK Ink only. For data elem ents or questions requiring text responses, print In block letters avoiding contact with the edges of the boxes. P lease solidly A ll bubbles for choloe responses, and submit only original form s for processing. C lin ic a l R e s p o n s e CML Disease Phase Please Indicate disease phase at on study and how many of that phase the participant has experienced: O Chronic O 1st O 4th O Accelerated ------► 0 2 nd O 5th O Blast Crisis O 3rd O Data collection complete Complete Blood Count with Leukocyte Differential and Platelet Count D ate of H em atologic Findings: / RBC |___[-j l_ |x l< ftp L Neutrophils | | J * | | % WBC | | [ | . [ ] x 1 0 V Bands | | | . | | % Hob I I I ! 1 nm /rnn mi (only patients untransfused a L L I'l JgmflOOml within4 weeks) * « • i i i n % Hct L . (onty patients untransfused I I I'l I % within 4 weeks) Eosinophils | | | | | % Platelets x1C?/uL (onty patients untransfused Basophils [ j | . n % Promyelocytes I I I I I in blood: | I |» | |% Lymphocytes | | | | | % Blasts In blood: I I j [ j % Monocytes | | |. [ | % B o n e M arro w V a lu e s Promyelocytes In marrow: Blasts In marrow: O D ata c o lle c tio n c o m p le te ]-D% ] • □ * Date Of bone marrow aspiration: m /n~M P h y s ic a l E x a m in a tio n F in d in g s W as the patient's spleen removed after diagnosis? O Y e s --------------- O D a ta c o lle c tio n c o m p le te O No, spleen previously removed O No, spleen present > . If yes, date of I 1 | / I I I splenectomy: I I I • I I * . mm 3d and size prior I to removal: I 1 cm below costal j margin W es extramedullary leukemia present? O Y e s ------------------------- ^ if yes, complete the following: - O N o CNS leukemia O Yes O No Chlorome O Yes O N o Other, specify: O Yes O N o 63722 0 Copyright City o f Hope CO H 2003v00 Rev: 05/01/2003 P age 1 of 3 164 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued Research Participant # DISEASE ASSESSMENT - ON STUDY Chronic Myelogenous Leukemia Participant Initials Accession Sea # m O Data collection complete C y t o g e n e ti c R e s p o n s e NOTE: Report BCR/ABL gene rearrangement below. W ere cytogenetic tests performed during the on-study evaluation? O Yes, with evaluable mitoses — ► if yes, fax copy of cytogenetic report to COH and complete sections 1-3 below: O Yes, but no mitoses evaluable — ^ if y# it fBX co p y Qf cytogenetic report to COH and complete section 1 only: O No, cytogenetic tests were done during the on-study evaluation O Unknown Date of sample collection: J / 1_ / mm dd yyyy Source of ceils: O Blood O Bone marrow W as the specimen adequate for cytogenetic analysis? O Yes O No W as Ph-chromosome t(9;22) O Y e s detected at diagnosis? q no Number of mitotic cells analyzed: O Unknown Number of mitotic cells positive for Philadelphia chromosome: % Ph positive: W ere other cytogenetic abnormalities detected? O Y e s . O N o If yes, Specify karyotype: M olueul.ir T e s tin g Source of cells: O Blood O Bone marrow FISH W as PISH analysis performed during the on-study evaluation? O Y e s - O N o O Unknown Number of Interphase nuclei screened for BCR/ABL fusion gene: PCR Date of sample collection: O Data collection complete / [ Number of cells positive for BCR/ABL fusion gene; BCR/ABL positive: W as PCR analysis performed during the on-study evaluation? O Y e s ^ Q No Source of cells; O Unknown O Blood O Bone marrow Date collection: O Data collection complete a - m / m / i BCR/ABL positive: (Qualitative) O Y e s- O N o Quantitative PCR: | | | [ j | # c o p les/p g RNA W as a p 2 i0 splice detected? 0 Y e s -------► [O Splice 1 O No [ o Splice 2 O Unknown O Copyright City of Hope COH2003v00 Rev: 05/01/2003 P age 2 of 3 i n 165 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued ■ Research Participant # DISEASE ASSESSMENT - ON STUDY Chronic Myelogenous Leukemia Participant Initials Accession S eq # m D i s e a s e S t a tu s O Data collection complete D isease status at on-study: S ee response codes page m D isease status date: :m / i Primary method used to determine response: O Pathology O Cytogenetic O Radiology O Laboratory panel O Clinical assessm ent F o r m C o m p le tio n In fo rm a tio n FULL NAME (Pleas* Print) Physician (Signature) Date Completed: L D / H M HI/CD'I m m 3 3 Date Reviewed: O Copyright City of Hopo COH2003v00 Rev: 05/01/2003 P ag e 3 of 3 166 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued RESPONSE CODES R e s p o n s e C o d e s R • Clinical (Complete Clinical Remission) a. WBC < 10,000/ul b. Hemoglobin > 11.0 gm/dl c. Platelet count < 500,000/ul e. No palpable splenomegaly Rule: To m eet definition of Complete Clinical R esponse criteria a and b and c and d and e must be present. i Cytogenetic (Complete Cytogenetic Remission) 0% Ph+ m etaphases (minimum # of cells 20) or 1 % by FISH (minlmun of 200 cells) I Molecular (Complete Molecular Remission) No detectable bcr-abl mRNA by RT- P C R R • Clinical (Partial Clinical Remission) a. WBC > 10,000/ul but < 60,000/ul and 50% below pretreatment value b. Hemoglobin > 9.0 but < 11.0 gm/dl c. Platelet Count > 500,000/ul d. Differential > 1% precursor cells e. Palpable splenomegaly Rule: To m eet definition of Partial Clinical Response, criteria a or b or c or d or e m ust b e present. R • Cytogenetic (Partial Cytogenetic Remission) Record actual percentage of Ph+ m etaphases or # of interphase cells that are positive. • Molecular (PartlalMolecular Remission) N/A for CML R L • Clinical (Clinical Relapse) a. Persistent leukocytosis with immature forms (promyelocytes and blasts) In the peripheral blood b. Extremedullary m anifestations of the disease with documented Ph + cells Rule: To m eet definition of Complete Clinical Relapse, criteria a or b must be present. # Cytogenetic (Cytogenetic Relapse) a. No hematologic abnormalities b. No extramedullary abnormalities (e.g. chloromas present) c. Have Ph+ cells in blood or bone marrow, on two or m ore occasions R l Molecular (Molecular Relapse) 1 0 x or greater increase in the relative expression of the marker gene detected and confirmed by a minimum of 3 consecutive quantitative PCR analysis. Sam ple can be either blood or bone marrow 167 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued RlCiivot h J Hope R esearch Participant # PRODUCT EVALUATION Chronic Myelogenous Leukemia Participant Initials Accession Seq # Course# m Fax completed study form to: (626) 286-8686 Procedure # Protocol ID 0 1 1 1 3 California Cancer Consortium: Consortium Participant ID: Consortium Protocol ID: B ecau se this is a com puter read form , please use BLACK ink only. For data elem ents or questions requiring text responses, print In block letters avoiding contact with the edges of the boxes. P lease solidly fill bubbles for choice responses, and submit only original form s for processing. Procedure Date: I M j / mm dd yyyy O Data collection complete C y t o g e n e ti c R e s p o n s e NOTE: Report BCR/ABL gene rearrangement below. W ere cytogenetic tests performed? 0 Yes, with evaluable mitoses — ► If y es, fax copy o f cytogenetic report to COH an d com plete se ctio n s 1-3 below: O Yes, but no mitoses evaluable — ► if yea, fax copy of cytogenetic report to COH an d com plete sectio n 1 only: O No, cytogenetic tests were done during this evaluation period O Unknown Date of sample collection: m ' c p m m <o^ Source of cells: O Blood O Bone marrow W as the specimen adequate for cytogenetic analysis? O Yes O N o W as Ph-chromo8om e t(9;22) O Yes detected at diagnosis? q n 0 Number of m itotic cells analyzed: O Unknown Number of m itotic cells positive for Philadelphia chromosome: % Ph positive: □ » W ere other cytogenetic abnormalities detected? O Yes • O N o If y es, Specify karyotype: M o le c u la r T e s tin g FISH W as FISH analysis performed? Source of cells: O Y e s 1 O No O Unknown O Blood O Bone marrow Date of sample collection: Number of Interphase nuclei screened for BCR/ABL fusion gene: Number of cells positive for BCR/ABL fusion gene: O Data collection complete ' Q Id BCR/ABL positive: / | H © Copyright City of Hope COH2014v O O Rev: 04/09/2003 P ag e 1 o f 2 17613 ■ n r 168 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued R esearch Participant # PRODUCT EVALUATION Chronic Myelogenous Leukemia Participant Initials A ccession S eq # Course # Procedure # M o le c u la r T e s ti n g C on tin u ed E£R W es PCR analysis performed? O Data collection complete O Y e s 1 O N o O Unknown Source of cells: BCR/ABL positive: (Qualitative) O Blood O Y e s - O No Date of sample collection; m / m / ; mm <w yyyy Quantitative PCR: I I I | | | # co p ies/u g RNA W as e p210 splice detected? O Y e s -------► fO Splice 1 O No I P Splice 2 O Unknown CRA FULL NAM E {PtMM Print) Physician (Signature) F o rm C o m p le t io n I n fo rm a tio n Date Completed: m / m / ' □H'CP'l m m 3 o Date Reviewed: ©Copyright City of Hope COH2014v00 Rev: 04/09/2003 P age 2 of 2 I T 169 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued R esearch Participant# DISEASE ASSESSMENT - FOLLOW-UP Chronic Myelogenous Leukemia Participant Initials Accession S ec # m Fax completed study form to; (626) 256-6656 Course/Evaluation # Protocol ID 0 1 1 1 3 California Cancer Conaortlum: Consortium Participant ID: Consortium Protocol ID: B ecau se thla la a com puter read form, please use BLACK Ink only. For data elem ents or questions requiring text responses, print In block letters avoiding contact with the edges of the boxes. Please solidly fill bubbles for choice responses, and submit only original form s for processing. Evaluation Start Date: | j J / / Evaluation Stop Date: J | | / | / mm dd yyyy mm dd yyyy BMT Seq # [ | | Evaluation Period: O Transplant O 6 mos O 1 yr O 1 .5 yrs O 3 yre O 3,5 yrs O 4 yrs O 4.5 yrs C lin ical R e s p o n s e 0 2 yrs 0 2.5 yrs O 5 yrs CM L D is e a s e P h a s e P lease Indicate disease phase at follow-up and how many of that phase the participant has experienced: 0 Chronic 0 1 st 0 4 t h O Accelerated ___ O 2nd 0 5 t h O Blast Crisis 0 3rd O Data collection complete Complete Blood Count with Leukocyte Differential and Platelet Count D ate of H em atologic Findings: C D ' C p mm od R 0C Q | [ | xIofypL Neutrophils | j | . ( | % w e c m i i . r u v Bands | | | . | | % n l .l u < > o mi Segs | | | . | \ % Hct 1 (onfypalbnts untransfuaed [_. 1 1*1 1 ™ wtthln 4 weok*) Eosinophils | | | _ | | % Platelets xlfftyuL (only patients unlrantfuaod Basophils | | 111 | % Promyelocytes I I I I 1 in Wood: L i I * I I % Lymphocytes | j | _ | | % Blasts In blood: | J | * | I % Monocytes j | | J | % Bone Marrow Values Promyelocytes In marrow: Blasts In marrow: Physical Examination Flndlnge W as the patient's spleen removed during this evaluation period? O Yes — ..................... If yes, date of splenectomy: O No. spleen previously removed ^ O No, spleen present W as extramedullary leukemia present? O Yes ......— ► If yes, complete the following: O N o O Data collection complete Date of bone marrow aspiration: / m / i yyyy O Data collection complete ] / ad and size prior to removal: 1 cm below costal J margin O Copyright City of Hope COH2013V00 Rev: 04/09/2003 CNS leukemia 0 Yes O No Chloroma 0 Yes O No Other, specify: O Yes o No P age 1 of 3 52374 170 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued DISEASE ASSESSMENT - FOLLOW-UP Chronic Myelogenous Leukemia □□ □ □ □□ □ □□ □ m i □ □ □ O Data collection complete NOTE: Report BCR/ABL gene rearrangement below. W ere cytogenetic tests performed since the prior evaluation period? O Yes, with evaluable m itoses — ► if yea, fax copy of cytogenetic report to COH a n d complete sections 1 -3 below: O Yes, but no mitoses evaluable — ^ if yea, fax copy of cytogenetic report to COH and complete section 1 only: O No, cytogenetic tests were done during this evaluation period O Unknown s " ’ 1 ----------------- ----------------------------------------------------- Date of sample 1 j 1 / 1 collection: j | | / | / mm d yyyy Source of cells: O Blood O Bone marrow W as the specimen adequate for cytogenetic analysis? O Yes O N o W as Ph-chromosome t(9;22) O Yes detected at diagnosis? q n 0 Number of mitotic cells analyzed: O Unknown Number of mitotic cells positive for Philadelphia chromosome: % Ph positive: • D a Were other cytogenetic abnormalities detected? O Yes • O N o If yes, Specify karyotype: M o le c u la r T e s ti m j FISH W as FISH analysis performed since the prior evaluation period? O Y e s 1 O No O Unknown Source of cells: O Blood O Bone marrow Date of sample collection: Number of interphase nuclei screened for BCR/ABL fusion gene: Number of cells positive for BCR/ABL fusion gene: O Data collection complete D/[ ■ 3 d BCR/ABL positive: PCR W as PCR analysis performed since the prior evaluation period? O Y e s + ^ q Source of cells: O Blood O Unknown O Bone marrow Date of sample collection: O Data collection complete m / m / BCR/ABL positive: O Y e s- (Qualitative) q No O Copyright City of Hope COH2013v00 Rev; 04/0ftT2003 Quantitative PCR: # co p les/p g RNA W as a p210 splice detected? 0 Y e s -------► [ 6 Splice 1 O No [ 0 Splice 2 0 Unknown 52374 P ag e 2 of 3 171 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued R esearch Participant # DISEASE ASSESSMENT - FOLLOW-UP Chronic Myelogenous Leukemia Participant Initials Accession S ea # Course/Evaluation # m R esponse code: S a e re sp o n se c o d e s p ag e R esponse date: R e s p o n s e m / m m m or O Data collection complete Primary method used to determine response: O Pathology O Cytogenetics O Radiology O Laboratory panel O Clinical assessm ent F o r m C o m p le t io n I n f o r m a tio n CRA FULL NAM E (PtoaM P rffH ) P hyalclan Date Completed: m / m / i C D ' E P ' 1 mm oa Date Reviewed: O Copyright City of Hope COH2Q13vOO R ev: 04/09/2003 P age 3 of 3 h 7 T 172 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued RESPONSE CODES R e s p o n s e C o d e s R • Clinical (Com plete Clinical R em ission) a. WBC < 10,000/ul b. Hemoglobin > 11.0 gm/dl c. Platelet count < 500,000/ul e. No palpable splenomegaly Rule: To m eet definition of Complete Clinical R esponse criteria a and b and c and d and e must be present. • Cytogenetic (Com plete C ytogenetic R em ission) 0% Ph+ m etaphases (minimum # of cells 20) or 1 % by FISH (mlnlmun of 200 cells) R • Molecular (Com plete M olecular R em ission) No detectable bcr-abl mRNA by RT- PCR • Clinical (Partial Clinical R em ission) a. WBC > 10,000/ul but < 50,000/ul and 50% below pretreatment value b. Hemoglobin > 9.0 but < 11.0 gm/dl c. Platelet Count > 500,000/ul d. Differential > 1% precursor cells e. Palpable splenomegaly Rule: To m eet definition of Partial Clinical R esponse, criteria a or b or c or d or e must be present. • Cytogenetic (Partial C ytogenetic R em ission) Record actual percentage of Ph+ m etaphases or # of Interphase cells that are positive. I Molecular (PartlalM otecular R em ission) N/A for CML L • Clinical (Clinical Relapse) a. Persistent leukocytosis with Immature forms (promyelocytes and blasts) In the peripheral blood b. Extramedullary manifestations of the disease with docum ented Ph + cells Rule: To m eet definition of Complete Clinical Relapse, criteria a or b must be present. • Cytogenetic (C ytogenetic Relapse) a. No hematologic abnormalities b. No extramedullary abnormalities (e.g. chioromas present) c. Have Ph+ cells in blood or bone marrow, on two or m ore occasions • Molecular (M olecular R elapse) 1 0x or greater increase in the relative expression of the marker gene detected and confirmed by a minimum of 3 consecutive quantitative PCR analysis. Sam ple can be either blood or bone marrow 173 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission. APHERESIS PERIPHERAL STEM CELL AND CD34+ CELL COLLECTION P ro to co l# : C o H 0 1 1 1 3 P atient I n itia ls :___________ M.R. #: ____________ Diagnosis: ____________ W eight/kg: ____________ . k g BMT S e q N u m b er P atien t's Physician: Priming: G -C SF d o se : O ther Agent: 01 C o u rse N u m b e r CD 34+ R e q u e ste d : Min C D 34+ R eq u e ste d : No. o f R einfusions: A g en t C ode: Procedure Date Procedure Number Product Number Cefl Doseftg 10s to date C034-Mcg xltf* Total 0034**9X 10“ to date Cryopreserved WBC/kgxiO* CD34+Agx10* 1 2 3 4 5 6 7 8 9 1 0 11 1 2 13 14 1 5 TOTAL W BC CELL YIELD x 1 0 TOTAL W BC CELLS/KG _____ _____ x 1 0 ® TOTAL C D34+ CELLS _____ x 1 0 7 TOTAL C D34+ CELLS/kg bw _____ _____ x 1 0 * CRA D ate # O F BAGS CR Y O PRESERV ED_____ i Physician D ate Form: X2011 Version: 4.16.03 -■ 4 Appendix B : Continued Appendix B: Continued COUNT RECOVERY Chronic Myelogenous Leukemia Fax completed study form to: (626) 256-8666 R esearch Participant # fuse OS# tor outside pedants) Participant Initials Accession I I I S e q # I I I Course/ Evaluation # Protocol ID 0 1 1 1 3 California Cancer Consortium: Consortium Participant ID: Consortium Protocol ID: B ecau se this is s com puter read form , please use BLACK Ink only. For data elem ents or questions requiring text responses, print in block letters avoiding contact with the edges of the boxes. P lease solidly 6 1 1 bubbles for choice responses, and submit only original form s for processing. Com plete th is form for e a ch c o u rse of induction chem otherapy. Course: 1 st course of Hydroxyurea @ 3 .5 gm/rr? 2nd course of Hydroxyurea @ 4.5 gm/m2 Nadir* C ount D O Data collection complete 1. Lowest (nadir) WBC x10 /pL 2. Lowest (nadir) ANC x10 /pL □ m / L D / D I I I I/I I I/I ' Nadir counts are recorded after each course of treatment with Hydroxyurea. Additional details about this treatment are found on the Protocol Treatment form. 1. Recovery of erythropolesls was: 2. Recovery of granulopoiesis was: R e c o v e ry of H c in o to p o ie s is O Complete O Partial O None O Complete O Partial O None Date ANC (neutrophils) were >500 xIO /pL 3 Date ANC (neutrophils) were >1000 x10 /pL 3. Recovery of megakaryopolesis was: Date untranBfused platelets >25 x1<7*/pL Date untransfused platelets >50 xlcftpL Date untransfused platelets >100 xIofyjL m/Qj/c ra/m/r mm dd yyyy O Complete O Partial O None LU'm'L □ '□C m/m/r O Data collection complete O Not achieved O Not achieved O Not achieved O Not achieved O Not achieved F orm C o m p le tio n In fo rm a tio n CRA PULL NAME (Please Print) Physician (Signature) Date Completed: ED'CH'I m ™ Date Reviewed: O Copyright City of Hope COH2004v00 Rev: 03/24/2003 P age 1 of 1 175 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued a J g t y o f U P N □ □ □ □ HEMATOPOIETIC CELL TRANSPLANT INTAKE MODULE -I,— I r - n o f f s i t e * . INI I n s t i t u t i o n P t ID #: . O ff S ite * I n s titu tio n * C O H # : l Ml 1 1 1 I n s titu tio n : ID #: P a t i e n t s N a m e : D a te o f T r a n s p l a n t : / B M T S e a # : 1 1 I L ast, First Mi mm dd y y y y S al eel prim ary d iagnosis, then ch eck appropriate d is e a s e s tatu e from th e related colum n to th e right. AML ALL APL BPL/BAl OX: S ta tu s : IF _ 1CR 2CR 3CR >4CR 1PR 2P R 3P R 1RL HD LBL NHL OX: S ta tu s : 1CR 2CR 3C R >4CR IF P P PR 1RL 2RL 3RL >4RL OX: CLL I S ta tu s : CR nP R PR Stable P rogressive Not Eval Unknown CML C OX: S ta tu s : ( • 2 ) ( - 9 ) IF 1C P 2C P >3C P 1AP 2AP 1BC ___ If other, specify: OX: M D8 □ RA RARS RAEB CMML-t RAEB-t B reast MM O varian SAA Testicular O ther If in R elapse: "W S R * N ote: D ise a se S tatu s not applicable for Multiple M yeloma. S e v e re A plastic A nem ias, solid tum ors (excluding lym phom as), and A utoim m une d ise a se . TRA N SPLA N T TYPE; 1 "A llogeneic 2>A utotogous IF ALLOGENEIC, DONOR I I SO U R C E: 1 "S y n g en eic 2-Slbllng 3»M atched R elated 4 »M atched U nrelated THERAPY T YPE: I I 1-BM T 2-H D C T with Re-infuslon 3 -H D C T w ithout Re-lnfuslon 4 -D o n o r L eukocyte Infusion 6-N on-m yeloablatlve 7 -T an d em Material • B one Marrow » Peripheral stem cad • C ord Blood • D onor L eukocytes CONDI HONING HI.GIMt' M an ip u latio n • Prim ing • Purging • Cell Selection « G en e T herapy A g en t t VP-16 • Cytoxan • IL-2 • G -CSF Therapy ♦ CD-34 ♦ T-Oepletkwi ♦ G e n e T herapy (Description) CONDITtONING REGIMEN/HIGH D O SE CHEMOTHERAPY. NAME: AGENT CODE: (To be completed bv BkMtatlftlce) _______________ I I I I I N I GVHD PR O f’HYl AXIS GVHO PROPHYLAXIS (A llo g en eic only): I i I NAME: AGENT CODE: (To be completed bv Bloetatlsttoe) I I I I i L - L - L - i - . - ] I I I I I * Shaded a r e a s n o t e n te r e d Into BITS, fo r data c o lle ctio n only. COHH00v02.doc C City of Hope National Medical Center HCT Intake: Page 1 of 2 Version: 07/25/2003 176 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued Fir i g ty °f M M Hope UPN □ □ □ □ HEMATOPOIETIC CELL TRANSPLANT INTAKE MODULE PATIENT NAME: PATIENT MR*: PATIENT DOB: PATIENT SEE PREVIOUS PAGE SEE PREVIOUS PAGE _ / /___ i dd yyyy I’ATILNT / DONOR INFORMATION DONOR NAME: OONOR MR*: DONOR DOB: GENDER: I I M»Male F»Female (Circle) (Circle) H E I G H T : ___________in /cm W E IG H T .___________ lbs /Kg BLOOD OROUP: I I Rh FACTOR: I I 1«A 0-Negative 2=8 1 -Positive 3*AB 4«0 CMV: Negative Positive H DONOR (Allogeneic only) I I ___ mm dd yyyy GENDER: ( i M-Mele F-Female If donor it female, indicate perH y: 0 Pregnancies | | i t Pregnancies I I BLOOD GROUP: 1-A 2»B 3«AB 4 -0 0-Negative 1-Positive CMV: Negative Positive Bloetatletlcs Diagnosis Sequence *: |~' | | j | j Transplant Confirmed: Q O 1 1»yes Nurse Coordinator: Ordering Physician:^ Data Entry: Date Completed: Date Reviewed: Date Entered: / /_ mm dd yyyy 0 City o( Hop* NiOon* Caniar HCT Imak* Page 2 erf 2 177 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued ENGRAFTMENT Fax completed study form to: (626) 156-8656 Research Participant # Participant Initials BMT Seq # Protocol ID California C ancer C onsortium : Consortium Participant ID Consortium Protocol ID B ecause th is Is a com puter read form, please use BLACK Ink only. For data elem ents or questions requiring text responses, print In block letters avoiding contact with the edges of the boxes. P lease solidly fill bubbles for choice responses, and submit only original form s for processing. THIS FORM COVERS THE PERIOD FROM DAY 0 TO DAY 100 POST BMT: Date of Transplant: Day 100 Post BMT: yyyy R ecovery of H em atopolesls 1. Recovery of erythropoiesls was: O Complete O Partial O None 2. Recovery of granulopoiesis was: O Complete O Partial O None 3 Date ANC (neutrophils) w ere >500x10 /pL I i I'l I M Date ANC (neutrophils) w ere >1000 x103 /pL I I I'l I |/| mm dd yyyy 3. Recovery of megakaryopolesis was: O Complete O Partial O None Date untransfused platelets >25 xl03 /pL I I |/| i i'l 3 Date untransfused platelets >50 x10 IpL I I |/| i i'i Date untransfused platelets >100x10%L I I M i i'i I O D ata collection co m plete O Not Achieved O Not Achieved O Not Achieved O Not Achieved O Not Achieved dd 4. Overall Evaluation of Hematopoietic Engraftment (select only one): O A. Stable engraftment definitely occurred O B. Patient achieved a stable graft & then ____ lost the graft O C. Engraftment never occurred O D. Not certain w hether engraftment occurred (Note: Do not use relapse as sole criterion for graft failure) ^ D a te g r a f t lost a s fTl / fH I I confirmed by V K JT dd— y physician: 2. In the treating physician's opinion, the cause w as: (select only one) O a. Not known O b. Due to graft rejection O c. Due to non-lmmune fa c to rs p- |fYe»: (select all that apply) O 1. S epsis O 2. Myelotoxic drugs O 3. Other, specify F o rm C o m p le tio n In fo rm atio n CRA FULL NAME (Pleas© Print) Physician (Signature) Date Completed: I Date Reviewed: ] ' I L L ©Copyright City of Hope, C O H 2005v00 Rev: 03/24/2003 P age 1 o f 1 E e S ■ 178 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued PRE-EXISTING CONDITIONS Fax completed study form to: (626) 256-8656 R e se a rc h P articip an t #: P articipant Initials: A ccession | j | S e q #: Form * □ P rotocol ID: California Cancer Consortium: Consortium P articipant ID: Consortium Protocol ID: B ecau se th is Is a com puter read form , please use BLACK Ink only and print In block letters avoiding contact with the edges of the boxes for questions requiring text responses. P lease eolldly fill bubbles for choice responses. P lease submit onlyorlginal form s for processing. P ro -E x istin g C o n d itio n s D o es th e patien t h a v e pre-existing c o n d itio n s? ^ Y es O No Toxicity Code* Toxicity (describe) 1 1 i I ‘Sam e a s CTC toxicity codes 1 FULL NAME (P leau Print) □ □ □ □ □ □ □ □ □ □ I S ig n a tu re s P h y sic ia n (Signature) Date Completed: Date Reviewed: O Data collection complete C om m ents I Other, specify “ Grade: use 0-5 1 1 1 / 1 |/| mirnc © Copyright City of H ope, COH1993vOO Rev: 03/24/2003 P age 1 of 1 179 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued City of Hope National Medical Center CTC Version 2.0 Toxicity Collection Form (Adapted from National Institute of Health: National C ancer Institute CTC V2.0) BMT ONLY IN STITU TIO N : Protocol # : ______ COH and/or R esearch P a rtic ip a n t# : _ Other Institution, SPECIFY: Seq. No.: C onsortium ID #: _ C o u rs e # /C y c le # : Start D ate: /__ P a rtic ip a n t’s In itials: Day 3 0 0 6 0 0 9 0 0 1 0 0 0 1 5 0 0 1 8 0 0 240 0 270 0 360/363 (lyr) 0 73Q (2yr)0 l095(3yr)O Stop Date: / /______ CTC Publish Date: / /________ dd yyyy dd yyyy Category /Code Toxlcltv w P r» B tfrp fE v tn t AHrih. t Grade utlon* h, > Report« DLT? ULLL gAE? DateSAE Submitted bv CRA** ALLERGY/IMMUNOLOGY Toxicity Code: __________ Yea g No 0 Toxicity "If Yea", complete the following: ._ /_____ /____ J___/_ _ / _____/___ J_ _ /__ _/_ _ /__ n d d yyyy Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N - - - ---1 Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N mm d d yyyy AUDITORY/HEARING Toxicity Code: Yea 0 No □ "If Yea", complete the following: Toxicity /_ /_ /_ /_ __________________ l_ m m dd yyyy •Attribution Key: Unrelated 1 The adverse event (toxicity) is not related to the protocol. Unlikely 2 The adverse event (toxicity) Is doubtfuBy related to the protocol. Possible 3 The adverse event (toxldty) may be related to die protocol. Probable 4 The adverse event (toxicity) is likely related to the protocol. Definite S The adverse event (toxldty) is dearly related to the protocol. t Grade: Use 0-6 * Refer to protocol for definition of reportable AE. Circle Appropriate response— Y(yea) or N(no) * * If ADEERS, enter dale submitted to Data Coordinating Center (for consortium) or Pi (non-consortium) * * * Circle appropriate response— Y(yes) or N(no) COH 1098 (DIS Version 06.01,09/25/2003) O City of Hope. January 1997 P ag e 1 of 10 180 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued P ro to c o l #: R e s e a rc h P a rtic ip a n t #: _ BMT ONLY S e q . # : _______ P a rtic ip a n t's In itials: C o u r s e # / C y c le # : Day: Category /Code “ Pro- “ “ f 1 Grade Attrib ution* * * * Report- DLT able 1 9AE? Pate 8 AE Submitted bv CRA** BLOOD/BONE MARROW Yes n No □ “If Yee", com plete the following: Toxlolty Code: Toxldty 10018676 Hemoglobin (Hgb) / / Y N Y N Y N 90004010 Hemoglobin (Hgb) for leukemia ____ 1 ____ /____ Y N Y N Y N 10024286 Leukocytes (total WBC) _ / / Y N Y N Y N 90004014 Leukocytes (total WBC) for BMT „ / _ / „ Y N Y N Y N / / 90004022 Leukocytes (total WBC) for Pediatric BMT ____ /____ /____ Y N Y N Y N ______/______ /___ 10029363 Neutrophils/granulocytes (ANC/AGC) ____ /____ 1 ____ Y N Y N Y N _ / L . . 90004006 Neutrophils/granulocytes (ANC/AGC) for BMT / / Y N Y N Y N _ _ / ______/_ Neutrophils/granulocytes (ANC/AGC) for 90004008 Leukemia ____ 1 ____ /____ Y N Y N Y N ______/______ /_ _ 10035528 Platelets / / Y N Y N Y N 90004026 Platelets for BMT ____ /____ /____ Y N Y N Y N ____ 1 ____ / _ _ 90004020 Platelets for leukemia / / Y N Y N Y N 10035543 Transfusion: platelets / / Y N Y N Y N / / 90004004 Transfusion: platelets for BMT / / Y N Y N Y N 1 I 10033359 Transfusion: pRBCs ____ /____ /____ Y N Y N Y N J _ J 90004016 Transfusion: pRBCs for BMT ____ /____ /____ Y N Y N Y N __ / /___ 90004134 Failure to engraft ____ /____ /____ Y N Y N Y N ---------1 --------- /— 90004132 Stem cell Infusion complications ____ /____ /____ Y N Y N Y N ______/______ /___ 10025327 Lymphopenia ____ /____ /____ Y N Y N Y N ____ /____ /_ _ „ / / Y N Y N Y N Y N Y N Y N C om m ent*: BMT COMPLEX Yee Q No 0 "If Yee", com plete the following: Toxicity Code: Toxicity 10018651 Graft versus host disease (GVHD) / / Y N Y N Y N / / C1000 Acute graft versus host disease (AGVHD) / / Y N Y N Y N / / C1001 Chronic graft versus host disease (CGVHD) *• ____ /____ /____ Y N Y N Y N Y N Y N Y N Y N Y N Y N ____ /____ /_ _ Comment*: m m dd yyyy m m d d yyyy ** Chronic QVHO: 2 ■ Limited, 4 ■ E xtenek* 6 ■ Oeeth, (Oo not um 1 of 3} •Attribution Key: Unrelated 1 The adverse event (toxldty) Is not related to the protocol. t Grade: Use 0-5 Unlfcely 2 The adverse event (toxicity) Is doubtfuty related to the protood. Refer to protocol for definition of reportable AE. Circle Possible 3 The adverse event (toxicity) may be related to the protocol. Appropriate response— Y(yes) or N(no) Probable 4 The adverse event (toxicity) is likely related to the protocol. If ADEERS. enter date submitted to Data Coordinating Definite 5 The adverse event (toxicity) is clearly related to the protocol. Center (for consortium) or Pt (non-consortium) * * * Circle appropriate response— Y(yes) or N(no) COH 1098 (DIS Version 06.01.09/25/2003) O City of Hope, January 1997 P age 2 of 10 181 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued P ro to c o l # : _______________ P a r tic ip a n t's I n itia ls :____ R e s e a rc h P a rtic ip a n t # : . C o u rs e # I C y cle # : ____ D ay: _ BMT ONLY ^ □ □ L D S e q . # : _______ C a te g o ry /Cotje l£ [fc T o x lcltv PatSgfEYSnl Extetlno I ELI afels 2 g r a d e a ilS tL j S S E ? 'R eport- Date 8AE S u b m itte d f e y SPA** CARDIOVASCULAR (ARRHYTHMIA) T o x ic ity C o d e : Yes □ No □ “If Yes", com plete th e following: T o x icity J 1 Y N — Y N Y N / J . / /____ Y N — - Y N Y N / U - . ____ /____ /____ Y N Y N Y N ____ /____ /____ ____ /____ /____ Y N Y N Y N _ / J ____ /____ /____ Y N Y N Y N „ / / ____ /____ /____ Y N Y N Y N 1 1 CARDIOVASCULAR (GENERAL) Yes □ No □ “If Yes", com plete th e following: J L Toxicity Code: Toxicity 10028600 Cardiac-ischem la/infarctlon 10024119 Cardiac left ventricular function 10021099 Hypotension 10020782 Hypertension 10030114 Edem a Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N COAGULATION Yes □ No P “If Y es", co m p lete th e following: T o x ic ity C o d e : T o x icity 10013442 Disseminated Intravascular Coagulation (PIC) ... Y N Y N Y N Y N Y N mm dd yyyy Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N •A ttribution Key. Unrelated Unlikely P ossible P robable Definite 1 T h e a d v e rse e v en l (toxicty) (s not related to th e protocol. 2 T h e ad v e rse e v en t (toxldty) Is d o ubtfuly related to th e protocol, 3 T he a d v e rse ev en t (toxicity) m ay b e related to th e protocol, 4 T h e a d v e rse ev en t (toxldty) Is likely related to th e protocol. 5 T h e a d v e rse e v e n t (toxldty) Is d e a rty related to th e protoool. t G rade: U se 0 -5 R efer to protocol for definition of reportable AE. Circle A ppropriate re sp o n se —Y(yes) o r N(no) ** If A DEERS, en ter d a te subm itted to D ata C oordinating C enter (for consortium ) o r PI (non-consortium ) *** C ird e appropriate r e s p o n s e — Y(yes) o r N (no) COH 1098 (DIS Version 06,01,09/25/2003) © City of Hope, January 1997 P age 3 of 10 182 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued Protocol # :_______ Participant's Initials: Research Participant # '■________________ Course # I Cycle # : _____ _____ Day:. BMT ONLY Seq. # :_____ 'R tngll- DateSAE ^ Submitted bv I SAEx_________ CRA** C a te g o ry f ^ o d o * Pro- Toxloltv D a te o fE v o n f E d i t i n g 1 t Attrib- Grade UllfiQ! CONSTITUTIONAL SYMPTOMS Toxicity Coda: 10016256 Yes □ N o Q "If Y es”, co m p lete the following; Toxicity Fatigue 10047695 Weight loss Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N OERMATOLOOY/SKIN Toxicity Code: Yee □ No □ Toxicity "If Yes", com plete the follow ing; 10001760 Alopecia 1 / Y N 10012457 Rash/desquam atlon j /____ Y N 90004040 Rash/dermatitis associated w/hlgh dose chemo or BMT studies / / Y N 90004044 Rash/desquam atlon a sso ciated w/GVHDfor BMT studies / / Y N 10046749 Urticaria (hives, welts, w heals) 1 1 Y N 10022096 Injection Site Reaction / / Y N /_ L _ Y N ____ L J _ Y N - J J Y N C o m m tn ir m m dd yyyy ENDOCRINE Toxicity Code: Yes Q No Q "If Yes", com plete the following: Toxicity ____ 1 ____ /____ Y N ____ /____ /____ Y N ____ /____ /____ Y N C o m m in U : m m dd yyyy Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N I_____I____ Y N j_____ /____ Y N _____ /____I____ Y N ______/___ I____ Y N ______I___ I____ Y N ____ ,_/____I____ Y N I_____ /____ Y N I_____ /____ Y N I_____/____ mm d d yyyy Y N Y N Y N Y N Y N Y N I __/__ /____f____ / I __ mm dd yyyy •Attribution Key: Unrelated Unlikely Possible Probable Definite 1 The adverse event (toxicity) Is not related to the protocol, 2 The adverse event (toxldty) la doubtfully related to the protocol. 3 The adverse event (toxldty) may be related to the protocol. 4 The adverse event (toxldty) Is likely related to the protocol. 5 The adverse event (toxicity) is dearly related to Vie protocol. t Grade: Use 0*5 * Refer to protocol for definition of reportable AE. Circle Appropriate response— Y(yes) or N(no) * ’ If ADEERS, enter date submitted to Data Coordinating Center (for consortium) or PI (non-consortium) * * * Cirde appropriate response— Y(yes) or N(no) COH 1098 (OIS Version 06.01. 09/25/2003) Q City of Hope, January 1997 P age 4 of 10 183 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued Protocol # :________________ Research Participant #:. BMT ONLY U P N D C D D P a rtic ip a n t's I n itia ls : C o u rs e # I C y cle # : _______________ D a y :___________ S e q ._# : _______ S g g t Mtllt B titiiU ym t s j B ^ (jg jjjji S t flT* aflSjgjjua GASTROINTESTINAL Yea □ N o Q “If Y es”, com plete th e following: Toxicity Code: Toxicity 10002646 Anorexia / / Y N 10012174 Dehydration ____ I____ /____ Y N 90004048 Diarrhea (pts with colostomy) ____ 1 ____ /____ Y N 10012745 Diarrhea (pts w ithout colostomy) / /____ Y N 90004052 Diarrhea a sso c ia te d w/GVHDfor BMT 1 i Y N 90004056 Diarrhea for Pediatric BMT _ _ J ____ 1____ Y N Dysphagia, esophagitis, odynophagia 10030220 (painful swallowing) ____ / _ _ / ____ Y N 10048899 Dysphagia-esophapeal related to radiation / / Y N 10028813 N ausea ____ /____ /____ Y N 10042128 Stomatitis/pharyngitis / 1 Y N Stomatitis/pharyngitis for BMT 90004054 (oral/pharyngeal mucositis) 1 i Y N 10047706 Vomltlnp l i Y N 10010774 Constipation ____ I____ /____ Y N 10013948 Dyspepsia/heartburn / / Y N ____ /____ /____ Y N ____ /____ I____ Y N ____ /____ I____ Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N mm dd yyyy mm dd yyyy HEMORRHAGE Toxicity Code: 90004060 10018968 Y et 0 No 0 “If Y e t1 ', com plete the following: Toxicity Hemorrhage/bleeding w ith grade 3 or 4 thrombocytopenia__________________________ ______ Hemorrhage/bleeding w ithout grade 3 or 4 thrombocytopenia J V N □ □ I _ _ I __ /_ _ /__ I _ _ I __ /_ _ I __ mm dd yyyy Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N J__ /_ . J ____/_ J ____ /_ J ____/_ J ____/_ •Attribution Key: Unrelated Unlikely Possible Probable Definite 1 The adverse event (toxldty) is not related to the protocol. 2 The adverse event (toxldty) is doubtfully related to the protocol. 3 The adverse event (toxicity) may be related to the protocol. 4 The adverse event (toxldty) Is likely related to the protocol. 5 The adverse event (toxicity) is dearty related to the protocol. t Grade: Use 6-6 * R efer to protocol for definition o f rep o rtab le A E. Circle A ppropriate re sp o n se —Y(yes) o r N (no) ** If A D EERS, e n te r d a te subm itted to D ata Coordinating C en ter (for consortium ) o r PI (non-consortium ) *** Circle appropriate re sp o n se —Y (yes) o r N(no) COH 1098 (DIS Version 06.01,09/25/2003) ©City of Hope, January 1997 P ag e 5 of 10 184 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued Protocol # :________________ Research Participant # :. B M T O N LY Participant's Initials: Course # / Cycle # _: _______________Day: Seq. #: C*CQd0V_______________________ IggJcltY____________ P tfttfE v M l E y Qr^ fl ^ fii S S w f t o HEPATIC Yes G N o O "If Yes", com plete th e following Toxicity Code: Toxicity 10005384 Bilirubin ____ 1 ____ I____ Y N Y N Y N ____ I____ /____ 90004064 Bilirubin associated w/ GVHD for BMT ____ /____ /____ Y N Y N Y N ____ /____ /____ 10003461 SGOT (AST) / Y N Y N Y N ____ t _ J ____ 10001551 SGPT (ALT) / / Y N Y N Y N ____ _____ /____ 10005313 Alkaline Phosphatase ____ 1 ____ /____ Y N Y N Y N /____ /___ C1000 Acute graft versus host disease (AGVHD) ____ 1 ____ /____ Y N Y N Y N ____ / _ / _ C1001 Chronic graft versus host disease (CGVHD) . _ J _ J ____ Y N Y N Y N j i 10052612 Veno-occluslve disease (VOD) L J Y N Y N Y N / _ J _ 10018651 Graft vs. host d isease Weight galn-veno-occluslve disease (VOD) for ____ /____ /____ Y N Y N Y N / 90004036 BMT (under constitutional symptoms) _ / J _ Y N Y N Y N J ___ 10020942 Hypoalbumlnemla ____ /____ / Y N Y N Y N ____ /____ / _ 1 i Y N Y N Y N / / _ . ____ t____ /____ Y N Y N Y N ____ /____ /____ mm dd yyyy mm dd yyyy INFECTION/FEBRILE NEUTROPENIA Yes □ No □ “If Yes", com plete th e following: Toxicity Code: 10007810 Toxicity Catheter-related infection 10010288 Febrile neutropenia (fever of unknown origin without clinically or mlcroblologlcally documented Infection. (ANC <1.0 x 10®/L. fever > 38.5) 90004070 Infection (documented clinically or micro- biologlcally) with grade 3 or 4 neutropenia (ANC < 1.0 x 10®/L) 10021842 Infection without neutropenia 90004066 Infection with unknown ANC 90004068 Infection, other (specify) C1003 Bacterial Infection C1004 Viral Infection C1005 Fungal Infection J L Y N Y N I __/_ _ __ / _____ /______ /__I_ _ /____ /_____ I __I_ _ /__/_ _ mm dd yyyy □ □ □ □ Y N Y N Y N Y N Y N — Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N — Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N J L. _/____ /__ J ____ I____ J ____ /____ _/____ I__ J ____/____ _ /__/__ _/_____/__ J__/__ J__/__ <w yyyy •Attribution Key: Unrelated Unlikely Possible Probable Definite 1 The adverse event (toxicity) is not related to the protocol. 2 The adverse event (toxldty) Is doubtfuly related to the protocol. 3 The adverse event (toxldty) may be related to the protocol. 4 The adverse event (toxldty) Is likely related to the protocol. 5 The adverse event (toxldty) is dearly related to the protocol. COH 1098 (DIS Version 06.01. 09/25/2003) © City of Hope, January 1997 t Grads: Use 0-5 Refer to protocol for definition e rf reportable AE. Circle Appropriate response— Y(yes) or N(no) * * If ADEERS, enter date submitted to Data Coordinating Center (for consortium) or PI (non-consortium) •** Circle appropriate response— Y(yes) or N(no) P age 6 of 1 0 185 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued P ro to c o l #: R e s e a rc h P a rtic ip a n t #: BMTONLY P a r tic ip a n t's In itials: C o u rs e # / C v cle # : Day: S e a . #: Category /Coda **• Pre-. Tntflrltv Date of Event Exlstlna i Grade Aft rib- uflop* "* fRenort- DLT able 2 StEL DateSAE Submitted bv CRA" LYMPHATICS Toxicity Code: Yee □ No O “If Yee", co m p lete the following Toxicity t 1 Y N _ ----- Y N Y N J . J , ____ /____ t____ Y N Y N Y N ____ /____ /___ __ /__/__ Y N Y N Y N __/__ /_ Commtnta: mm dd yyyy mm dd yyyy METABOLIC LABORATORY Toxicity Code: 10000493 10001687 Yes □ No □ “If Yes", com plete th e following Toxicity Acidosis (metabolic or respiratory) ___ J ____ /____ Alkalosis (metabolic or respiratory) ___ J J Y N Y N p i p Y N Y N Y N Y N 10005328 Amylase / / Y N Y N Y N 10005359 Bicarbonate ____ 1 ____ /____ Y N Y N Y N / / _ 10005470 CPK ____ 1 ____ /____ Y N Y N Y N 10020583 Hypercalcemia ____ / 1 Y N Y N Y N _ / 1 10020803 Hypercholesterolemia ____ /____ /____ Y N Y N Y N __/__ /_ 10020637 Hyperglycemia __ 1 1 Y N Y N Y N 10020646 Hyperkalemia .... 1 / Y N Y N Y N 10020669 Hypermagnesemia ____ / / Y N Y N Y N 10020679 Hypernatremia / ...... / Y N Y N Y N 10020903 Hyperuricemia ____ /____ /____ Y N Y N Y N 10020947 Hypocalcemia / / Y N Y N Y N 10020996 Hypoglycemia ____ /____ 1 ____ Y N Y N Y N __ 1__ /_ 10021015 Hypokalemia ____ /____ /____ Y N Y N Y N 10021027 Hypomagnesemia /__ /_ Y N Y N Y N _ / _ J _ 10021030 Hyponatremia 1 1 Y N Y N Y N J t 10021058 Hypophosphatemia ____ 1 ____ 1 ____ Y N Y N Y N . J I - Y N Y N Y N _ / / - Y N Y N Y N Y N Y N Y N J L Y N Y N Y N - Y N Y N Y N __ /__ 1_ Y N Y N Y N Commtnts: mm dd yyyy mm dd yyyy •Attribution Key: Unrelated 1 The adverse event (toxicity) la not related to the protocol. Unlikely 2 The adverse event (toxicity) le doubtfully related to the protoco Possible 3 The adverse event (toxicity) may be related to the protocol. Probable 4 The adverse event (toxldty) Is likely related to the protocol. Definite 5 The adverse event (toxicity) Is dearly related to toe protocol. I Grade: Use 0-5 Refer to protocol for definition of reportable AE. Circle Appropriate response— Y(yes) or N(no) If ADEERS, enter date submitted to Data Coordinating Center (for consortium) or PI (non-consortium) Clrde appropriate response— Y(yes) or N(no) COH 1098 (DIS Version 08.01.09/25/2003) ©City of Hope, January 1997 P ag e 7 of 10 186 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued Protocol # :_______ Participant's Initials: Research Participant #:. _______ Course # / Cycle # : _______________Day: _ BMT ONLY upnQ Z D D Seq. # :_____ Category /Code Toxlcitv —— — Attrib* — RBPort‘ Date SAE Pate ef Event Eitlillne 0 [^ | t ul|0n. ^ |M * Submitted fry _______________ aaRL________cra* * MUSCULOSKELETAL Toxicity Code: Yea □ No □ “If Yes", com plete th e following: Toxicity ___________________ I __/_ _ ___________________ I __I_ _ ___________________ I __/_ _ mm dd yyyy Y N Y N Y N Y N Y N Y N Y N Y N Y N I __ /__ /__ yyyy NEURO LO G Y Toxicity Code: Yee □ N o D Toxicity “If Yee", com plete th e following: 10048658 Neuropathy-cranial / / Y N 10034580 Neuropathy-motor ____ /____ /____ Y N 10034620 Neuropathy-sensory / / Y N Y N / / . Y N / Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N mm dd yyyy OCULAR/VISUAL Toxldty Code: Yes Q No g Toxldty “If Y es", com plete th e following: J__ J__ yyyy Y N Y N BB Y N Y N Y N Y N FAIN Toxicity Code: 10019216 10006002 Bone Pain Yes Q No q “If Y es1 ’, com plete the following: Toxldty /_ /_ I_ mm dd Y N * ■ “ Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N •Attribution Key: Unrelated Unlikely Possible Probable Definite 1 The adverse event (toxicity) is not related to the protocol. 2 The adverse event (toxldty) is doubtfufly related to the protocol. 3 The adverse event (toxldty) may be related to the protocol. 4 The adverse event (toxldty) Is likely related to the protocol. 5 The adverse event (toxldty) Is clearly related to the protocol. t Grade: Use 0-6 * Refer to protocol for definition of reportable AE. Cirde Appropriate response— Y(yes) or N(no) * * If ADEERS. enter date submitted to Data Coordinating Center (for consortium) or PI (non-consortium) * * * Circle appropriate response— Y(yes) or N(no) COH 1096 (DIS Version 06.01. 09/25/2003) © City of Hope, January 1997 P ag e 8 of 10 187 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued Protocol # :________________ Research Participant # :_____________________ Participant's Initials:__________ Course # ( Cycle # : ______________Day:_________ Seq. #: BMT ONLY C/cod«n'_____________________ Ia&ltlfa__________________Biw afEw ffl a w in g 0 fl |t SjSfc BjLI |M |? autmjttgUa PULMONARY Y»» □ NoO "If Yea", complete th« following: Toxicity Code: Toxicity 10035755 Pneumonitis/Pulmonary Infiltrates____________ _____ 10001052 ARDS (Adult respiratory distress syndrome) ___ 10013972 Dyspnea (shortness of breath)_______________ _____ Y N — - — Y N Y N Y N _ Y N Y N Y N — Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N _ “ Y N Y N dd y y y y i dd yyyy RENAL I GENITOURINARY Toxicity Code: C1006 Yes q "It Yes", com plete th e following: Toxicity Cystitis 10005483 Creatinine C10Q7 Fanconl'8 Syndrome Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N mm dd yyyy SECONDARY MALIGNANCY Toxicity Code: Yes Q No □ "If Y es", com plete th e following: Toxicity Y N “ ■ Y N Y N Y N Y N Y N Y N _ Y N Y N Y N Y N Y N Y N _ _ Y N Y N mm dd yyyy •Attribution Key: Unrelated Unlikely Possible Probable Definite 1 The adverse event (toxicity) Is not related to the protocol. 2 The adverse event (toxicity) Is doubtfully related to the protocol. 3 The adverse event (toxicity) may be related to the protocol. 4 The adverse event (toxicity) is likely related to the protocol. 5 The adverse event (toriclty) is dearly related to the protocol. t Grade: Use 0*5 * Refer to protocol for definition of reportable AE. Circle Appropriate response— Y(yes) or N(no) •• If ADEERS. enter date submitted to Data Coordinating Center (for consortium) or PI (non-consortium) * * * Circle appropriate response— Y(yes) or N(no) COH 1098 (DIS Version 06.01,09/25/2003) © City of Hope, January 1997 P a g e 9 of 10 188 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued B M T O N LY u p Nnnnn Protocol#:____ ____________ Research Participant # :_______________________ — — — — Participant's Initials: _ __________ Course# / Cycle# : ______________ Day:________ S eq.#:______ Category n . . p . + Attrlb- .cry DstS8A£ /code isidslfit P its lit Evsnl E sM nfl Ql ^ ution* StffL Subm ittal h< __________________________________________ -___________ -_* E = _____C B A 2 __ SEXUAL/ REPRODUCTIVE FUNCTION Toxldty Code: 10024419 Yes Q No □ "If Yes", com plete th e following: Toxicity Libido 10052003 Erectile Impotence yyyy Y N Y N Y N Y N Y N Y N Y N Y N Y N Y N “ Y N Y N Y N Y N Y N Y N Y N Y N mm dd yyyy S IG N A TU R E S Date Reviewed: Physician CRA Data Entry Date C o m p le te d :_____ /_____ /_ Date Entered: •Attribution Key: Unrelated Unlikely Possible Probable Definite 1 The adverse event (toxicity) Is not related to the protooot. 2 The adverse event (toxldty) Is doubtfully related to the protocol. 3 The adverse event (toxldty) may be related to the protocol. 4 The adverse event (toxldty) Is likely related to the protoool. 5 The adverse event (toxicity) Is dearly related to the protocol. t Grade: Use 0*5 Refer to protocol for definition of reportable AE. Circle Appropriate response— Y(yes) or N(no) * * If ADEERS. enter date submitted to Data Coordinating Center (tor consortium) or PI (non-consortium) - Circle appropriate response— Y(yes) or N(no) COH 1098 (DIS Version 06.01. 09/25/2003) © City of H ope. January 1997 P ag e 10 of 10 189 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission. PATIENT FOLLOWUP LOG CRA: WEEK FU k a o v sl in Daji* Coop Gtp ID No Reason off ActiM Tbetipy +t Dtte Off Aetna Tbetapy Reason off A o n * Therapy +: O ff Therapy Dsk Off Active Therapy R a m off Active Thenpy +: D aeOffA eim Tbnpy Coop Gcp ID No i for Off Active TberapyOff h m a i 5 * Other (Specify) 5 - Other (Specify) 6 * O m f c Physicisa/Hospiral 2 "Study Drag 1 - O tte r Dtscaae-fU lued Tfaoapy i - COH P hysciu 4 • D m M m fc r !• Specify the number o f dtys a wtoch patient mast be (-9-Lost to FU. -8-No FU. 0-Dead) (C o p y ri£ * C ity o f H ope, A pril 1989) Appendix B : Continued Appendix B: Continued u p n D C D D Institution: CITY OF HOPE NATIONAL MEDICAL CENTER FOLLOW-UP FORM AFTER BMT COH Q and/or Other Institution: Q S pecify o th er Institution:________ R e se a rc h P artlclpent N u m b e r:. P articipant In itia ls:_________ Seq. N o:. M issin g v a lu e c o d e s tor fill in blanks'. *6« N /A a n d - 9 » m ls » ln g , u n k n ow n or n o t d o n e . P l e a s e d o n ot u s e m issin g v a lu e c o d e s in d a t e field s. Has Phone # changed since last follow-up? □ Yes O No Phone: (____) __________ -_______________________________ Has A ddress changed since last follow-up? □ Yes □ No Address:____________________________________________ •Use 1" BMT If >1. Use date of 1* Infusion If >1 (_______) Diagnosis at BMT: _____________________________ Typeof.BM T: n ’AUo Q A u to □ MUD □ MRD BMT Date: / I m m d d yyyy □ 6mo □ 9mo Q l2 m o D l8 m o D 2 4 m o □ 36mo □ 4 8 m o □ Annual Outside Physician Information? □ Form covers the following period: I I t o I I____ mm dd yyyy mm dd yyyy 1. SURVIVAL STATUS Survival Status Section Completed? Yes □ No □ If no, skip to section (2) D isease Status Current KPS: ALIVE - Date of most recent contact with patient: / / LOST TO FOLLOW-UP □ Date of last contact: / /______ DEAD - Date of Death: / . _/ Death Attribution (Cause of Death): □ D isease Progression □ Infection □ Study Drug □ Other (specify)__________ □ Other Disease-Related Therapy □ Information not available IRB Num ber:____, ______ ________ indicate cause of death. iC heck only o n e prim ary c a u se o f d eath ). If underlying disease for which transplant was performed was present at time of death, it should be checked a s the primary cause Irrespective of the proximate cause. Persistence or Recurrence of Underlying Disease New Malignancy Acute GVHD Chronic GVHD GVHD & Interstitial Pneumonia Interstitial Pneumonia (IP) P lease ch eck ; BCNU ________ Radiation IP g. Other Pneumonia h. Bacterial Infection f, Primary Cause □ □ □ □ □ □ Contributing Cau»9(») □ □ □ □ □ □ S p e c ify CMV IP Idiopathic Viral , I. Viral Infection □ □ □ □ □ □ COH1024VO3.03.iWc 05/30/2003 191 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued D a te o f L a s t R e p o rt; / / U P N /P a tie n ta I n i t i a l s :_____ 1. SURVIVAL S T A T U S ( c o n tin u e d ) P leaee check: CMV ________ Herpes Other j. Fungal Infection k. Protozoal Infection l. Unclassified Infection m. Adult Respiratory Distress Syndrome n. Graft Failure/Rejection o. Organ Failure t. Other Autopsy: Yes □ No Q Missing □ (If yes, ploaso attach a copy o f the a u to p sy report) □ □ □ □ □ □ □ COH1024V03.03.doc 05/30/2003 192 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued Date o f Last R eport:___> UPN/Patients Initials:__ 1 / . l | D isease S ta tu s Section C om pleted? Yes 0 No □ If no, skip to section (3] Interim Events j I Check appropriate box for first disease status since last folfowup: Unknown Continued Remission D □ — ► (Skip to » ] Date Documented Sites T reatm ents Radiation Chemo Surgery Persistent Disease Relapse □ / / □ / i □ □ □ U If relepeed, determined by. Cytogenetic* □ Clinical 0 Pathological □ If relapsed or persistent disease, what Is status now? Date Documented Sites Treatments Radiation Chemo 8urgery Complete Remission □ □ □ Stable Disease □ / / □ □ □ Progressive Disease □ 1 / □ □ a Check appropriate box for second disease status since last followup: Unknown Continued Remission □ □ — ►(Skip to #3) Dpt* Documented site* Treatments Radiation Chemo Surgery Persistent Disease Relapse 0 . /_ / . □ / / □ □ □ L > If relepeed, determined by: Cytogenetics □ Clinical 0 Pathological 0 If relapsed or persistent disease, whet Is status now? Date Documented Sites Treatments Radiation Chemo 8urgery Complete Remission □ I I □ □ Q Stable Disease d i i □ □ □ Progressive Disease □ i i □ □ □ Check appropriate box for third disease status since last followup: Unknown Continued Remission □ D -----► (Skipto*3) Dete Documented Sltee Treatments Radiation Chemo Surgery Persistent Disease Relapse □ 1 1 □ / / □ o n !-► If relapeed, determined by: Cytogenetics □ Clinical 0 Pathological 0 If relapsed or persistent disease, what Is status now? Date Documented Sites Treatments Radiation Chemo Surgery Complete Remission □ 11 □ □ □ Stable Disease d i i □ □ □ Progressive Disease □ i i □ □ □ COH1024V03-03.doc 05/30/2003 3 193 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued Date o f Last R eport:___ /___ /_ UPN/Patients Initials:________ 3. INI'LKIM FV L N I'S Interim E vents Section C om pleted? Yea Q No D If no, skip to section (4) Bone Marrow Exam ] Hospitalizations V eal Noi U n k j1 If yes, com plete *“ L—1 th is sectio n : Dates: / / R easons: . Transfusion Dependent | ( j ( if n o sin c e last report: V e s n N ° n U nkL j Date of lastR B C transfusion: Date of lest platelet transfusion: Vaccinations Yes No Unk Type of vaccination: Hepatitis □ MMR □ DT □ Flu shot O Polio □ Pneum oax □ H. Influenzae □ Other Specify: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Current Medications Yes[ | Noj [ Unkj | S p e c i f y : ___________________________________________________________ PostBM T Yo bQ No Q Unfc | 1 Comments1 . _ Pregnancies 4. HO NC M A R R O W EXA M Bone Marrow Section C om pleted? Yes □ N o P If no. skip to section (5) Cytogenetics 1 Recent Bone Yes f 1 No □ U n k Q If yes: Date Documented: I / Marrow _ _ .___. Results: No D isease | | Disease (PleMe attach a copy of tha report) !i. C Y T O G L N I'T IC S [ C ytogenetics S ection C om pleted? Yes □ No □ If no, skip to section (6) Complications Since Last Report ] Recent Cytogenetics: Yes E D No EE ] Unk I 1 If yes: Date Documented: / I (Please attach a copy of the report) Abnorm al Yes EE] No Q D isease Y e s ^ j No [ | Comment: (Not computerised) _ _ _ _ _ _ _ _ _ _ _ _ _ COHl024VO3.Q3.doc 05/30/2003 194 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued Date o f Last Report: / / UPN/Patients Initials:_______ 6. CO M PLICATIONS SINCE LAST R EPO R T | Com plication* S ection C om pleted? Yes □ No □ If no. aklplo section (7) Laboratory R esults ) C heck appropriate box(ee): IfY ee: O neet Reeolved Date Specify T reatm ent Date Renal/GU * Other (900186) Yes □ No C D Unk □ / / Renel/GU • Other (900186) Yes □ No O Unk □ / / Renal/GU • Other (900100) Yes □ No C D Unk □ Neurologic-Other (900176) Yes □ No O Unk □ Neurologic-Other (900176) Yea □ No □ Unk □ / / / / Neurologic-Other (900176) Yes □ NO □ Unk □ Personality/ Behavioral (18124) Yes □ □ O z Unk □ Personality/ Behavioral (18124) Yes □ □ 0 z Unk □ Circulatory or cardiac 'Other (900124) Yes □ □ 0 z Unk □ Circulatory or cardiac 'O ther (900124) Yes □ □ 0 z Unk □ / / Circulatory or cardiac 'O ther (900124) Yes □ No C D Unk □ / / Hepatic -Other (900158) Yes □ No 0 Unk □ / / Hepatic -Other (900156) Yes □ No O Unk □ / / Gl - Other (900144) Yes □ No □ Unk □ / / Gl - Other (900144) Yes □ No C D Unk □ Gl - Other (900144) Yes □ no C D Unk □ / / Avascular Osteonecrosis (18299) Yes □ □ 0 z Unk □ Joint, muscle, or bone -O ther (900174) Yea □ □ 0 z Unk □ , , / 1 COH1024VO3.03.doc 05/30/2003 5 195 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued Date o f Last Report: / / UPN/Patients Initials:________ If Yes: O nset Date Specify Treatm ent Resolved Date Joint, muscle, or bone -O ther (900174) Yes □ No □ Unk □ / / / / Cataracts (10205) Yes □ No □ Unk □ IfY ee: OD OS BOTH Unk Date Developed: ____ / / ____/ / Date o f Surgical Repair: ____1 1 / /____ Hypothyroidism (1081) Yes □ No □ Unk □ 1 1 / / Endocrine -Other (900140) Yes □ No □ Unk □ , / / / Endocrine -Other (900140) Yes □ No □ Unk □ / I I 1 Endocrine -Other (900140) Yes □ No □ Unk □ / / i / Sexual/Repro ductive function (900190) Yes □ No □ Unk □ 1 / / I Hematology- Other (900104) Yes □ No □ Unk □ / / 1 i Hematology - Other (900104) Yes □ No □ Unk □ , , Dental Problems (C1012) Yes □ No □ Unk □ / / / / Dental Problems (C1012) Yes □ No □ Unk □ / 1 / 1 Dermatologic (Skin) (C1013) Yes □ No □ Unk □ 1 i / / Hearing-Other (800102) Yes □ No □ Unk □ / / / / Failure to engraft (900236) Y68 □ No □ Unk □ / / / / Benign Tumor (C1014) Yes □ No □ Unk □ / 1 / / Secondary Malignancy - Other (900166) Yes □ No □ Unk □ Secondary Malignancy - Other (900188) Yes □ No □ Unk □ / / Metabolic • Other (900172) Yes □ No □ Unk □ / 1 / / Metabolic • Other (900172) Yes □ No □ Unk □ I / / / COH1024VO3.03 doc 05/30/2003 6 196 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued Metabolic - Other (900172) Yes □ No □ O cu lar-O th er (900178) Yes □ No □ Ocular - Other (900178) Yes □ No □ Pulmonary - Other (900184) Yes □ No □ Pulmonary - Other (900184) Yes □ No □ Pulmonary ~ Other (900184) Yes □ No □ Intersltlal Pneumonltlts (IP), NOS (C1017) Yes □ No □ IP, BCNU (C1018) Yes □ No □ IP, Radiation (C1019) Yes □ No □ IP, Idiopathic (C1020) Yes □ No □ IP, Viral (C1021) Yes □ No □ Bacterial Infection (C1003) Yes □ No □ Bacterial Infection (C1003) Yes □ No □ Bacterial Infection (C1003) Yes □ NO □ Viral Infection (C1004) Yes □ No □ Viral Infection (C1004) Yes □ No □ Viral Infection (C1004) Yes □ No □ Fungal Infection (C1005) Yes □ No □ Fungal Infection (C1005) Yes □ No □ Herpes Zoster (C1015) Yes □ No □ COH1024VO3.03.doc 05/30/2003 Date o f Last Report: / / UPN/Patients Initials:_______ If Y es: O n set Resolved Date Specify T reatm ent Date Unk C D / / / Unk O / ! /___________ Unk [H I I I _______________________________________ / Unk (H I / I _______________________________________ / Unk m i ____ / / I___________ Unk [ I ] / I / Unk m i / / I Unk [H I / / / Unk [H I / / _________________ ___________________ Unk m i / / I Unk [ I ] / / I Unk E H / / I Unk [ I ] I _I _______________________ ____________________ Unk m i / / / Unk O I I ______________________ ____________________ Unk m i I I _______________________________________ 1 ________ Unk m i / I _______________________________________ I_______ Unk (H I / / __________________ ____________________ Unk G il / I __________________ ____________________ ____ Unk [H I / / I ___________ 7 197 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued Dale o f Last Report: / / UPN/Patients Initials:_______ If Y e a : O nset R esolved Date Specify T reatm ent Date Hepatitis A (C1022) Yes □ No □ Unk □ / / / / Hepatitis B (C1023) Yes □ No □ Unk □ / / 1 1 Hepatitis C (C1024) Yes □ No □ Unk □ / / t / Hepatitis D (C1025) Yes □ No □ Unk □ / / / t Hepatitis E (C1026) Yes □ No □ Unk □ / / / / CMV (C1016) Yes □ No □ Unk □ / / / / Infection, NOS (900164) Yes □ No □ Unk □ / / / / CGVHD (C1001) Yes □ No □ Unk □ / / (If yes, complete Section 8.) / / N ote: If o th e r Is s p e c if ie d a ls o g iv e CTC o r COH c o d e . O th e r : C o d e : ( ) Y e s □ N o □ U n k □ / / . . . / / O th e r : C o d e : ( ) Y e s □ N o □ U n k □ ' ' / / O th e r : C o d e : ( ) Y e s □ N o □ U n k □ ' ' / / O th e r : C o d e ; ( ) Y e s □ No □ U n k □ ' ' / / O th e r . C o d e : ( ) Y e s □ N o □ U n k □ ' ' / / O th e r : C o d e : ( ) Y e s □ N o □ U n k □ ' ' / / O th e r : C o d e : ( ) Y e s □ No □ U n k □ ' ' / / 7. L A B O R A T O R Y R t S U L . T S [ L aboratory R esults S ection C om pleted? Yes □ No □ If no, skip to section (8) For Allogeneic BMT Recipients Only ) (If >1 use more complete one) . ____ % . _____ % W as CBC done since Yes Q NoLj Unk L_J If Yes: Date Documented: I I_____ last visit? H G B : _______ . ____G% Lymphs: ___ P la te le ts:___________ x103 Neutrophils:____ WBC: . x103 COH1024VO3.03.doc 05/30/2003 198 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued Date o f Last Report: / / UPN/Patients Initials:_______ 8, C G VHD (Tor Allo()om?ic BMT R e c ip ie n ts ONLY) [ CQVHD? □ Yes □ No If no. skip to section (9) Signatures If CGVHD was present, complete this section: Grade: Limited Q Extensive Q (see definitions below) DEFINITIONS Limited chronic QVHD Extensive Chronic QVHD Either or both Either 1. Localized skin involvement 1. Generalized skin Involvement, or 2. Hepatic dysfunction due to chronic GVHD 2. Localized skin Involvement and/or hepatic dysfunction due to chronic GVHD Plus 1. a) Liver histology showing chronic aggressive hepatltlB, bridging necrosis, or drrosls, or b) Involvement of eye (Schlrmer's test with less than 5 mm wetting), or c) Involvement of minor salivary glands or oral mucosa demonstrated on labial biopsy, or d) Involvement of any target organ Check O rgan Involvem ent Yes No Yes No Cutaneous Involvement □ □ Hepatitis □ □ Joint Involvement □ □ Chronic Diarrhea □ □ Orel Involvement □ □ W eight Loss □ □ Ocular Involvement □ □ Chronic Lung Disease □ □ Esophageal Involvement □ □ Liver Function T e s t: □ Abnormal Other □ □ If v es. aoeclfv: Has therapy been used to treat chronic GVHD? Yes □ □ o z If Yea, check appropriate boxes: Methotrexate □ ALS, ALG, ATS, ATG, □ Cyciosporine □ FK506 (PROGRAF) □ Systemic Corticosteroids □ CELLCEPT (MMF) □ Topical Corticosteroids □ PUVA □ Thalidomide □ Photophoresis □ Other Agents (specify) CO H 1024V O3.03.doc 05/30/20G3 199 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix B: Continued Date o f Last Report: / / UPK/Patients Initials:_______ 0. S IG N A TU R ES Date Completed: I I______ Date Reviewed: I_____I______ Date Entered: / /______ mm dd yyyy COH1Q24VO3.03.doc 06/30/2003 | Q Physician Data Entry 200 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C California Cancer Research Program Graduate Student Award Application C alifornia C a n c e r R e s e a rc h P rogram Electronic Forms Package Hyperlinked Table of Contents Form 1A F ace P age Form 2 Table of C ontents Form 1C R esponsiveness to C R P 's G oals, Priority A reas and S elected Award M echanism s Form 3 Scientific Abstract Form 4 Lay A bstract Form 5 Certification and C andidate's R eference List Form 6 Key P ersonnel Form 7 A nnual Budget S heet Form 8 Sum m ary Budget S h eet Form 9 Budget Justification Form 10 Biographical Sketch Form 11 O ther Support Form 12 Facilities and R esources Form 13 R esearch Plan Form 14 S tatem ent of Distinction from O ther Funded Work (skipped) Form 15 C areer Plan Form 16 H uman Subjects Form 17 V ertebrate Animals Form 18 Appendix Cover S heet Form 19 Cover S h eet for Institutional A ssurances for Hum an S ubjects and V ertebrate Animals Form 20 Demographic Data for Statistical P urposes (S ee sep arate file: Form _19.doc) (skipped) 201 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): J o y c e ly n n e M. P a lm e r________ F orm 1A ?.a''I°r. n^ CanCer Research Pr° a ram - CV cle A bstract Confirm abon No. F o r all ap p licatio n s e x c e p t O R C A -P ilo t a n d Q R C A -Full 1. PROJECT TITLE (D o n o t e x c e e d 6 0 c h a ra c te rs a n d s p a c e s .) 2. APPLICATION HISTORY L eukem ia: In v estig atin g C a u s e s of D eath & D is e a s e R e c u rre n c e NEW X R EV ISIO N A P P # N/A RENEW AL A P P # N/A 3. PRINCIPAL INVESTIGATOR First, M l. L ast. D e g re e s PO SIT IO N T ITLE Jo y c e ly n n e M. P a lm e r, M S S u p p o rt S cie n tist D EPAKTM ENT/LABORATOftY INSTITUTION D ivision o f Inform ation S c ie n c e s C ity o f H o p e N ational M edical C e n te r C O M P L E T E MAILING A D D R E S S (S tre e t, P o s t O ffice B ox, Internal Mail S tatio n , City, S ta te , Z p> 1 5 0 0 E a st D u a rte R o ad , Bldg. 171 R o o m 1006. D u arte. C alifornia 9 1 0 1 0 -3 0 0 0 FA X (626) 3 0 1 -8 3 9 3 E-MAIL A D D R E SS JM P A L M E R fiJC O H .O R G 4a. HUMAN S U B JE C T S | NO Y E S | X 4b. VERTEBRATE ANIMALS | N O X | Y E S | If Y es F W A/M PA# M 1043 If Y es IA C U C # Institutional R ev iew B o ard A pproval D ate: 0 9 /0 4 /2 0 0 3 D a te 6. DURATION OF PROJECT (# M onths) 36 6. BUDGET FOR ENTIRE PROJECT PERIOD TAXPAYER ID! 9 5 -1 6 8 3 8 7 5 $ 1 3 4 ,7 2 4 .9 5 $ 1 0 ,7 7 8 .0 0 $ 1 4 5 ,5 0 2 .9 4 TOTAL D IR EC T C O S T S TOTAL IN D IRECT C O S T S TOTAL C O S T S 7. NAME OF APPLICANTS ORGANIZATION OR INDIVIDUAL 8. RESEARCH PERFORMANCE SITES City o f H o p e N ational M edical C e n te r MAILING A D O R E S S (S tre e t, P .O . Box. M S. City. C ounty, S ta te . Zip) City of H o p e N ational M edical C e n te r 1 5 0 0 E a s t D u a rte R o ad D u arte. C alifornia 9 1 0 1 0 -3 0 0 0 Division of Inform ation S c ie n c e s 15 0 0 E a s t D u a rte R o ad Bldg. 171 R o o m 1006 D u arte, C alifornia 9 1 0 1 0 -3 0 0 0 9. CONTRACTS AND GRANTS OFFICIAL (N a m e , D e g re e (s)) 10. OFFICIAL SIGNING FOR ORGANIZATION (N a m e . D eg ree(s)) Sylvester C arreathers S ylvester C arreathers MAILING A D D R E S S (Title. S tre e t. P .O . Box, City, S ta te , Zip) MAILING A D O R E S S (include title a n d official o rganization) G ra n ts a n d C o n tra c ts M a n a g e r C ity of H o p e N ational M edical C e n te r 1 5 0 0 E a s t D u a rte R o a d D u arte. C alifornia 9 1 0 1 0 -3 0 0 0 G ra n ts a n d C o n tra c ts M a n a g e r C ity of H o p e N ational M edical C e n te r 15 0 0 E a s t D u a rte R o a d D u arte. C alifornia 9 1 0 1 0 -3 0 0 0 P H O N E (6 26) 3 0 1 -8 4 3 8 | FAX | (6 2 6 ) 3 0 1 -8 8 4 3 PHONE (626) 3 0 1 -8 4 3 8 | FAX |(6 2 6 ) 3 0 1 -8 8 4 3 E-MAIL S P O N S R E S ® C O H . O R G E-MAIt SPON SR E S ® COH .ORG 11. PR IN C IPA L IN V ESTIG A TO R A SSU R A N C E : 1 a g re e to a c c e p t res provide th e re q u ire d p ro g re ss re p o rts if a grant is aw a rd e d a s a res )onsibility for th e s c ie alt of th is application. itific co n d u ct a n d integrity of th e re s e a rc h , a n d to SIGNATURE OF THE PERSON NAMED I N I (In b lu e Ink please.) PROW SIG N A T U R E N O T A CCEPTA B LE. X 12. CERTIFICATION AND ACCEPTANCE: I certify th a t th e s te te m e n ts h erein a re tru e a n d co m p lete to th e b e s t of m y k n ow ledge, a n d a c c e p t th e obligation to com ply with California C a n c e r R e se a rc h P ro g ram te rm s a n d co n d itio n s if a g ra n t is a w a rd e d a s a resu lt of this application SIGNATURE OF THE P feted N NAMSb IN 16. Fn blue ink please.) ‘P ftO W SIGNATURE N6 T A C t f f ’fA B L g X P a g e l 202 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): J o y cely n n e M. P a lm e r FORM 2 This form is required for all applications TABLE OF CONTENTS APPLICATION FORM NO. CHECKLIST________________________________________________________________________________________________ PAGE NO. 1A Face Page for A ll Award Types Except CIRCA 1 1B Face Page for CIRCA-Pllot, C l RCA-Full N/A 2 Table of Contents 2 1C Responsiveness to CRP's Goals and Priority Areas and Selected Award Mechanism 3-4 3 Scientific Abstract 5 4 Lay Abstract 6 5 Certification and Candidate’ s References List for N IA , CSDA. and GSA-HPR Appications 7 6 Key Personnel 8 7A-C Budget Detail (Separate page for each project fiscal year) 8A-8C 8 Budget Summary (N /A for C IRCA-Pllot) 8D 9 Budget Justification 9-11 10 Biographical Sketches 12-19 11 Other Support - Research and Non-Research Activities 20-31 12 Facilities and Resources 32-33 13 Research Plan 34-45 14 Statement of Distinction from Other Funded W ork 46 15 Career Plan (N IA , GSA-HPR, and CSDA Only) 47 16 Human Subjects 48-50 17 Vertebrate Animals 51-52 18 Appendix Cover Sheet O f required) 53 19 Institutional Assurances of Human Subjects and Vertebrate Animals (see section 25 for additional guidelines) 54 20 Demographic Data for Statistical Purposes N/A To b e considered com plete, grant subm issions m ust Include ALL of th e following: • Original application plus 22 copies; • Scientific A bstract subm itted via our Application Module on the C R P web: w w w .d h s .c a .g o v /c r p . click on 'G o to Cycle III' under California C ancer R esearch Program , fill out th e Scientific A bstract Subm ission, include the A bstract Confirmation N um ber in the upper right hand com er of the F ace P age (Form 1A or 1 B); • Disk copy of the grant application (not including signatures, Form 20, an d appendix), labeled with the PI, title, abstract confirmation num ber, and com puter format (PC or Mac); • Three sep arate collated copies of the Executive Summary, • S ealed Letters of Support, if required. If you are unable to supply one or m ore of the required electronic fom rats, you m ust contact the CRP BEFO RE the deadline to arrange for other m ean s of submitting the required m aterials. There is no alternative subm ission for the original application, copies and executive sum m ary.________________________________________________________________ P ag e2 203 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M. P a lm e r F O R M IC Required for all applications.__________________________________________________________________ R e sp o n siv e n ess to CRP’s G oals, Priority A reas and Selected Award M echanism 1. PRIORITY AREA: (P lease check the shad ed box for onivone. S ee Section 2 for descriptions of priority areas.) C ancer Biology, Etiology, and Pathogenesis Clinical R esearch - Early D etection/Screening Health Communications R esearch C ancer Health C are - Delivery Clinical R esearch Innovative D laanostc Techniques Primary Prevention C ancer Health Care - Econom ics i ' Clinical R esearch - Innovative Treatm ent •- Psychosocial/Cuttural Issu es C ancer Health C are - Pollcv X . Epidemiology Technology Transfer 2. AW ARD M ECHANISM : (P lease check onlv one.) Award for Care Enhancem ent (ACER) Investigator-Initiated Award: Clinically-Based (CB-IIA) Small B usiness Award. P h a se II (SBA, P h ase II) Clinical Scientist Development Award (CSDA) Investigator-Initiated Award: Laboratory-Based (LB-IIA) Special Populations R esearch Award (SPRA) Community-Initiated R esearch Collaboration Award: Pilot fCIRCA-Pllot) Investigator-Initiated Award: Populatlons-Based (PB-IIA) Community-Initiated R esearch Collaboration Award: Full (CIRCA-Full) New Investigator Award (NIA) : (TRFA)#1: Researching and Reducing the Unequal Burden of C ancer in California X G raduate Student Award for Human Population- B ased R esearch (GSA-HPR) Pilot and Feasibility Study Award (PFSA) - (TRFA) #2: Diet and Behavior C hange and Cancer Prevention 3. CANCER/OROAN SITEIS): (P lease check all that apply.) Cervix O v ary U te ru s E ndom etrium P ro sta te V ag in a Fallopian T u b e T e stis V ulva G e n d e r-S p ec ific B lad d er X L eukem ia N a so p h a ry n x Brain Lung O ral C h ildhood Lym phom a P a n c re a s C olo rectu m M elan o m a ~ R en al G e n e ra l M yelom a Skin O th e r (P le a s e sp ecify :) 4. DOES YOUR APPLICATION DEAL WITH THE MEDICALLY UNDERSERVED OR SOCIO-ECONOMICALLY DISADVANTAGED? X YES NO SPECIFY: T h is ap plication e x a m in e s, in p art, th e tre a tm e n t o u tc o m e s a m o n g eth n ic m inorities (e.g . African- A m e ric a n s, A sian -A m erican s a n d H isp an ic-A m erican s), th e m ed ically u n d e rs e rv e d , a n d th e so cio -e co n o m ica lly d isa d v a n ta g e d . P age 3 204 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M. P a lm e r________ FORM 1C (Continued) P lease limit this explanation to one page with 12 pt. font text and 1 1nch m argins. 5. EXPLANATION OF RESPONSIVENESS O ne of the prim ary evaluation criteria is responsiveness to the C R P priorities. A strong preference will be given to applications that study 1) high risk populations (e.g., the ethnically and culturally diverse, the m edically underserved, the socio-econom ically disadvantaged) and/or 2) cancer-ongan sites listed in section 3 of Form 1C. 11/3/2003: B ased on feedback from Joycelynne Palm er's dissertation subcom m ittee*, this item w as intentionally left blank. *: Drs. S usan Preston-M artin, W endy Mack, and Stan Azen (alternate for Dr. David Snyder) P age4 205 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M. P a lm e r FORM 3 Required for all applications.__________________________________________________________________ Scientific Abstract PROJEUI ItiLE (Do not exceed 60 characters and spaces.) L eukem ia: Inv estig atin g C a u s e s of D eath & D is e a s e R e c u rre n c e _________________________________ DEPARTMENT AND ORGANIZATION (if applicable) Division of Inform ation S c ie n c e s . C ity of H ope N ational M edical C e n te r__________________________ (P lease limit abstract to this p ag e with 12 pt. font text and 1-Inch m argins) T h e overall o b jective of th is p ro p o s a l is to e x a m in e fa c to rs th a t m a y s e rv e a s p ro g n o stic in d icato rs of cy to g e n e tic re la p s e an d /o r d e a th in p a tie n ts w ho h a v e u n d e rg o n e allo g e n e ic blood o r m arro w tra n sp la n ta tio n (Allo-BMT) for tre a tm e n t of ch ro n ic m yeloid le u k em ia in ch ro n ic p h a s e (C M L-C P). T h e clinical c o u rs e for p a tie n ts d ia g n o s e d w ith C M L -C P is h e te ro g e n e o u s . P re v io u s s tu d ie s h a v e d e m o n s tra te d th a t p ro g n o s is v a rie s w idely d e p e n d in g on th e risk profile of p a tie n ts: risk profiles a r e u su ally b a s e d on p a tie n t c h a ra c te ris tic s, clin ic a l/d ise a se fe a tu re s at p re s e n ta tio n a n d prior th e ra p y (type, am o u n t a n d du ratio n ). M ultivariate risk classific a tio n s a n d sco rin g s y s te m s b a s e d on p re tre a tm e n t fe a tu re s h a v e b e e n th e su b je c t of n u m e ro u s p ro g n o stic s tu d ie s (T ura, 1981: C e rv a n te s , 1982: S o k al, 1984: S o k al. 1985: K antarjian, 1985: K antarjian, 1990: Italian G ro u p . 1991: T hiele, 1991: H eh lm an n , 1992; T hiele. 1993; Italian G ro u p . 1994; C o rte s. 1997; H asford. 1998). [In m o st c a s e s , th e s e e a rlie r s tu d ie s w e re lim ited to ev a lu a tin g th e relativ e im p act of p re tre a tm e n t fe a tu re s on overall survival.] A s a resu lt, se v e ra l m o d e ls h a v e b e e n d e v e lo p e d th a t c a te g o riz e p a tie n ts into different g ro u p s with distinctive survival c h a ra c te ris tic s (S o k al. 1984: H asford. 1998), h o w ev er, th e reproducibility a n d g en eralizab ility of m o s t of th e s e sco rin g s y s te m s h a v e b e e n re p e a te d ly q u e s tio n e d b e c a u s e th e s e s y s te m s w e re re stric te d to ce rtain th e ra p e u tic re g im e n s. A pplication of th e v ario u s risk m o d e ls a n d sco rin g s y s te m s to c o h o rts with o th e r tre a tm e n t m o d alities, in p articu lar Allo-BM T, freq u en tly d e m o n s tra te a significant lack of p ro g n o stic efficiency with ov erlap p in g risk discrim ination (G ratw ohl. 1998; C lark. 2 0 0 1 ; M ichallet. 20 0 1 ; R adich, 2001; G ratw ohl, 2 0 0 3 ). W hile a n u m b e r of p ro g n o stic m o d e ls for non-B M T p a tie n ts h a v e b e e n d e v e lo p e d a n d a re well d o c u m e n te d in th e literatu re, a u sefu l sco rin g sy ste m /p ro g n o stic m o d e l h a s n o t b e e n d e v e lo p e d fo r C M L-C P p a tie n ts th a t u n d e rg o Allo-BMT. T h e p u rp o s e of th is a n a ly s is is to e v a lu a te th e p ro g n o stic sign ifican ce of p atien t, d is e a s e , a n d tre a tm e n t c h a ra c te ris tic s for p a tie n ts w h o h a v e u n d e rg o n e Allo-BMT for tre a tm e n t of C M L-C P. A n ex a m in atio n of th e role of p atien t, clinical a n d tre a tm e n t fa c to rs co llected b oth at th e tim e of d ia g n o sis a n d Allo-BMT will b e d o n e to a s s e s s th e predictive v a lu e of th e s e fa c to rs on a p a tie n t's risk for d is e a s e re c u rre n c e an d /o r d e a th follow ing Allo-BMT. An o n g o in g c a s e - s e r ie s of 3 9 3 C M L -C P p a tie n ts tre a te d at th e C ity of H o p e N ational M edical C e n te r with Allo-BM T from 1 9 8 1 -2 0 0 2 will b e u s e d for th is an a ly sis. T his s tu d y will a ls o ex p lo re th e predictive v a lu e of th re e g e n e ra lly a c c e p te d p ro g n o stic sco rin g s y s te m s (S o k al. H asford a n d G ratw ohl) in th is la rg e sin g le c e n te r Allo-BM T pop u latio n . T h e q u e s tio n a n d sele ctio n of optim al tre a tm e n t d e p e n d s on m a n y fa c to rs, w hich in c lu d e d is e a s e c h a ra c te ris tic s, p re v io u s tre a tm e n t, a n d individual p a tie n t c o n s id e ra tio n s . T h e re s u lts of th is s tu d y will c o n trib u te to th e overall u n d e rs ta n d in g of C M L-C P p ro g n o s is in th e Allo-BM T settin g a n d cou ld a s s is t clinicians with tre a tm e n t d e c is io n s re la te d to Allo-BMT. P a g e 5 206 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M. P a lm e r FORM 4 Required for all applications. Lay Abstract PRO JE CT TITLE (Do not exceed $0 characters and spaces.) Leukemia: Investigating C au ses of Death & D isease Recurrence PRINCIPAL INVESTIGATOR (First, Ml, Last. D egrees) Joycelynne M. Palm er, MS INSTITUTION (if applicable) City of H ope National Medical C enter TOTAL GRANT AMOUNTTDUftMloN OF AWAftf) (Months) $ 1 4 5 ,5 0 2 .9 4 /3 6 m o n th s PRIORITY AREA (only list one, see page 1C) Epidemiology CANCERIORGAN SITE(S) Leukem ia/Bone Marrow AWARD MECHANISM (see page 1C) G raduate S tudent Award for H uman Population- B ased R esearch (GSA-HPR) LA Y ABSTRACT (P lease limit abstract to this p age vkth12 point font text and 1-Inch m argins) W hile tre a tm e n t is b eliev ed to in flu en ce d is e a s e o u tc o m e , th e w ide variation in survival a n d rem issio n r a te s a m o n g p a tie n ts with ch ro n ic m yeloid le u k e m ia (CML) d e m o n s tra te s th a t th e e ffe c tiv e n e s s of tre a tm e n t a p p e a r s to b e m odified b y p a tie n t c h a ra c te ristic s, d is e a s e fe a tu re s , a n d a p p ro a c h to m a n a g in g th e d is e a s e (e .g ., m onitoring). B e c a u s e th e len g th of survival for p a tie n ts d ia g n o s e d w ith CML v a rie s w idely d e p e n d in g o n 'risk profile', it h a s b e e n d e te rm in e d by th e le ad in g CML p h y sic ia n s a n d s c ie n tis ts th a t fu tu re im p ro v e m e n ts in th e tre a tm e n t of CML is d e p e n d e n t on o u r ability to d istin g u ish b e tw e e n p a tie n ts w h o a re likely to h a v e long-term d is e a s e fre e survival a n d th o s e w h o a r e not. T h e goal of th is p ro p o s e d stu d y is to e x a m in e fa c to rs th a t m a y s e rv e a s clinical in d icato rs of (high risk f e a tu r e s for) re -e m e rg in g le u k em ia o r e a rly d e a th in p a tie n ts w h o h a v e u n d e rg o n e a llo g en eic blood or m a rro w tra n sp la n ta tio n (Allo-BM T) for tre a tm e n t of CML. T h e re s u lts o f this (clinical) ep id em io lo g ic in v e stig atio n will n ot on ly provide a n im p ro v ed u n d e rs ta n d in g of th e relativ e im p act of risk fa c to rs on fu tu re d e a th a n d /o r re la p s e ev e n ts, b ut it will a ls o a s s is t clinicians with identifying high-risk p a tie n ts prior to tra n sp la n t s o th a t a lte rn a te tre a tm e n t o p tio n s ca n b e c o n s id e re d . P age 6 207 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M. P a lm e r________ FO R M 5 This form is required in applications for New Investigator Awards. Clinic el Scientist Development Awards, and G raduate Student Award for Human Population-Based R esearch Obtain signatures and include with the original application. Copies of th e application must also contain the required signatures. However, all information accept the signature is sufficient for the submitted electronic file S ee Section 25 in the Application Packet for additional information. Certification and C andidate's Reference List SIGNATURE OF DEPARTMENT CHAIR (a letter of support is REQUIRED in addition to department chair signature) X NAME OF DEPARTMENT CHAIR: TITLE: Ronald K. R oss, MD, Ph.D. Chair and Professor, D epartm ent of Preventive Medicine INSTITUTION University of Southern California, Keck School of Medicine L is t in d iv id u a ls p r o v id in g l e t t e r s o f r e c o m m e n d a tio n : (minimum of 2 to a maximum of 4, including the m entor if required, excluding D epartm ent Chair): NAME TITLE INSTITUTION Joyce C. Niland, Ph.D. Chair, Division of Information S ciences Director, D epartm ent of Biostatistics City of H ope National Medical Center David S . Snyder, M.D. A ssociate Director, H em atology and Bone Marrow T ransplantation City of H ope National Medical C enter P ag e7 208 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): J o y cely n n e M. P a lm e r FORM S Required for all applications. S ee Section 25 in Aprtication Packet for additional instructions. Key Personnel NAME, DEGREE: (S) p o s i w N m e DEPARTMENT in stitutio n PROJECT ROLE Joycelynne M. Palm er, MS Support Scientist Division of Information S ciences City of H ope National Medical C enter Principal Investigator (Doctoral C andidate in Epidemiology) Joyce C. Niland, Ph.D. Chair, Division of Information S ciences Director, D epartm ent of Biostatistics City of H ope National Medical C enter Co-Investigator/Biostatistician/ (Mentor) David S . Snyder, M.D. A ssociate Director, H em atology and Bone Marrow Transplantation City of H ope National Medical C enter Co-Investigator/Hem atologist/ Oncologist S usan Preston-M artin, Ph.D. Professor and Principal Investigator, D epartm ent of Preventive Medicine University of Southern California Keck School of Medicine Consultant/Epidem iologist/ (Dissertation Comm ittee Chair) P age 8 209 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal in v e stig a to r (First, Ml, L ast N am e) FORM 7A-Fiscal Year 1 T his fa rm is required fo r ail ^ ip lfca tio n t P lease foliow instructions in Section 25 of the Application Packet for Form 7 Jo y c ely n n e M. P a lm e r C Y CLE III FISCA L Y E A R 1 B U D G E T J u ly 1 ,2 0 0 2 th r o u g h J u n e 3 0 ,2 0 0 3 A. PE R S O N N E L E X P E N S E S NANE J O B TITLE ANNUAL SALARY % FTE •PPt 2 % effort on project 3 % FTE salary request 4 TOTAL 1: Jc v ce iy n n eM . Palm er. S u p p o rt S cientist 100.00% 5 0 0 0 % 5 0 0 0 % 2: J o /c e C. N ila n d .P h D . P ro fesso r 100% 2% 2.00% 3: O a 4 d S S n y d e r, M.D. A sso c iate D irector H em (P hysician 100% 2% 2.00% 4 $ 0 0 0 5 $0.00 S $ 0 0 0 7 $ 0 0 0 3 $ 0 0 0 T o ta l P e r s o n n e l E x p e n s e s B. FRIN G E B EN E FIT S < 174 % JM Palmer 1 FR IN G E B EN EFITS 29.7 * JC N Iand 1 FR IN G E B EN EFITS 275 * D8 8nyder s C. O PE R A TIN G E X PE N SE S D. EQ U IPM E N T E X PE N SE S E. T R A V EL AND P E R DIEM $ 1 ,8 5 0 00 F. SU B C O N T R A C T S $ 0 0 0 1 2 G. O T H E R C O S T S $ 0 0 0 1 2 3 4 H. T O TA L D IR E C T C O S T S IN D IRECT C O S T S 8 % of Me O h ad Total D irect C oats H J. TOTAL CRP Form7A $48,047.811 Page 8A 210 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator {First. Ml. Last Name) Joycelynne M. Palmer FORM 7B - Fiscal Year 2 T N t form it required for all multiyear applications Please follow instructions in Section 25 of the Application Packet for Form 7 CYCLE I I I FISCAL YEAR 2 BUDGET July 1, 2003 through June 30,2004 A. PERSONNEL EXPENSES NAME JO B TITLE ANNUAL SALARY % FTE appt % effo rt onprojact % FTE •alary request TOTAL 1: Jo y c ely n n e M. P alm er, S u p p o rt S cientist 100.00% 50 00% 50 00% 2: J o y c e C. N iland, P h D . P ro fesso r 100% 2% 2 00% 3 D a r id S S n y d e r, M O A sso c iate D irector H em (P hysician 100% 2% 2.00% 4 $ 0 0 0 5 $ 0 0 0 6 $0.00 7 $ 0 0 0 9 $ 0 0 0 Total Personnel Expenses B. Fringe benefits C 1 7 4 % J P Palmar 3 FRINGE BENEFIT! 29 7 % JCN Iand FRINGE BENEFIT! 2 7 5 % D8 8nyder C. OPERATING EXPENSES D. EQUIPMENT EXPENSES E. TRAVEL AN D PER D IE M F. SUBCONTRACTS G. OTHER COSTS H . TOTAL DIRECT COSTS INDIRECT COSTS ft 6 % o f Modtfled Total Direct Expent TOTAL = | W B W I Page 8B 211 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued ’nncipal Investigator (First. Ml, Last Name Joycelynne M. Palmer F O R M 7 C - Fiscal Year 3 T his fo rm is required fo r a ll three-year p ro je c t qtptfcatkm s P lease follow instructions m Section 25 of the Application Packet for Form 7 CYCLE III FISCAL YEAR 3 BUDGET July 1, 2004 through June 30, 2005 A. PERSONNEL EXPENSES NAME JOB TITLE ANNUAL SALARY % FTE aopt % effort on protect 3 % FTE salary request 4 TOTAL 1: Joy c ely n n e M Palm er. Support S cientist 100 00% 5 0 0 0 % 4 7 5 0 % 2 Jo y c e C . N ila n d .P h D P ro fesso r 100% 2% 2 00% 3: D avid S . S n y d e r, M.D. A sso c iate D irector H em (P hysician 100% 2% 2.00% a $0.00 5 $ 0 0 0 S $ 0 0 0 7 $ 0 0 0 3 $ 0 0 0 Total Personnel Expenses B. Fringe benefits C 1 7 4 % J.P Pdrrwr FRINGE BENEFITS 2 9 . 7 % JC Nland FRINGE BENEFITS 2 7 5 % 08finyder J ■ C. OPERATING EXPENSES D. EQUIPMENT EXPENSES E. TRAVEL AND PER DIEM F. SUBCONTRACTS G. OTHER COSTS H. TOTAL DIRECT COSTS I. INDIRECT COSTS ( k . J. TOTAL 8 % o f Modified T ot* Olrect Coats Page 8C 212 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal lnvestigator:(First. Ml. Last Name) Joycelynne M Palmer FORM 8 — Budget Summary T h is f o rm i< r e q u ir e d on «U a p p lic a tio n s P lease follow instructions in Section 25 of the Application P acket for Form 8 BU DG ET SUMMARY Budget Categories Column 1 FORM7A Fiscal Year 1 7/1/2002thru 6/30/2003 Column 2 FORM 7B Fiscal Year 2 7/1/2003 thru 6/30/2004 Colum n? FORM 7C Fiscal Year 3 7/1/2004 thru 6/30/2005 Column 4 Totals A. PERSONNEL EXPENSES $ 3 7 ,6 6 8 .0 0 $ 3 9 .2 2 9 4 0 $ 3 9 ,1 4 7 .4 3 $ 1 1 6 ,0 4 4 .8 3 B. FRINGE BENEFITS f t v a r ia b le % $ 5 ,4 3 3 6 7 $ 5 ,7 0 5 3 6 $ 5 ,6 9 1 .0 9 $ 1 6 ,8 3 0 12 C. OPERATING EXPENSES $0.00 $ 0 .0 0 $ 0 .0 0 $ 0 .0 0 D. EQUIPMENT EXPENSES $ 0 .0 0 $ 0 .0 0 $ 0 0 0 $ 0 0 0 E. TRAVEL AND PER DIEM $ 1 ,8 5 0 0 0 $ 0 .0 0 $ 0 .0 0 $ 1 ,8 5 0 0 0 F. SUBCONTRACTS $ 0 .0 0 $ 0 .0 0 $ 0 .0 0 $ 0 .0 0 G. OTHER COSTS $ 0 .0 0 $ 0 .0 0 $ 0 .0 0 $ 0 0 0 H. TOTAL DIRECT COSTS $ 4 4 ,9 5 1 .6 7 $ 4 4 ,9 3 4 .7 6 $ 4 4 ,8 3 8 .5 2 $ 1 3 4 ,7 2 4 .9 5 1 . INDIRECT COSTS A 8 % of Modified Total Cost* $ 3 ,5 9 6 13 $ 3 ,5 9 4 7 8 $ 3 ,5 8 7 .0 8 $ 1 0 ,7 7 8 .0 0 J. TOTAL $48,647.81 $48,629.54 $48,425.60 $145,502.94 P age 8D CRP Form 8 (Revised 7/0® 213 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M. P a lm e r FORM 9 Required for all applications. S ee Section 25 in the Application P acket for further instructions.________________________________________ Budget J ustlflcatlon (P lease use 12 pt. font text and 1-Inch m argins for budget justification. There Is no page Imlt for Form 9.) P e r s o n n e l E x p e n s e s : J o y c e l y n n e M. P a lm e r, M .S., P rin c ip a l I n v e s tig a to r (50% effort, 5 0 % s a la ry a n d b en e fits) [C ity o f H o p e N a tio n a l M ed ica l C e n te r a n d C ity o f H o p e B e c k m a n R e s e a r c h Institute]: J o y c e ly n n e P a lm e r h a s b e e n a S e n io r L evel A naly st a t th e City o f H o p e N ational M edical C e n te r s in c e 199 8 . M s. P a lm e r re c e iv e d h e r m a s te r's o f s c ie n c e d e g re e in ‘A pplied B io statistics a n d E pidem iology' in 19 9 5 from th e U niversity of S o u th e rn C alifornia a n d is in th e p r o c e s s of com p letin g h e r P h.D . in E pidem iology. S h e h a s o v er s e v e n y e a rs of e x p e rie n c e in ep id em io lo g ic r e s e a r c h m e th o d o lo g y , s tu d y d e s ig n , a n d statistic al an a ly sis. Jo y c e ly n n e P a lm e r will s e rv e a s th e P rincipal In v estig ato r on th is stu d y , co n d u c tin g a n d o v e rs e e in g all a s p e c ts w hich include: e x e cu tin g /m o n ito rin g p roject activities, d a ta collection, d a ta b a s e c o n stru c tio n , statistical an a ly sis/m o d e lin g , m a n u sc rip t p re p a ra tio n , a n d co m m u n ic atin g with th e c o -in v e stig a to rs on th e p roject. S h e will m e e t with th e co -in v estig ato r, m e n to r, a n d c o n su lta n t a s s h e im p le m e n ts th e p ro je ct plan. T h e s a la ry b a s e for Ms. P a lm e r is c o m m e n s u ra te with o th e r s e n io r level a n a ly s ts a s d ic ta te d b y th e City of H o p e N ational M edical C e n te r. M s. P a lm e r h a s b e e n b u d g e te d for 5 0 % effort d u ring Fiscal Y e a rs 0 1 . 0 2 a n d 03. A 5 % in c re a s e in M s. P a lm e r's s a la ry b a s e is a n tic ip a te d for F iscal Y e a rs 02 a n d 03. J o y c e C. N ila n d , P h .D ., M e n to r a n d C o - I n v e s tlg a to r (2% effort. 2 % s a la ry a n d b en e fits) [City o f H o p e N a tio n a l M ed ica l C en ter a n d C ity o f H o p e B e c k m a n R e s e a r c h Institute]: Dr. J o y c e N iland re c e iv e d h e r B a c h e lo rs d e g re e in H u m an B iology from S tan fo rd U niversity in 19 7 5 . a M a ste rs d e g r e e in P h y sical T h e ra p y from th e U niversity of S o u th e rn C alifornia (U S C ) in 1978, a s e c o n d M a ste rs in B io statistics from U S C in 1979, a n d h e r d o c to ra te in B io statistics from U SC in 1984. A fter serv in g on th e U S C facu lty for fo u r y e a rs , s h e b e c a m e D irector of B iostatistics at th e C ity of H o p e N ational M edical C e n te r in 1988. Dr. N iland is a Full P ro fe s so r in th e B ec k m an R e s e a rc h Institute at th e City of H o p e N ational M edical C e n te r, a n d h o ld s a joint a p p o in tm e n t in th e K eck S ch o o l of M edicine a t U SC . W ith e x p a n d in g re s o u rc e s a n d k n o w led g e in b iom edical in form atics a t th e City o f H ope N ational M edical C e n te r, Dr. N iland fo u n d e d a D e p a rtm e n t of B iom edical Inform atics in 19 9 8 . At th a t tim e s h e w a s p ro m o te d to ch a ir a n ew D ivision of Inform ation S c ie n c e s , joining th e D e p a rtm e n ts of B iom edical Inform atics a n d B iostatistics. In 1996 Dr. N iland re c e iv e d a 2 -y e a r p la nning g ra n t in inform ation integration from th e N ational Library of M edicine (NLM), follow ed by re c e ip t of a 5 -y e a r im p lem en tatio n g ra n t in 1998. A m ong o v e r 35 p restig io u s institutional recip ie n ts of th is g ran t natio n w id e, C O H is th e only 'fre e sta n d in g ' C a n c e r C e n te r to h a v e re c e iv e d th is aw a rd . In 1997 C O H w a s c h o s e n a s th e D ata C o o rd in a tin g C e n te r (D C C ) for th e first s h a r e d o u tc o m e s s tu d y in c a n c e r for th e N ational C o m p re h e n s iv e C a n c e r N etw ork. F or th is s tu d y of th e quality of c a re in o u r n a tio n 's le ad in g c a n c e r c e n te rs . Dr. N iland d ire c ts th e D C C , a n d le d th e d e v e lo p m e n t of o n e of th e first In ternet- b a s e d re s e a rc h d a ta s y s te m s , now s u c c e ssfu lly d ep lo y e d for o ver four y e a rs . In 199 8 Dr. N iland w a s e le c te d Fellow of th e A m erican S tatistical A sso ciatio n for h e r o u tsta n d in g c o n trib u tio n s in th e field s of B io statistics a n d B iom edical Inform atics. S h e s e r v e s a s a n ex p e rt rev iew e r for th e N ational In stitu tes of H ealth , is A s s o c ia te E ditor of tw o m ajor jo u rn a ls, a n d h a s p u b lish e d o v e r 80 p ee r-re v ie w e d p a p e rs in b io m ed ic al re s e a rc h . A s a m e m b e r of th e N ational C a n c e r Institute (NCI) Inform atics A d v isory F>anel in 19 9 9 , Dr. N iland h e lp e d g u id e th e d e v e lo p m e n t of th e inform ation in fra stru ctu re for th e n a tio n 's c a n c e r re s e a rc h . In 2 0 0 0 s h e p a rtic ip a te d on an NCI T a sk F o rc e to d e v e lo p b e s t p ra c tic e s in electro n ic d a ta secu rity , in an ticipation of fo rth co m in g n atio n al legislatio n . B eginning in th e fall of 2001 s h e s e rv e d a s th e P ag e9 214 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M. P a lm e r________ C h air of th e NLM B iom edical L ibrary R eview C o m m itte e for th e review of g ra n ts in inform ation s c ie n c e s . Dr. N iland will s e rv e a s Ms. P a lm e r's m e n to r a n d a s a C o -In v estig ato r on th e g ran t m e etin g w ith Ms. P a lm e r a s s h e im p le m e n ts th e p ro je ct plan. T h e s a la ry b a s e for Dr. N iland is c o m m e n s u ra te with o th e r 'C h a ir' level p o sitio n s a s d ic tated b y th e City of H ope N ational M edical C en ter. Dr. N iland h a s b e e n b u d g e te d for 2% effort durin g F iscal Y ears 0 1 . 02 a n d 03. D av id S . S n y d e r, M .D ., C o - I n v e s tig a to r (2% effort. 2 % s a la ry a n d b en e fits) [City o f H o p e N a tio n a l M ed ica l C e n te r]: D avid S. S n y d e r h a s b e e n a S taff P h y sician in th e Division o f H em a to lo g y /B o n e M arrow T ra n sp lan tatio n for 20 y e a rs a n d th e A ss o c ia te D irector of th e D ivision s in c e 199 3 . H e h a s e x te n s iv e e x p e rie n c e in tre atin g p a tie n ts with CM L. His clinical a n d re s e a rc h in te re s ts fo c u s on P h ilad elp h ia c h ro m o so m e -p o sitiv e (P h + ) le u k e m ia s , w hich include b oth CML a n d P h+ A cu te L ym p h o b lastic L eu k em ia. A s C h air of th e CM L d is e a s e c o m m ittee at C ity of H ope. Dr. S n y d e r is re s p o n s ib le for d ev e lo p in g a n d prioritizing clinical a n d re s e a r c h p ro to c o ls fo r CML. a n d fo r collecting a n d m ain tain in g th e d a t a b a s e s for th e s e p ro to c o ls in co njunction with Jo y c e ly n n e P alm er. H e is a m e m b e r of th e N ational C o m p re h e n s iv e C a n c e r N etw ork CML P an e l, w hich is c h a rg e d with d ev e lo p in g tre a tm e n t g u id e lin e s for p a tie n ts with CML. H e h a s w o rk ed clo se ly with J o y cely n n e P a lm e r on a v ariety of s tu d ie s a n d m a n u sc rip ts re la te d to P h+ le u k e m ia s s in c e Ms. P a lm e r jo in e d C ity of H ope in 19 9 8 . Dr. S n y d e r will pro vide clinical e x p e rtis e s e rv in g a s C o -In v estig ato r on th is p roject. His effort a n d s a la ry /b e n e fits a r e bo th b u d g e te d at 2% durin g F iscal Y e a rs 01, 0 2 a n d 03. S u s a n P re s to n -M a rtln , P h .D ., C o n s u lta n t (2% effort. 0 % s a la ry a n d b e n e fits) [U niversity o f S o u th e rn California, K e c k S c h o o l o f M edicine, D e p a r tm e n t o f P r e v e n tiv e M ed icin e]: Dr. S u s a n P resto n -M artin . a te n u re d facu lty m e m b e r in E p id em io lo g y is th e P rincipal In v estig a to r's d isse rta tio n c o m m ittee ch a ir for h e r d o cto ral d e g r e e in E pidem iology. Dr. P resto n -M artin h a s a g re e d to pro v id e g u id a n c e (ep id em io lo g ic e x p e rtis e ) re la te d to epidem io lo g ic m e th o d o lo g y on th is p ro je ct a n d is n ot re q u e s tin g c o m p e n s a tio n . U s e o f P e r s o n n e l o f A ffilia te d E n tity : C ity o f H o p e M ed ic a l G ro u p P e r s o n n e l (C ity o f H o p e N a tio n a l M e d ic a l C e n te r a n d C ity o f H o p e B e c k m a n R e s e a r c h I n s titu te P e r s o n n e l O n ly ): M em b e rs of th e M edical S ta ff or P ro fe ssio n a l S ta ff of th e City of H o p e N ational M edical C e n te r w orking on g ra n ts a re . b e c a u s e of ce rta in re q u ire m e n ts of C alifornia law , e m p lo y e d b y a s e p a r a te C alifornia p ro fe ssio n a l m e d ical c o rp o ratio n doing b u s in e s s a s C ity of H o p e M edical G ro u p . T h e s e rv ic e s of th e s e individuals, including r e s e a rc h s e rv ic e s, a re p ro v id e d to City of H ope N ational M edical C e n te r a n d C ity of H ope B ec k m an R e s e a rc h Institute b y City of H o p e M edical G ro u p u n d e r a P ro fe ssio n a l m e d ical S e rv ic e s A g re e m e n t b e tw e e n C ity of H ope M edical G ro u p a n d C ity of H o p e N ational M edical C e n te r. A s m e m b e rs of th e C ity of H ope N ational M edical C e n te r M edical S taff a P ro fe ssio n a l Staff, a n d u n d e r th e te rm s of th e P ro fe ssio n a l M edical S e rv ic e s A g re e m e n t, C ity of H o p e M edical G ro u p p e rs o n n e l w h o w ork on g ra n ts of City o f H o p e N ational M edical C e n te r or C ity o f H o p e B ec k m an R e s e a rc h Institute a r e su b je c t to all legal re q u ire m e n ts a n d s p o n s o r re q u ire m e n ts of th e g ra n ts to th e s a m e ex te n t a s if th e y w e re e m p lo y e e s of C ity of H ope N ational M edical C e n te r a n d C ity of H o p e B ec k m an R e s e a rc h Institute. F o r b u d g etin g a n d g ra n t re im b u rs e m e n t p u rp o s e s with re s p e c t to g ra n ts a w a rd e d to C ity of H ope N ational M edical C e n te r or City of H o p e B ec k m an R e s e a rc h Institute. C ity of H ope M edical G ro u p p e rs o n n e l a re tre a te d a s e m p lo y e e s of C ity of H o p e N ational M edical C e n te r or City o f H ope B eck m an R e s e a rc h Institute, a s th e c a s e m a y b e. City of H o p e M edical G ro u p is not tre a te d a s a s u b c o n tra c to r for th is p u rp o s e , a n d n o C ity of H ope M edical G ro u p F&A ra te is a d d e d to th e c h a rg e for th e effort of th e City of H ope M edical G roup p e rs o n n e l. T h e ap p lic a b le F&A ra te of City of H ope N ational M edical C e n te r or City of H ope B eck m an R e s e a rc h Institute is ap p lied d irectly to s a la ry a n d fringe b en e fit c h a rg e s for C ity of H ope M edical G ro u p p e rs o n n e l, a s it is for C ity of H ope N ational M edical C e n te r a n d City of H ope B ec k m an R e s e a rc h Institute P age 10 215 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M. P a lm e r________ em p lo y e e s. F rin g e B e n e fits : F ringe b e n e fits in c lu d e payroll ta x e s , w o rk m a n 's c o m p e n s a tio n , g ro u p h ea lth p la n , m ed ical, d en ta l a n d life in s u ra n c e , re tirem e n t. SU I, a n d long te rm disability. T h e frin g e b en e fit ra te s for th e different g ro u p s of e m p lo y e e s a re a s follows: R e s e a rc h S c ie n tis ts O rg an izatio n (Jo y c e ly n n e M. P alm er): 1 7 .4 % R e s e a rc h S c ie n c e O rg an iza tio n (J o y c e C. Niland): 2 9 .7 % M edical G ro u p (D avid S . S n y d er): 2 7 .5 % O p e r a tin g E x p e n s e s : S u p p lie s: M iscellan eo u s office s u p p lie s a n d c o m p u te r su p p lie s will b e p ro v id e d b y th e C ity of H ope N ational M edical C e n te r. O th e r e x p e n s e s : P h o to co p y in g e x p e n s e s , m a in te n a n c e of th e P rincipal In v e stig a to r's p e rs o n a l co m p u ter, a n d se c re ta ria l su p p o rt will b e c o v e re d by th e City of H ope N ational M edical C en ter. E g u lp m e n t E x p e n s e s : N one re q u e s te d . T h e eq u ip m e n t n e e d e d for th is p roject, (e.g . c o m p u te r w o rk statio n , printer, facsim ile, a n d te le p h o n e ) will b e p ro v id e d b y th e C ity of H ope N ational M edical C e n te r. Travel: W e h a v e b u d g e te d for th e principal in v e stig ato r to a tte n d o n e scientific m e e tin g during Fiscal y e a r 01 for th e p u rp o s e of p re s e n tin g s tu d y re su lts. For F iscal Y e a r 01, a to tal of $ 1 8 5 0 h a s b e e n b u d g e te d for airfare, ho tel, a n d trav el re la te d e x p e n s e s . T ravel in s u b s e q u e n t fiscal y e a rs to p ro fessio n al m e e tin g s will b e s u b sid iz e d by th e C ity of H o p e N ational M edical C en ter. S u b c o n tr a c ts : N one. O th e r C o s ts : N one. In d ire c t C o s t s : Indirect c o s ts a re c a lc u la te d a t th e ra te of 8 % to c o v e r th o s e ce n tra liz e d s e rv ic e s w hich c a n n o t b e read ily identified a n d a llo c a te d to sp ecific p ro je cts. T h e s e c o s ts co v e r th o s e s e rv ic e s su c h a s utilities, m a in te n a n c e , ac co u n tin g , re s e a rc h ad m in istra tio n , a n d th e library. P age 11 216 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M. P a lm e r FORM 10 Required for all applications. S ee Section 25 in Application Packet for additional instructions. Biographical Sketch Give the following information for each person listed on the Key P ersonnel Form, including consultants and collaborators, and begin with the principal Investigator. Reproduce th ese two p ag es for each person. P ag es should be num bered sequentially within the application. NAME POSITION TITLE Jo y c e ly n n e M ichelle P a lm e r S u p p o rt S cien tist EDUCATION: (Begin with baccalaureate or other Initial professional education, such a s nursing, and include postdoctoral training.) INSTITUTION AND LOCATION DEGREE YEAR CONFERRED FIELD OF STUDY U n iversity o f C alifornia, Irvine B.S. 1 9 9 3 Biology U niversity o f C alifornia, Irvine B.A. 1 9 9 3 P sy c h o lo g y U n iversity o f S o u th e rn C alifornia (U S C ), K eck S ch o o l of M edicine M.S. 1 9 9 5 A pplied B io statistics/ E p idem iology U n iversity o f S o u th e rn C alifornia (U S C ), K eck S ch o o l of M edicine Ph.D . In p ro g re s s P rev en tiv e M edicine: E p idem iology RESEARCH ANDfOR PROFESSIONAL EXPERIENCE: Concluding with present position, list, in chronological order, previous employment, experience, and honors. Include present membership on any Federal Government public advisoiy committee. List, In chronological order, the titles, all authors, and complete references to all publications during the past three years end to representative earlier publicaions pertinent to this application. If the list of publications in the last three years exceeds two pages, select the most pertinent publications. DO NOT EXCEH) THESE TWO PAGES. Do not send reprints or manuscripts as part of this form. Professional Background: Assistant Editor. Computational Statistics and Data Analysis Journal, 1993-1995 Statistical Consultant, Statistical Consultation and R esearch Center, USC D epartm ent of Preventive Medicine. 1993-1996 D ata Coordinator/Biostatistician, ‘Ethnicity and Attitudes toward Advance Care Directives’, USC D epartm ent of Medicine -Center for Health Policy and Ethics, 1993-1997 Assistant Project Coordinator. ‘ W om en's Estrogen-Progestin Lipid Lowering Hormone A therosclerosis R egression Trial'. USC Departm ent of Medicine, 1994-1996 Data Coordlnator/Biostatlstlclan, ‘Effectiveness of Two Occupational Therapy Treatm ents for the E lder!/, USC D epartm ent of Occupational Therapy, 1994-1998 Project Coordinator/Epidemiologist, ‘Environmental Health Effects Study', University of Callfomia-lrvlne D epartm ent of Medicine -Division of Epidemiology. 1996-1998 Senior D ata Anatyst/Biostatlsticlan, City of H ope National Medical C enter-D epartm ent of Biostatistics, 1998-2001 Support Scientist, City of Hope National Medical Center -Division of Information S ciences. 2002-present Honors and Awards: D ean’s Honor List, University of Califomia-lrvlne B accalaureate Cerem ony Scholastic Achievement Honoree, University of Callfomla-lrvine National institutes of Health G raduate R esearch Scholarship, University of Southern California. 1994-1996 National institutes of Health G raduate R esearch Fellowship -Clinical Science. University of Southern California. 1996-1997 Invited Lecturer: Improving Statistical Analysis and Design in Clinical R esearch Trials Barnett International's 2nd Annual Conference on Statistical Analysis and Design, Philadelphia. PA. 2001 Minority W omen; Mind. Body and Spirit California's W om en's Health Coalition, Third Biennial Health Care Symposium. O range, CA, 2001 Data Collection's Impact on Statistical O utcom es Clinical Trials Data M anagem ent Training Course, City of Hope National Medical Center, Duarte. CA. 2001-2004 Epidemiological M ethods to Estim ate Risk; Background and Application Intensive Course In C ancer Risk A ssessm ent for Genetic Counselors and A dvanced Practice N urses. C ancer Genetics Technology Transfer R esearch -City of Hope National Medical Center, Duarte. CA. 2001-2002 P a g e 12 217 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M. P a lm e r________ FORM 1 0 (Continued) I RESEARCH AND/OR PROFESSIONAL EXPERIENCE (C ontinued) S elec te d P u b lic a tio n s: Murphy ST, P alm er JM. Azen S P, Frank G. Michel V . Blackhali LJ. Ethnicity and advanced care directives. Journal o f Letw, Medicine and Ethics 24:108-17.1996. Clark F, Azen SP, Zemke R. Jackson J, Carlson M. M andel D, Hay J, Jo sephson K, Cherry 8. H essel C. P alm er JM , Lipson L. Occupational therapy for Independent-living older adults: A random ized controlled trial. Journal o f the American Medical Association 278:1321-1326.1997. Snyder DS. N adem anee AP. O'Donnell MR, Parker PM, Stein AS. Margolin K. Somio G, Molina A, Spielberger R, K ashyap A, Fung H. Vora N, Slovak ML. Niland JC, P alm er JM. Negrin RS, Amyl on MD. Blume KG, Form an S J. Allogeneic bone marrow transplantation for bcr-abl positive acute lymphoblastic leukemia. Acute Leukemia VIII Proceedings, Publisher Sprfnger-Veriag Heidelberg, Germ any 1999. Azen SP. P alm er JM , Carlson M, M andel D, Cherry BJ, Fanchlang S, Jackson J. Clark F. Psychometric properties of a C hinese translation of the SF-36 health survey questionnaire in the well elderly study. Journal o f Aging and Health 11(2): 240-251,1999. Blackhali LJ, Frank G. Murphy ST. Michel V. P alm er JM , Azen S P. Ethnicity and attitudes towards life sustaining technology. Social Science and Medicine 4 8 :1 779-1789.1999. Kashyap A, Kandeef F. Yamauchi D. P alm er JM . Niland JC, Molina A, Fung H. Bhatia R .K rishnan A. N adem anne A, O'Donnell MR. Parker P. Rodriguez R. Snyder D, Spielberger R, Stein A, N a d e r J. Forman S J. Effects of allogeneic bone marrow transplantation on recipient bone mineral density: A prospective study. Biology o f Blood and Marrow Transplantation 6: 344-351, 2000. Snyder DS (Acknowlegement: P alm er, JM ). A logenelc stem cell transplantation for Philadelphia chrom osom e positive acute lymphoblastic leukem ia. Biology o f Blood and Marrow Transplantation 6:597-603, 2000. O’Donnell MR, Hu W. Stein A, P alm er JM . Amylon M, Chao N, Parker P . Snyder DS. N adem annee A. Smith EP, Molina A, Rodriguez R. Niland JC , Margolin K, Spielberger R. Kashyap A. R osenthal J, Krance R, Blume K, Forman S. The effect of allogeneic bone marrow transplantation for treatm ent of severe aplastic anem ia (SAA): A twenty year perspective. (In Review) Rodriguez R, N adem anee AP, P alm er JM , N land JC, Forman SJ. H igh-dose therapy and autologous stem ceft transplant for patients with primary m ediastinal large cell lymphoma. (In Preparation) Stein AS, K ashyap A, P alm er JM . Niland JC . Form an S J. Oral busulfan in combination vtfth fractionated total body irradiation (FTBI) and etoposide (VP-16) as a preparative regimen for allogeneic bone m arrow transplant (BMT) for patients with advanced leukem ias. (In Preparation) S e lected A b s tra c ts : (Out of 11 PubRshed Scientific Abstracts) Molina A, N adem anee A, O'Donnell M, Snyder D. P alm er JM , Fung HC. Parker PM. Stein AS, Kashyap A. Spielberger RT. Somlo G, Krishnan A. Bhatia R. Clinkenbeard D. Vora N. Niand J. Form an SJ. Autologous and allogeneic stem cell transplantation for poor-risk m antle cell lymphoma: The City of H ope experience. Blood, Journal o f the American Society o f Hematology 92(10):459a, 1998. N adem anee A. Molina A. P alm er JM. Rodriquez R. O'Donnell M, Stein A. Snyder DS, Parker P, Fung HC. K ashyap R. Spielberger R, Krishnan A, Bhatia R. Hyde S, Nil a id JC. Form an S J. Hlgh-dose therapy and autologous stem cell transplant for patients with primary m ediastinal large cell lymphoma: Analysis of prognostic factors. B bod, Journal o f the American Society o f Hematology 92(10):462a, 1998. Fung HC, Snyder D, K ashyap A. Stein A, Molina A. N adem anee A, O ’Donnell MR. P a lm e r JM, Hllger J, Slovak ML, Spielberger R. Parker P. Vora N, Krishnan A, Rodriguez R. Bhatia R, Niland JC, Blume K. Forman S J. Long term follow-up report of aiogeneic bone marrow transplantation for patients with acute leukemia in first complete remission utiRzing fractionated total body irradiation (FTBI) and high dose etoposide: Late relapse Is an uncomm on ca u se of treatm ent failure. Program/Proceedings, American Society o f Clinical Oncology 18: 8a, 1999. Fung H. Jam ieson C, Snyder D, O'Donnell M. C hao N. Stein A. N adem anne A, Molina A, P alm er JM . Negrin R. Hilger J, Slovak ML. Spielberger R. Parker P, Forman S. K ashyap A. Vora N. Krishnan A . Rodriguez R, Bhatia R. Niland JC , S e n tz e r D. Arber D, Amylon M, Arbayo C, Blume KG, Forman S J. Allogeneic Bone Marrow Transplantation (BMT) for AML in First Rem ission (1CR) Utilizing Fractionated Total Body Irradiation (FTBI) and V P-16: Analysis of Risk Factors for R elapse and D isease-Free Survival. Blood, Journal o f the American Society o f H ematology 94(10): 7 30,1999. Fung HC, N adem anee A. P alm er JM , Molina A, K ashyap A, Spielberger R, Hllger J, O'Donnell M, Snyder D, Stein A, Parker P, Bhatia R. Krishnan A. Rodriguez R. Vora N. Mland J, Form an S J. High D ose Therapy Followed by Autologous Stem Cell Transplantation (ASCT) for Patients with Prim ary Refractory Hodgkin's D isease (HD): Evaluation of Prognostic Factors. Blood, Journal of the American Society of Hematology 94(10): 7 61.1999. P age 13 218 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M. P a lm e r FORM 10 Required for all applications. S ee Section 25 in Application Packet for additional instructions. Biographical Sketch Give the following information for each person listed on the Key Personnel Form, including consultants and collaborators, and begin wtth the principal Investigator. Reproduce th ese two p ag es for each person. P ag es should b e n u n b ered sequentially within the application. NAME A o s i r t o N m e Joyce Carol Niland Chair, Division of Information S ciences Director, D epartm ent of Biostatistics EDUCATION: (Begin with baccalaureate or other Initial professional education, such a s nursing, and include postdoctoral training.) INSTITUTION AND LOCATION DEGREE VEAft CONFERRED FIELD OF STUDf Stanford University, Palo Alto B.A. 1975 Human Biology University of Southern California, Los A ngeles M.S. 1978 Physical Therapy University of Southern California, Los A ngeles M.S. 1979 Biometry University of Southern California, Los A ngeles Ph.D. 1984 Biometry RESEARCH ANOfOR PROFESSIONAL EXPERIENCE: Concluding with present position, list, in chronological order, previous employment, experience, end honors. Include present membership on any Federal Government public advisoiy committee, List, in chronological order, the titles, all authors, and complete references to all publications during the past three years and to representative earlier publications pertinent to this application. If the list of publications in the last three years exceeds two pages, select the most pertinent publications. DO NOT EXCEED THESE TWOPAGES. Do not send reprints or manuscripts as part of this form. P ro fessio n al B ack g ro u n d : 1977-1984 R esearch A ssodate, Department of Preventive Medicine. Division of Biometry. University of Southern California (USC) School of Medicine. Los Angeles 1980-1984 Instructor, Department of Preventive M edidne, Division of Biometry. USC 1983 Visiting Instructor. University of California at Irvine. School of Medidne 1985-1988 Assistant Professor, Department of Preventive Medicine. Division of Biometry. USC 1985-1988 Co-Director, Biostatistics Core, Transfusion Safety Study, USC 1988-1995 Associate R esearch Scientist. Department of Biostatistics. City of Hope National Medical Center (COHNMC) 1988-present Clkiical Associate Professor of Preventive M edidne. USC 1988-present Director. Department of Biostatistics. COhMMC. Duarte, CA 1991-present Principal Investigator, integrated Advanced Information M anagement System s (IAIMS) Planning and Operational Grants, COHNMC 1995-present R esearch Scientist, Department of Biostatistics, COHNMC 1997-present Chair. Division of Information S ciences, COHNMC H onors and A w ards: 1977 Graduation wtth honors. M.S. In Physical Therapy. USC 1979-present Phi Kappa Phi National Al-Unlverslty Honor Society 1997 W omen of Achievement Award. S an Gabriel Valley YWCA 1998 Elected Fellow of the American Statistical Association S e lected P e e r R eview P u b licatio n s (o u t o f o v e r 80 p u b lish e d p a p e rs) Parker P. Chao NJ, Ben-Ezra J, Statkin N, O penshaw H, Niland JC , Linker CA, Greffe BS, Kashyap A. Molina A. N adem anee A. O 'D onnel MR. P lan as I, Sheibani K, Smith EP. Snyder DS, Spielberger R, Stein AS, Stepan DE. Blume KG, Forman SJ. Polymyositis a s a manifestation of chronic graR-versus-host d isease. Medicine 1996:75:5:279-285. Chao NJ. Parker PM, Niland JC, W ong RM, Dagis A. Long GD. N adem anee AP. Negrin RS. Snyder DS. Hu WH, Gould KA. Tierney DK. Z w ngenberger K. Form an S J and Blume KH. Paradoxical effect of Thalidomide prophylaxis on chronic grafl-versus-host disease. Biology of Blood and Marrow Transplantation 2(2):86-92,1996. Gallez-Hawkins GM. Tegtmeier BR, ter V eer A, N iland J C , Forman S J. Zaia JA. Evaluation of a quantitative plasm a PCR plate a ssa y for detecting cytomegalovirus infection In marrow transplant recipients. Journal of Clinical Microbiology 1997:35:3:788-790. W lson, CS. Traweek. ST, Slovak ML, N iland JC , Forman S J. Brynes RK. Myelodysplastic syndrom e following autologous bone m arrow transplantatlon for lymphoma: morphologic features. American Journal of Clinical Pathology. 1997:108:4:369-377. Zaia JA, Gallez-Hawkins GM, Tegtmeier BR. ter V eer A. Li X, N iland J , Forman S. Late cytomegalovirus d isease in marrow transplantation Is predicted by virus load in plasm a. Journal of Infectious D iseases. 1997:176:3:782-785. N adem anee A. Molina A, O'Donnell MR. Dagls A. Snyder DS, Parker P. Stein AS. Smith E, Planas I, K ashyap A, Spielberger R, Fung HC, W ong KK. Somlo G. Margolin K, Chow W. S niednski I, Vora N, Blume KG. N iland J.Form an S J. Results of hlgh-dose therapy P a g e 14 219 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M. P a lm e r________ and autologous bone marrovtfstem c e l transplantation during remission In poor-risk Intermediate and high-grade lymphoma: international index high and high-intermediate risk group. Blood 1997:90:10:3844-3852. Long GD, Amylon MD, Stockerl-Goldstein KE, Negrin RS. C hao NJ, Hu WW, N adem anee AP, Snyder DS, Hoppe RT, Vora N, W ong R. N iland J . Reichardt VL. Forman S J. Blume KG. Fractionated total-body Irradiation, etoposide, and cyclophosphamide followed by allogeneic bone marrow transplantation for patients with high-risk or advanced-stage hematological m alignancies. Bioloov of Blood and Marrow Transplantation 1997:3:6:324-330. M omand J. Jung D, Wilczynski S, N iland J C . The MDM2 amplification d atab ase. Nucleic A dds R esearch 1998:26:15:3453-3459. Smith EP. Sniecinski I. Dagis AC, Parker PM. Snyder DS. Stein AS, N adem anee A, O’Donnell M l, Molina A, Schmidt GM. S tepan DE. Kapoor N, N iland JC . Forman SF. Extracorporeal photochem otherapy for treatm ent of drug-resistant graft-vs.-host d isease. Biology of Blood and M anow Transplantation 1998:4:1:27-37. Sektzaw a T, O penshaw H. Ohbo K, Sugam ura K, Itoyama Y. N iland J . C erebrosphal fluid Irterteukln 6 In amyotrophic lateral sclerosis: immunological param eter and com parison wtth inflammatory and non-inflammatory central nervous system diseases. Journal of the Neurological S cien ces. 1998:154:194-199. N iland J . NCCN Internet-Based Data System for the Conduct of O utcom es Research. Oncology 1996:12:11. Margolin K, Van Besien K, Champlin R. N iland J , Wright C, Fung H. K ashyap A. Molina A, N adem anee A. O'Donnell M. Parker P. Planas I. Smith E. Spielberger R. Somlo G. Snyder D, Stein A, W oo D. Brown A, Amin K. Thom as M. Snieclnsk I. Forman S. lnterieukin-2-activated autologous bone marrow and peripheral blood stem cells in the treatm ent of acute leukemia and lymphoma. Biology of Blood and Marrow Transplantation 1999:5:1:36-45. N iland J NCCN Outcom es R esearch D atabase: The First TWo Years of D ata Coltectlonand Analysis, Oncology. 1999:13:11A, N adem anee A. Molina A. Fung H. Stein A, Parker P. Plana I. O ’Donnell MR. Snyder DS, Kashyap A, Spielberger R Krishnan A. Sniecinski I, Vora N. Dagis A. Niland J . Forman S. High-dose chem o/radiotherapy and autologous bone marrow or stem cell transplantation for poor-risk advanced stag e Hodgkin's d isease during first partial or complete remission: results of a pilot study. Bioloov of Blood and Marrow Transplantation 1999:5:292-298. R oss M. Schmidt GM, N iland JC , Amylon MD, Dagis AC, Long GD. N adem anee AP, Negrin RS. O'Donnell MR, P arker PM. Smith EP. Snyder DS. Stein AS. W ong RM. Forman S J, Blume KG, Chao NJ. Cyclosporine. m ethotrexate, and prednisone com pared with cyclosporine an d prednisone for prevention of acute graft-vs.-host disease: effect on chronic graft-vs.-host d isease and long-term survival. Btoloqyjtf Blood andM arrow Transplantation 1999:5:5:285-291. Snyder. D.S.. N adem anee. A.P.. O’Donnell. M.R.. Parker, P.M.. Stein. A.S.. Margolin, K.. Somlo, G., Molina, A., Spielberger, R., K ashyap. A.. Fung, H., Vora. N., Slovac. M., Niland, J.. Palm er, J., Negrin, R.S., Amylon. M.D., Blume, K.G., and Forman. S J . Allogeneic bone marrow transplantation for BRC-ABL positive acute lymphoblastic leukemia. Acute Leukemia Vlil Proceedings, Publisher Springer-Vertag Heidelberg, G erm any 1999. Krishnan A, Bhatia S, Slovak ML. Arber DA. Niland JC . N adem anee A, F ung H. Bhatia R, Kashyap A. Molina A. O'Donnell MR. Parker PA, Sniecinski I, Snyder DS. Spielberger R. Stein A. Forman S J. Predictors of therapy-related leukemia and myelodysplasia following autologous transplantation for lymphoma: an a ssessm en t of risk factors. Blood 2000:95:5:1588-1593. Chao NJ, Snyder DS. Jain M. Wong RM, Niland JC , Negrin RS, Long GD, Hu WW, Stockerl-Goldstein KE, Johnston L J. Amylon MD. Tiemey DK. O'Donnell MR. N adem anee AP. Parker P. Stein A. Molina A. Fung H. K ashyap A. Kohler. S. Spielberger R. Krishnan A. Rodriguez, R. Forman S J. Blume KG. Equivalence of 2 effective graft-versus-host d isease prophylaxis regim ens: results of a prospective double-blind random ized trial. Bioloov of Blood and Marrow Transplantation 2000:6:3:254-261. Stein AS. O'Donnell M l. Slovak ML. N adem annee A. Dagis A. Schmidt GM, Parker PM, Snyder DS, Smith EP. Somlo G. Margolin KA, Arber D. Niland J . Forman S J. High-dose cytosine arabinoslde and daunorubicin induction therapy for adult patient with de novo non M3 acute m yelogenous leukemia: impact of cytogenetics on achieving a complete remission. Leukemia 2000:14:1191-1196. K ashyap A. Kandeel F. Yam auchl D. Palm er JM. N iland J C , Molina A, Fung H. Bhatia R. Krishnan A. N adem anee A. O'Donnell MR. Parker P, Rodriguez R, Snyder D. Spielberger R, Stein A. Nadler J, Form an S J. Effects of allogeneic bone marrow transplantation on recipient bone mineral density: a prospective study. Biology of Blood and Marrow Transplantation 2000;6:344-351. N iland JC . NCCN Outcom es R esearch D atabase: D ata Collection Via the Internet. Oncolocv 2000:14:11 A. Bhatia. S, Louie. AD, Bhatia, R, O'Donnell, MR. Fung. H. Kashyap, A, Molina. A, N adem anee. A, Niland, J C , Parker. PA. Sniecinski, I, Snyder DS. Spielberger, R. Stein, A. Form an, S J. Solid cancers following bone marrow transplantation. Journal of Clinical Oncology. 2001:1:15:19(2): 464-71. P a g e 15 220 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M. P a lm e r FORM 10 Required for all applications. S ee Section 25 in Application Packet for additional instructions. Biographical Sketch Give the following information for each person listed on the Key P ersonnel Form, including consultants and collaborators, and begin wtth the principal Investigator. Reproduce th ese two p ag es for each person. P ag es should be num bered sequentially within the application. N A M E POSmONTfTLE David S. Snyder A ssociate Director, H em atology and Bone Marrow Transplantation EDUCATION: (Begin wtth baccalaureate or other initial professional education, such as nursing, and include postdoctoral training.) INSTITUTION AND LOCATION DEGREE YEAR CONFERRED FIELD OF STUDY Yale College, N ew Haven, CT B.S. 1 9 7 3 Biophys/Biochem Harvard Medical School, Boston, MA M.D. 1 9 7 7 Medicine RESEARCH A N O T O R PROFESSIONAL EXPBUENCE: Concluding with present position, list, in chronological order, previous employment, experience, and honors. Include present m em bership on any Federal Government public advisory committee. List, in chronological order, the titles, all authcrs, and com plete references to all publications during th e past three years a i d to representative earlier publicaions pertinent to this application. If the list of publications in th e last th ree y ears exceeds two pag es, select the m ost pertinent publications. D O NOT EXCEB) THESE TW O PAGES. Do not send reorints or m anuscripts a s part of this form. P ro fessio n al B ackground: 1977-1978 Intern in Medicine, Columbia-Presbyterian Hospital, New York. NY 1978-1980 Junior and Senior Resident In Medicine. Beth Israel Hospital. Boston, MA 1980-1982 R esearch Fellow in Immunology, Dept, of Pathology. Harvard Medical School, Boston, MA 1982-1983 Clinical Fellow in Hematology-Oncology. Tufts-New England Medical Center. Boston. MA 1983-1984 R esearch Fellow in Hem atology-Oncoiogy, Tufts-New England Medical Center, Boston, MA 1984-1993 Staff Physician. D epartm ent of Hematology and Bone Marrow Transplantation, City of Hope National Medical Center, Duarte, CA 1993-presertt A ssociate Director. D epartm ent of Hematology and Bone Marrow Transplantation, City of Hope National Medical Center. Duarte. CA 2000-present National Com prehensive C ancer Network (NCCN): C M . Panel Member S e lected P e w R eview P u b lic a tio n s: Blume KG. Forman S J. O'Donnell MR, Doroshow JH. Krance RA. N adem anee AP, S n y d e r DS. Schmidt GM Fahey JL. M etier GE. Hill LR, Findley DO. Sniecinski IJ: Total Body Irradiation and High-dose Etoposide: A new preparatory regim en for bone marrow transplantation in patients vtfth advanced hematologic m alignancies. Blood 69:1015.1987. S n y d e r DS. Wright CL. Ting C: Inhibition of Human M onocyte Antigen Presentation, but not HLA-DR Expression, by Cyclosporine. Transplantation 44 :4 0 7 ,1 9 8 7 . Forman SJ, O'Donnell MR, N adem anee AP, S n y d er DS, Blerm an P J, Schmidt GM, Fahey JL, Stein AS, Parker PM, Blume KG: Bone Marrow Transplantation for Patients with Philadelphia Chrom osom e Positive Acute Lymphoblastic Leukemia. Blood 70: 5 8 7.1987. S n y d e r DS, Findley DO. Form an S J, N adem anee AP. O'Donnell MR. Schmidt GM. Bierm an P J, F ahey JL, Krance RA. Sniecinski IJ. Doelken A. Llpsett JA. Luk KH. Nethwanl MB. Hill LR, Blume KG: Fractionated Total Body Irradiation and High Dose Cyclophospham ide: A preparative regim en for b one m arrow transplantation for patients vtfth hematologic m alignancies in first complete rem ission, glut 57: 7- 13.1988. S n y d er OS, Castro R, Desforges JF: Antiprolferative Effects of Lipoxygenase Inhibitors on Malignant Hum an Hematopoietic Cell Lines. Exp Hematol 17: 6-9.1989. Lange W, S n y d e r DS, Castro R, Rossi JJ. Blume KG: Detection by Enzymatic Amplification of 8CR-ABL mRNA in Peripheral Blood and Bone Marrow Ceils of Patients wtth Chronic M yelogenous Leukemia (CML). Blood 73:1735-1741.1989. Ahuja H. Bar-Eli M. Clarke P, S n y d er DS. Forman S, Goldman J. Cline MJ: p53 Gene Aterations in Blast Crisis of Chronic M yelogenous Leukemia. C ancer Cells 7:117-1 2 0 ,1 9 8 9 . S n y d e r DS. Rossi JJ. W ang JL. Smeclnski IJ. Slovak ML, W allace RB, Forman S J: P ersistence of bcr-abl G ene Expression Following Bone Marrow Transplantation for Chronic M yelogenous Leukemia In Chronic P h ase. Transplantation. 51:1033-1040. 1991. Schmidt GM. Horak DA. Niland JC , Hogan IM. Hill LR. Wall FR, Gallez-Hawkins G. MoriorvBlackshere A. N adem anee AP, O'Donnell M l, Parker PM, S n y d e r DS, Smith E. Stein A, Kovacs AA. DeArmond B. Buhles W. DuMond C, Duncan SR. Chao NJ. Blume KG, Form an S J. Zaia JA: A Random ized Controlled Trial of Prophylactic Ganciclovir for Cytomegalovirus Pulmonary Infection in Allogeneic Bone Marrow Transplant Recipients. NEJM 324:1005-1011.1991. Ahuja H, Bar-Eli M, Arlin Z, Advani S. Allen SL. Goldman J, S n y d e r DS, Foti A, C in e M: The Spectrum of Molecular Alterations in P age 16 221 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M. P a lm e r________ the Evolution of Chronic Myelocytic Leukemia. J Clin Investigation. 87: 2042-2047,1991. S n y d e r DS, Wu Y, W ang JL. Rossi JJ, Swiderski P, Kaplan BE. Forman SJ: Rbozym e-M edlated Inhbition of bcr-abl Gene Expression in a Philadelphia Chrom osom e-Positive Cell Line. Blood 82: 660, 1993. S n y d e r DS, Taguchi J, Chao NJ, Amylon MD, Long GD. Negrin RS, N adem anee AP. O'Donnell MR. Schm idt GM. Stein AS, Parker PM. Smith EP, Stepan DE. Molina A. Lipsett JA. Hoppe RT, Niland JC . Dagis AC. W ong RM. Forman SJ, Blume KG: Fractionated Total Body Irradiation and High-Dose Etoposide a s a Preparatory Regim en for Bone Marrow Transplantation for 99 Patients wtth Acute Leukemia in First Complete Rem ission. Blood 82:2920.1993. Chao NJ, Schmidt GM, Niland JC . Amylon MD, Dagis AC. Leong GD, N adem anee A, Negrin RS. O’Donnell W*. Parker PM. Smith EP, S n y d e r DS. Stein AS. W ong RM. Blume KG. Forman S J: Cyclosporine, M ethotrexate, and Prednisone Com pared vtfth Cyclosporine and Prednisone for Prophylaxis of Acute Graft-Versus-Host D isease. NEJM (3271:1225-1230.1993. Brynes RK. McCourty A, Ho JP . Traweek ST, S n y d e r DS, Slovak ML: Detection of the Philadelphia Chrom osom e in Paraffin-Em bedded Tissue by Fluorescence In Situ Hybridization. Modem P dhology 8: 5, (1994). S n y d e r DS, Negrin RS, O'Donnell MR, Chao NJ, Amylon MD. Long GD. N adem anee A. Stein AS, Parker PM, Smith EP. Somlo G, Margolin KA, Lipsett JA. Hoppe RT, Slovak ML, Niland JC . Dagis AC, W ong RM, Forman SJ,Blume KG: Fractionated Total Body Irradiation and Hlgh-Dose Etoposide a s a Preparatory R egim en for Bone Marrow Transplantation for 94 Patients vdth Chronic M yelogenous Leukemia in Chronic P h ase. Blood Vol. 84 5 :1 6 72-1679,1994. Shuhart MC. Myerson D, Childs BH, Fingeroth JD. Perry J J, S n y d e r DS, Spurgeon CL, Bevan CA, McDonald GB: Marrow Transplantation from Hepatitis C Virus Seropositive Donors: Transm ission R ate and Clinical Course. Blood 84(9): 3229,1994. Chao NJ, Blume KG. Forman S J, and S n y d e r DS: Long Term Follow Up of Allogeneic Bone Marrow R ecipients for Philadelphia Chrom osone Positive Acute Lymphoblastic Leukemia. Blood 85: 3353-3354,1995. S n y d e r DS. Wu Y. McMahon R, Lijuan Y, Rossi JJ. and Form anSJ: Rlbozyme-Mediated Inhibtlon of a Philadelphia Chrom osom e Positive Acute Lymphoblastic Leukemia Ceil Line Expressing the P190 BCR-ABL O ncogene. Biology of Blood and Marrow Transplantation 3:179-1 8 6 ,1 9 9 7 . Khalldi HS. Brynes, RK, M edeiros LJ. Chang KL. Slovak ML, S n y d e r DS, Arber DA: The Immunophenotype Of Blast Transformation Of Chronic M yelogenous Leukemia: A High Frequency of Mixed Lineage Phenotype In "Lymphoid' Blasts And A Com parison Of Morphologic. Immunophenotypic, and Molecular Findings. Mod Path Dec: 11(12): 1211-1221.1998. S n y d e r DS, N adem anee AP, O'Donnell MR. P arker PM. Stein AS. Margolin KA, Somlo G, Molina A, Spielberger R. K ashyap A. Fung H. Vora N, Slovak ML. Niland JC. Palm er J. Negrin RS, Amylon MD. Blume. KG, Forman SJ: Allogeneic Bone Marrow Transplantation for BCR-ABL Positive Acute Lymphoblastic Leukemia. Acute Leukemia Vtli P roceedings. Publisher Springer-Verlag Heidelberg, G erm any 1999. S n y d e r DS. N adem anee AP, O'Donnell .MR, P arker PM. Stein AS. Margolin KA, Somlo G, Molina A, Spielberger R. K ashyap A, Fung H, Vora N. Slovak ML. Dagis A, Negrin RS, Amylon MD, Blume KG, Form an SJ: A logeneic Bone Marrow Transplantation for Philadelphia Chrom osom e-Positive Acute Lymphoblastic Leukemia In First Complete Remission: Long Term Follow-up. Leukemia 13: 2053-2058, 1999. W uY , Yu L, McMahon R, Rossi JJ, Forman S J, S n y d e r DS: Inhibition o f bcr-abl O ncogene Expression By Novel Deoxyribozymes (DNAzvmesl. Human G ene Therapy 10(171 1999. Chao NJ. S n y d e r DS, Jain M. W ong RM, Niland JC . Negrin RS. Long GD. Hu WW. Stockerl-Goldstein KE. Johnston LJ, Amylon M.D, Tierney DK, O’Donnell MR, N adem anee AP. Parker P, Stein A, Molina A, Fung H, K ashyap A. Kohler S. Spielberger R, Krishnan A. Rodriguez R, Forman S J and Blume KG. Equivalence of 2 Effective Graft-Versus-Host D isease Prophylaxis Regim ens: Results of a Prospective Double-Blind Random ized Trial. Bioloov of Blood and Marrow Transplantation. 6:254-2 6 1 ,2 0 0 0 . S n y d er DS. Allogeneic Stem Cell Transplantation for PhBadelphia Chromosome-Positive Acute Lymphoblastic Leukemia. Bioloov of Blood and Marrow Transplantation 6:597-6 0 3 ,2 0 0 0 . Arber. DA. Snyder. DS. Fine M. Dagis A. Niland JC . Slovak M . M yeloperoxidase Immunoreadivtty in Adult Acute Lymphoblastic Leukemia. Am. J. Ciln. Pathology 116: 25-33. 2001. P a g e 17 222 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M, P a lm e r FO R M 1 0 Required for all applications. S ee Section 25 in Application Packet for additional instructions. Biographical Sketch Give the following information for each person listed on the Key Personnel Form, including consultants and collaborators, and begin wtth the principal Investigator. Reproduce th ese two p ages for each person. P a g e s should be num bered sequentially within the application. NAME W tifrtON TITlE S usan Preston-M artin P rofessor and Principal Investigator, D epartm ent of Preventive Medicine EDUCATION: (Begin with baccalaureate or other Initial professional education, such a s nursing, and Include postdoctoral training.) INSTITUTION AND LOCATION DEGREE YEAR CONFERRED FIELD OF STUDY Swarthm ore College, Pennsylvania BA. 1963 Experimental Psychology University of California, Los A ngeles, CA MPH 1972 Health S ervices/ Epidemioloqy University of California, Los A ngeles, CA Ph.D. 1978 Epidemiology RESEARCH ANOTOR PROFESSIONAL EXPERIENCE: Concluding with present position, list, in chronological order, previous employment, experience, and honors. Include present membership on any Federal Government public advisory com mi tree List, in chronological order, the titles, all authors, and complete references to all publications dunng the past three years and to representative earlier publications pertinent to this application. If the list of publications in the last three years exceeds two pages, select the most pertinent publications. DO NOT EXCEED THESE TWO PAGES. Do not send reDnnts or mmuscriots as Dart of this form. P ro fessio n al B ackground: 1972-1977 Head of Field O perations. Los Angeles County C ancer Surveilance Program 1978-1983 Assistant Professor of Preventive Medicine. University of Southern California (USC) 1984-1989 Associate Professor of Preventive Medicine. USC 1990- Professor of Preventive Medicine. USC H onors and A w ards: Swarthmore College: Full scholarship; Mortar Board Honor Society; Honors Program; 1959-1963 UCLA: Delta O m ega; Medical Center Award: Outstanding Graduate Scholar 1972-1978 International Agency for R esearch on Cancer. Visiting Scientist Award. 1984-1985 American C ancer Society. Faculty R esearch Award. 1988-1992 Fogarty Senior International Fellowship, 1991-1992; 2000-2001 N ational A dvisory C o m rrtttees: Edlorlal Boards: Cancer C auses and Control. 1994-2002; Neuro-Oncology. 1998- present Scientific Advisory Board. Electric Power R esearch Institute, 1995-present Board of Directors, Central Brain Tumor Registry of the U nled States, 1995-present Science Coundl, Radiation Effects R esearch Foundation, Hiroshima, Japan, 1996-2001 R epresen tativ e R ecen t P ublications; Preston-M artln S, M ack W . Neoplasm s of the nervous system . In: Schottenfeld D .Fraum eni JF, Jr (Eds.). C ancer Epidemiology and Prevention, Second Edition. Chapter 58. New York, NY. Oxford University P ress, 1996. Preston-M artin S. Navidl W. Thomas D. Lee P-J, Bowman J. Pogoda J. Los A ngeles study of residential magnetic fields and childhood brain tumors.Am J Epidemiol 143:105-119,1996 Preston-M artln S. Navidl W. Thom as D, Lee P -J. Bowman, J, Pogoda J. Evolution of epidemiologic evidence on m agnetic fields and childhood cancers. Am J Epidemiol 143:133-134.1996. Preston-M artln S. Epidemiology of primary CNS neoplasm s. Neurologic Clin 14:273-290,1996. Preston-M artin S, Pogoda JM. M ueler BA. Hoity EA. Ujinsky W. Davis RL. Maternal consumption of cured m eats and vitamins in relation to pediatric brain tum ors. C ancer Epidemiology Blomarkers & Prevention 5: 599-605, 1996. P reston-M artin S. Gurney J. Pogoda J. Holly E, Mueller B. Brain tumor risk In children in relation to electric blankets and water bed heaters: results of the U.S. W est C oast Childhood Brain Tumor Study. Am JE p i 143:1116-1122.1996. Dubois-Blowers L, Preston-M artin S, Mack W J. Dietary and other lifestyle factors In Los Angeles County women wtth gliomas. Cancer C au ses and Control 6(1):5-12,1997. Gumey J, Pogoda J, Holy E. Hecht S , Preston-M artln S. Aspartam e use and childhood brain tumors. JNCI 89:1072-74.1997 Gum ey JG, Mueller BA. Preston-M artln S , McDaniel AM. Holly EA. P ogoda JM; Davis RL. A study of pediatric brain tumors and their association with epilepsy and anticonvulsant use. Neuroepidemtology 16:248-255,1997. Bam es P. Yang Z. Preston-M artin S. Pogoda JM, Jo n es BE. Otaya M. Eisenach KD. Knowles L. Harvey S, Cave MD. Patterns of P a g e 18 223 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M. P a lm e r________ tuberculosis transmission in Central Los Angeles. JAMA 278:1159-1163,1997 Douer D, Cozen W, W ang F., Chang E, Preston-M artbi S, Levine AM. Descriptive epidemiology of acute promyelocytic leukemia - report from the cancer registry for Los Angeles County. Blood 90 (sup 1):72a,1997 Davis F. P reston-M artin S . Epidemiology - incidence and survival in central nervous system neoplasia. In: Blgner DD (Ed ) Russell and Rubinstein's Pathology of Tumors of the Nervous System , Sixth Edition. London, UK, Edward Arnold (Publishers) Ltd. V. 1 :5- 4 5 .1 9 9 8 . Preston-M artin S, Pogoda JM. Mueller BA. Lubin F. Modan B. Holly EA, et al.. Results from an international case-control study of childhood brain tumors: the role of prenatal vitamin supplementation. Environ Health P erspectl 06 (suppl 3):887-892,1998. Barkan SE. Melnick SL. Preston-M artin S. W eber K. Kaltsh L, Mott). P. Young M, Padian N. Sacks H. Feldman J. for the WIHS Colaborative Study Group. The W omen's Interagency HIV Study (WIHS) - Design, m ethods, sam ple, cohort characteristics and comparison vrith reported AIDS cases in U.S. women.. Epidemiology 9 :117-125,1998 Preston-M artin S, Pogoda J. Schlehofer B. Blettner M. Howe GR. Ryan P. M enegoz F, G le s GG, Rodvall Y. Choi NW. Little J, Arslan A. Results from an International case-control study of adiit glioma and meningioma: the role of head traum a. Int'l J of Epidemiology 27:579-586,1998. Ron E, Doody MM, 8ecker D. Brill AB, Curtis RE, Goldman MB, Harris B. Hoffman DA, Maxon H. McConahey W. Preston-M artin S. W arshauerE .W ong L.Bolce J. Cancer mortally following treatment for adult hyperthyroldsm. JAMA 280(4):347-355.1998. McKean-Cowdln R, Preston-M artin S, Pogoda JM. Holly EA. Mueller BA. Da\4s RL. Parental Occupation and Chilcftood Brain tumors: astroglial and Primitive neuroectoderm al tumors. J Occ En\Hron Med 40:332-340,1998. Bunin G. Suravdcz T. Witman PA. Preston-M artin S. Davis F. Bruner JM. The descriptive epidemiology of craniopharyngioma. Journal of Neurosurgery 89 :547-551.1998 Preston-M artin S. Pogoda JM. Mueller BA. LublnF, Modan B, Holy EA, eta l. Prenatal vtam in supplem entation and pediatric brain tumors: huge friternational variation In use and possible reduction in risk. Child Nerv Syst 14:551-557,1998. Pogoda J. Preston-M artin S. Pesticide exposure and development of brain tumors In chfldren in Los Angeles County. Environ. Health Perspectives 105:1214-1220.1998 Preston-M artin S. Pogoda JM. Mueller BA. Lubin F. Modan B. Holy EA. Fil^pini G. Cordler S, Peris-Bonet R. Choi W. Little J, Arslan A.Prenatal vitamin use and risk of childhood brain tumors, int’l J of Cancer suppl. 11:17-22.1996. Holy EA. Bracci PM. Preston-M artin S, Mueller BA. Farm and farm animal exposures and pediatric brain tumors: Results form the U nled States W est C oast Childhood Brain Tumor Study. Cancer Epidemiol Blomarkers Prev 7:797-802,1998. Bam es PF, Yang Z, Pogoda JM, Preston-M artln S. Jo n es BE. O taya M. Knowles L,Harvey S . Eisenach KD, Cave MD. Foci of tuberculosis transmission in central Los Angeles. Am J Respiratory Crtt Care Med 159:1081-1086,1999. LaVecchia C, Ron E. Franceschl S, Dal Maso LD. Mark SD. Chatenoud L. Braga C. Preston-M artin S, et al. A pooled analysis of case- control studies of thyroid cancer. III. Oral contraceptives, m enopausal replacem ent therapy and other female horm ones. Cancer C au ses and Controls 10:157-166,1999. Negri E. Ron E. Franceschl S: Dal Maso L. Mark SD. Preston-M artln S , et al. A pooled analysis of case-control s tu d e s of thyroid cancer. I. Methods. Cancer C au ses and Controls 10:131-142,1999. N ey t E. Dal Maso L, Ron E, LaVecchia C. Mark SD, Preston-M artin S , et al. A pooled analysis of case-control studies of thyroid cancer. II. Menstrual and reproductive factors. Cancer C auses and Controls 10:143-155.1999. Schlehofer B, Blettner M. Preston-M artin S , . Niehoff D, W ahrendorf J, Arslan A. et al. The role of medical history in brain tumor development: results form the International adult brain tumor study. Int J C ancer 82:155-160,1999. McCredie M. Little J. Cotton S. Mueller B. Peris-Bonet R, Choi NW. P reston-M artin S. et al. A. SEARCH international case-control study of chikfrtood brain tumours: role of index pregnancy and birth and m other's reproductive history. Paediatric and Perinatal Epidemiol 13(3):325-341,1999. McKean-Cowdin R. P resto n -M artin S . Holly E, Mueller B. Reliability of demographic, smoking, and occupational data provided by mothers versus fathers In a childhood cancer study. Pediatric and Perinatal Epidemiol 14(3):257-262,2000. Dal Maso L, La Vecchia C. Franceschl S. Preston-M artin S , Ron E. Levi F. et al. A pooled analysis of thyroid cancer studies.V Anthropometric factors. C ancer C au ses and Control 11 (2): 137-44,2000. Haselkom T, Mack W , Preston-M artin S, Bernstein L, Cozen W. Descriptive epidemiology of thyroid cancer in Los A ngeles County. Cancer C au ses and Control 11(2):163-70,2000. Mueller BA, Newton K, Preston-M artin S, Holly EA. Residential w ater source, nitrates, nitrites, and the risk of childhood brain tumors.Envlomm ental Health Perspectives 109:551-556,2001. Preston-M artln S. Medical x-rays and adult-onset myeloid leukemia. MOnchner Medtzin Verlag On press) P ogoda J. Preston-M artin S. PaoffK J, UJInsky W .Survey of residual n lrtte levels in cured m eats in the United States and C anada. 1970-1991. Public Health Nutrition (in press). P reston-M artin S. Epidemiology. In: Petrovich Z. Brady LW. Apuzzo ML (Eds.) Combined Modality Therapy of Central Nervous System Tumors Chapter 1 Springer-Verlag, 2000, pp 1-17. P reston-M artln S, Davis F. McKean-Cowdin R. Epidemiology of primary brain tumors. In: Becker D. Liau LM (Eds.) Brain Tumo Im m unotherapy.Chapter 2. H um ana P ress Inc.. 2001, pp. 7-71. Preston-M artin S. Central Nervous Tumors, Epidemiology In: AminoffMJ. Daroff R B (Eds.) Encyclopedia of the Neurological Sciences Academic P ress, San Diego. CA. USA. (in press) Pogoda JM. Preston-M artin S. Nichols PW , R oss RK. Smoking and risk of acute myeioid leukem ia:results from a Los Angeles County case-control study. Am J Epidemiol. (In press) P a g e 19 224 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): J o y cely n n e M. P a lm e r FO R M 11 Required for all applications. S ee Section 25 in Application Packet for additional instructions.________________________________ Other Support NAME OF INDtVIDUAL(First Name. Middle Name. Last Name) D£GREE(S) Jo y c e ly n n e M ichelle P alm er, M .S. STATUS: NONE ACTIVE PROJECT NUMBER (Principal Investigator) SOURCE TITLE TOTAL DIRECT COSTS CA 3 0 2 0 6 (F o rm an ) NIH/NCI ^ ...................... B one M arrow T ran sp lan tatio n P ro g ram P roject. B iostatistics C ore $ 2 2 1 ,6 2 8 PERCENT EFFORT 5 0 % THE OBJECTIVES OF TH S STUDV T his application s e e k s su p p o rt for clinical a n d lab o rato ry s tu d ie s co n c ern in g th e m ajo r o b s ta c le s to s u c c e ssfu l allo g en eic blood/m arrow tra n sp lan tatio n for p atie n ts with leukem ia, including re c u rre n t m alignancy, viral infections a n d graft v e rs u s -h o st d is e a s e . T w o c o re s su p p o rt th e five in terrelated p ro je cts in th e application, o n e providing statistical e x p e rtise a n d o n e for adm inistration a n d coordination of re se a rc h . OVERLAP (Budnrtery, Scltntiflc: S « Section 88 In Application Packot) A d ju stm e n ts of effort will b e m a d e to a n ew B iostatistician in th e division w h en p e n d in g g ra n ts a re funded. NAME OF INDIV1DUAL(First Name. Middle N am . Last Name) DEGREE(S) Jo y c e ly n n e M ichelle P alm er. M .S. STATUS: NONE ACTIVE PROJECT NUMBER (Principal Investigator) CA 3 3 5 7 2 (Krontiris) SOURCE TITLE TOTAL DIRECT COSTS NIH/NCI C a n c e r C e n te r S u p p o rt G rant $ 1 ,2 2 5 ,8 7 6 '' PERCENT EFFORT 5 0 % THE OBJECTIVES OF THIS STUDV T o stim u late collaborative re s e a rc h in teractio n s b e tw e e n b a s ic s c ie n c e a n d clinical in v e stig ato rs a n d b etw e en re s e a rc h g ro u p s in different a r e a s of investigation. T o facilitate a n d e n h a n c e e s ta b lis h e d interdisciplinary p ro g ra m s in b a s ic a n d clinical re s e a rc h . T o d e v e lo p a n d su p p o rt c o re re s e a rc h facilities w hich im prove th e effe c tiv e n e ss a n d th e interdisciplinary n a tu re o f th e C e n te r's re s e a rc h p ro g ram s. OVERLAP fBudgetary. Scientific: Sea Svctton 26 In Application Packet) A d ju stm e n ts of effort will b e m a d e to a n ew B iostatistician in th e division w h en p e n d in g g ra n ts a re funded. Copy and p aste the above forms on additional p ag es a s n ee d ed , supplying th e requested information. P a g e 20 225 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M, P a lm e r Other Support (continued) NAME OF INDIVIDUAL(First Name, Middle Name. Last Name) DEGREE(S) J o y c e C aro l N iland. P h.D . STATUS: | NONE | ACTIVE | x | PENDING | PROJECT NUMBER (Principal Investigator) C A 3 3 5 7 2 (K rontiris) SOURCE NIH/NCI TITLE C a n c e r C e n te r S u p p o rt G ran t TOTAL DIRECT COSTS $ 1 ,2 2 5 ,8 7 6 | PERCENT EFFORT | 2 5 % THE OBJECTIVES OF TH S STUDY T o stim u late co llab o rativ e re s e a rc h in te ra c tio n s b e tw e e n b a s ic s c ie n c e a n d clinical in v e stig a to rs a n d b e tw e e n r e s e a rc h g ro u p s in different a r e a s of inv estig atio n . T o facilitate a n d e n h a n c e e s ta b lis h e d interd iscip lin ary p ro g ra m s in b a s ic a n d clinical re s e a rc h . T o d e v e lo p a n d s u p p o rt c o re re s e a rc h facilities w hich im p ro v e th e e ffe c tiv e n e s s a n d th e interd iscip lin ary n a tu re of th e C e n te r's re s e a rc h p ro g ram s. OVERLAP (Budgetary. Scientific: S « Section 26 In Application Packet! N one. NAME OF INDMDUAL(First Name. Middle Name. Last Name) DEGREE(S) J o y c e C aro l N iland, P h.D . STATUS: NONE I ACTIVE PROJECT NUMBER (Principal Investigator) SOURCE TITLE C A 3 0 2 0 6 (F o rm an ) TOTAL DIRECT COSTS NIH/NCI B o n e M arrow T ra n sp lan tatio n P ro g ra m P ro jec t, B iostatistics C o re $ 2 2 1 ,6 2 8 PERCENT EFFORT [ 5 % THE OBJECTIVES OF THIS STUDY T his applicatio n s e e k s s u p p o rt for clinical a n d la b o ra to ry s tu d ie s c o n c ern in g th e m a jo r o b s ta c le s to s u c c e s s fu l allo g e n e ic b lo o d /m arro w tra n sp la n ta tio n fo r p a tie n ts with le u k e m ia , including re c u rre n t m alig n a n cy , viral in fectio n s a n d g raft v e rs u s -h o s t d is e a s e . T h e five in te rre la te d p ro je c ts in th e application a re s u p p o rte d by tw o c o re s , o n e providing statistic al e x p e rtis e a n d o n e for ad m inistration a n d co o rd in atio n of re s e a rc h . OVERLAP (Budgetaty, Scientific; See Section 28 in Application Packet) N one. P a g e 21 226 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M. P a lm e r Other Support (continued) NAME O F INDIVIDUAL(First N am e. M iddle N am e. L a st N am e) D E G R E E (S) J o y c e C arol N iland, P h.D . STATUS: | N O N E | ACTIVE | X | PEN D IN G | PROJECT NUMBER (Principal Investigator) C A 3 0 2 0 6 (F o rm an ) SOURCE NIH/NCI TITLE B o n e M arrow T ra n sp lan tatio n P ro g ra m P ro jec t, Long T erm Follow -U p C o re (B h atia) TOTAL DIRECT COSTS $ 1 2 3 ,8 9 2 | PERCENT EFFORT | 5% THE OBJECTIVES OF THIS STUDV T o e n s u r e co m p le te follow -up of all p a tie n ts u n d e rg o in g tra n sp la n ta tio n at C O H in o rd e r to identify detail inform ation on th e in c id en ce a n d p o tential risk fa c to rs for d e la y e d c a rd io p u lm o n a ry dysfunction, g a stro in te stin a l, ren al, rep ro d u ctiv e or en d o c rin e d ysfunction a n d s u b s e q u e n t c a n c e rs ; to identify g ro u p s at in c re a s e d risk a n d m a k e re c o m m e n d a tio n s for s c re e n in g p a tie n ts identified to b e at in c re a s e d risk; to e v a lu a te p a tie n ts p ro sp ectiv ely in o rd e r to d e s c rib e h e a lth -re la te d quality of life in BMT survivors. OVERLAP (Budgetary, Scientific: S m Section 26 In Application Packet) N one. NAME 6 f lti)MbLlAL(First Name, Middle Name, Last klame) K<SRE£(5) J o y c e C aro l N iland, P h.D . STATUS: I NONE I ACTIVE I X 1 PENDING | p r o j e c t NUMBER (Principal Investigator) C M -07003-74 (G an d a ra /D o ro sh o w ) SOURCE NIH TITLE Early T h e ra p e u tic s D ev elo p m en t w ith P h a s e II E m p h a sis TOTAL DIRECT COSTS $3 7 2,981 I PERCENT EFFORT 1 5% THE OBJECTIVES OF THIS STUDY T his c o n tra c to r sh all c o n d u c t P h a s e II a n d e a rly clinical trials of N C I-sp o n so red a g e n ts , e v a lu a te biologic e ffe c ts of th e s e a g e n ts on th eir m o lecu lar ta rg e ts , e v a lu a te o th e r biologic e ffe c ts a n d d e te rm in e clinically rele v a n t o u tc o m e s /c o rre la te s , etc. OVERLAP (Budgetary, Scientific; See Section 26 In Application Packet) N one. P a g e 22 227 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): J o y cely n n e M. P a lm e r O ther S u pport (continued) NAME OF INDIVIDUAL!First N am e. M iddle N am e. L a st N a m e ) C E G R E E (S ) J o y c e C aro l N iland, P h.D . STATUS: PROJECT NUMBER (Principal Investigator) C A 3 3 5 7 2 (K rontiris) SOURCE TOTAL DIRECT COSTS NIH/NCI A R io t S tu d y of D ata C a p tu re M eth o d s to M e a s u re P a tte rn s of Q uality of C a re in th e C o m m u n ity S e ttin g $ 1 3 2 ,7 9 5 ................. ~ PERCENT EFFORT | 5% THE OBJECTIVES OF TH S STUDV T h e a im s of th is pilot stu d y a re to d e te rm in e th e feasibility of e x te n d in g N CCN d a ta collection te c h n iq u e s for b r e a s t c a n c e r o u tc o m e s re s e a rc h to 5 c o m m u n ity -b a se d facilities w ithin ap p ro x im ately 1 0 0 m iles of C O H : to d ev e lo p , im p lem en t a n d e v a lu a te altern ativ e d a ta collection te c h n o lo g ie s ; a n d to c h a ra c te riz e th e co m m u n ity p a tie n t pop u latio n c a p tu re d th ro u g h th is feasibility stu d y , a n d d e te rm in e th e r e p re s e n ta tiv e n e s s of th e pop u latio n stu d ie d to th e pop u latio n a t risk. OVERLAP fBudgttarv. Scientific: s « Section 26 In Aopllcitlon Pacfcrt) N one. NAME OF INOMOUAL(First N am e. M iddle N am e. L a st N am e) D E G R E E (S) Jo y c e C arol N iland, P h.D . T PE N D IN G | ' STATUS: PROJECT NUMBER (Principal Investigator) C A 6 2 5 0 5 (D oroshow ) SOURCE TITLE TOTAL DIRECT COSTS NIH/NCI _ _______ _________ P h a s e I M olecular a n d Clinical P h a rm a c o d y n a m ic Trials $ 2 ,0 2 1 ,5 9 0 _______________ ] PERCENT e f f o r t ] 5% _______ THE OBJECTIVES OF TH S STUDY A s a w orking g ro u p of clinical s c ie n tists, p h a rm a c o lo g ists , b a s ic sc ie n tis ts a n d m edicinal c h e m is ts , w e p ro p o s e to p erfo rm s tu d ie s in pro m isin g a r e a s of clinical dru g d ev e lo p m en t. W e will p erform P h a s e I a n d p h a rm a c o k in e tic s tu d ie s of halo p y rim id in es, th y m id y late s y n th a s e (T S ) ta rg e te d d ru g s, a n d folate an tim e ta b o litie s a lo n e or w ith b io c h em ical m o d u la to rs. T h e s e s tu d ie s will b e a c c o m p a n ie d by p h a rm a c o d y n a m ic c o rre la te s of r e s p o n s e a n d /o r e n d p o in ts re le v a n t to a tte m p ts at m o d u latin g th eir action OVERLAP (Budm ttrv. S d w tin c: S»» Section 26 In Appllc«Hon Packet) N one. P a g e 23 228 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M. P a lm e r O ther S u p p o rt (continued) NAME OF INDIVIDUAL(FifSt Name. Middle Name, Last Name) DEGREE(S) J o y c e C arol N iland, P h.D . STATUS: | NONE | ACTIVE | X | PENDING | p r o j e c t NUMBER (Principal Investigator) C A 4 6 3 6 8 (D oroshow ) SOURCE NIH/NCI TITLE C O H S o u th w e s t O n co lo g y G ro u p C linical T rials TOTAL DIRECT COSTS $ 5 2 1,921 j PERCENT EFFORT | 5% THE OBJECTIVES O FTH S STUDY S u p p o rt th e p articipation of th e C ity of H o p e N ational M edical C e n te r in th e in v estig atio n al clinical trials of th e S o u th w e s t O n co lo g y G roup. OVERLAP (Budgetary. Scientific; See Section 26 In Application Packet) N one. NAME OF INDIVIDUAL!First Name. Middle Name. Last Name) QEGREE(S) J o y c e C aro l N iland, P h.D . STATUS: NONE ACTIVE X PENDING PROJECT NUMBER (Principal Investigator) SOURCE TITLE TOTAL DIRECT COSTS 2 G 0 8 LM 0 5 6 9 7 (N iland) NIH ~ ' In te g ra te d A d v a n c e d Inform ation M a n a g e m e n t S y ste m s $ 5 5 0 .0 0 0 __________________I PERCENT EFFORT | 15% THE OBJECTIVES OF THIS STUDY T h e g o al of th is In te g rated A d v a n c e d Inform ation M a n a g e m e n t S y ste m . P h a s e II im p lem en tatio n g ra n t is to im p lem en t th e stra te g ic plan at th e C ity of H ope to c re a te a c o m p re h e n s iv e institution-w ide in te g ra te d c o m p u te r n etw ork. T h e s y s te m will em p lo y a c o m p re h e n s iv e view , w hich c o n s id e rs th e inform ation n e e d s of u s e r s from th e p atie n t c a re , b a s ic s c ie n c e re s e a r c h , clinical re s e a rc h , library s e rv ic e s , e d u c a tio n , a n d ad m in istratio n . OVERLAP (Buda«t«v. ScltnW lc: S « S.ctlon 26 In AppllctBcn P»ck«t) N one. P a g e 24 229 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): J o y cely n n e M. P a lm e r O ther S upport (continued) NAME OF INDMDUAL(First Name, Middle Name. Last Name) DEGREE(S) J o y c e C arol N iland. P h.D . STATUS: ACTIVE PENDING PROJECT NUMBER (Principal Investigator) T T P 1021 (W eitzel) SOURCE TITLE TOTAL DIRECT COSTS C alifornia C a n c e r R e s e a rc h P ro g ram C O H C e n te r fo r T e ch n o lo g y T ra n sfe r a n d T ra nslatio n al R e s e a rc h in C a n c e r G e n e tic s $ 2 8 0 .5 0 8 _________________ 1~ PERCEN TiFFO R r] 3 % ______________________________________ THE OBJECTIVES OF TH S STUDY T h e g o al of th is p ro g ra m is to a d d re s s th e n e e d fo r c a n c e r g e n e tic s te c h n o lo g y tra n sfe r a n d tra n sla tio n a l r e s e a rc h in c a n c e r g e n e tic s into th e prim ary c a re s e ttin g s th ro u g h th e e s ta b lis h m e n t of a C ity of H o p e C e n te r f o r T e c h n o lo g y T ra n sfe r a n d T ra n slatio n al R e s e a rc h in C a n c e r G e n e tic s. OVERLAP (Budfl«tuy. Scientific: See Section 26 In Application Ptck»ti N one. NAME OF IN3IVIDUAL(First Name. Middle Name. Last Name) DEGREE(S) J o y c e C aro l N iland. P h.D . STATUS: PROJECT NUMBER (Principal Investigator) 1R01 CA 7 8 9 3 8 -0 1 A 2 (B hatia) SOURCE TITLE TOTAL DIRECT COSTS N C I B o n e M arrow T ra n sp la n t S urvivors' S tu d y $ 3 1 9 ,4 4 0 PERCENT EFFORT 5 % THE OBJECTIVES OF TH S STUDY T h e o b jective of th is B o n e M arrow T ra n sp la n t S u rv iv o rs' S tu d y is to esta b lish a n d c h a ra c te riz e a c o h o rt of 1 ,8 9 4 p ed iatric a n d ad u lt lo n g -term su rv iv o rs of BMT in o rd e r 1) to identify th e in c id e n c e a n d risk fa c to rs for c a rd io p u lm o n a ry d is e a s e , e n d o c rin e a b n o rm alities, fertility, a n d s u b s e q u e n t c a n c e rs : 2) to d e s c rib e th e im p act of th e s e co m p lic atio n s on th e q uality of life of th e survivors: a n d 3) to c h a ra c te riz e th e h e a lth -re la te d b e h a v io rs a n d p a tte rn s of m e d ical c a re in th e survivors. OVERLAP (Budgetary. Scientific: S«» Section 26 In Application Packet! N one. P a g e 25 230 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): J o y cely n n e M. P a lm e r O ther S upport (continued) NAME OF IN D M D U A L (First N am e, M iddle N am e. L a st N am e) D E G R E E (S) J o y c e C arol N iland, P h.D . STATUS: NONE | ACTIVE I X~ PENDING PROJECT NUMBER (Principal Investigator) SOURCE TITLE TOTAL DIRECT COSTS R R 0 0 0 4 3 -4 1 S 1 (N iland) N CRR G C R C S u p p le m e n t: Fully In te g ra te d R e s e a rc h S ta n d a rd s a n d T e ch n o lo g y (F IR S T ) $ 2 ,9 4 3 ,0 8 2 I PERCENriFFORr] 10% THE OBJECTIVES OF TH S STUDV To d e v e lo p a fully in te g ra te d arch itec tu re, a p p licatio n s a n d k n o w le d g e -b a se to facilitate a n d su p p o rt all p h a s e s of clinical re s e a rc h . P ro jec t sp ecificatio n s, te stin g , s y s te m d ep lo y m en t a n d ev a lu atio n will involve a co n so rtiu m of th re e G e n e ra l C linical R e s e a rc h C e n te rs (G C R C s) c o n sistin g of U niversity of S o u th e rn C alifornia a s th e p a re n t G C R C , with C h ild ren 's H ospital Los A n g e le s a n d CO H a s sa te llite c e n te rs . OVERLAP (Budgttary, Scientific; S — S tc tio n 26 In Applicitfon Packtt) N one. NAME OF IN D M D U A L (First N am eTM iddle N am e, L a st N am e) DEGREE(S) J o y c e C arol N iland. P h.D . STATUS: ACTIVE | X PROJECT NUMBER (Principal Investigator) (N iland) SOURCE TITLE TOTAL DIRECT COSTS N ational C o m p re h e n s iv e C a n c e r N etw ork (N C C N ) D ata C o o rd in atin g C e n te r $ 5 8 0 ,6 7 5 I PERCENT EFFORT [ 5 % THE OBJECTIVES OF TH S STUDY To d ev e lo p , im prove, e n h a n c e a n d s u p p le m e n t th e N C C N -S p o n so re d O nco lo g ical O u tc o m e s S y s te m s utilizing th e b io sta tistic s, inform atics, so ftw are, ap p licatio n s, a n d d a ta b a s e d e v e lo p m e n t e x p e rtis e of th e Division of Inform ation S c ie n c e s a t C ity of H ope N ational M edical C e n te r. OVERLAP (Budgetary. Scientific: S — Stction 26 In Application Picket) N o n e . P a g e 26 231 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M. P a lm e r O ther S u p p o rt (continued) NAME OF IMJMDUALfFirst Name. Middle Name. Last Name) DEGREE(S) J o y c e C aro l N iland. P h.D .___________ STATUS: I NONE I PROJECT NUMBER (Principal Investigator) SOURCE TITLE TOTAL DIRECT COSTS R F A -G M -99-004 (K rontiris) G e n e tic D e te rm in a n ts of R isk a n d O u tc o m e in H um an C a n c e r $ 1 2 .2 7 6 .6 6 3 ______________ | p e r c e n t e f f o r t ] 5% ______________ THE OBJECTIVES OF TH S STU0V By exploiting a rapidly a c c u m u la tin g c o h o rt co n sistin g of a ffe c te d sib p a irs with b re a s t, colon, p ro s ta te , a n d lung c a n c e r a n d acq u irin g p h en o ty p ic d a ta - m ed ical history, e x p o s u re history, d ru g a n d th e ra p e u tic re s p o n s e s , o th e r clinical o u tc o m e s , a n d d ru g re a c tio n s to g e th e r with th e g e n e tic d a ta , w e will build a c o m p re h e n s iv e P h a rm a c o g e n e tic R e s e a rc h N etw ork D a ta b a s e . G e n o ty p e /p h e n o ty p e correlatio n will b e p e rfo rm e d , a n d th e resulting inform ation on h u m a n pop u latio n v a ria n ts will aid c e ll-b a s e d in v e stig atio n s th ro u g h o u t th e R e s e a rc h N etw ork. OVERLAP (Budgetary. SclinMflc: S— Section 26 In Application Packed A d ju stm e n ts of effort will b e m a d e to a n e w S e n io r B iostatistician in th e division w h en p e n d in g g ra n ts are fu n d e d P a g e 27 232 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): J o y cely n n e M. P a lm e r O ther S u p p o rt (continued) NAME OF iNDMOUAMFirst Name. Middle Name. Last Nana) D avid S . S n y d e r. M.D. STATUS: j NONE | ACTIVE | X | PENDING | PROJECT NUMBER (Principal investigator) NIH P O 1 C A 3 0 2 0 6 -2 0 (F o rm an ) SOURCE NIH/NCI TITLE B o n e M arrow T ra n sp lan tatio n P ro g ra m P ro jec t. H em ato lo g ic M alig n an cies TOTAL DIRECT COSTS $ 2 3 9 ,9 9 1 | PERCENT EFFORT j 10% THE OBJECTIVES OF THIS STUDY P roject I: C linical a n d biological s tu d ie s of blo o d /m arro w tra n sp la n ta tio n for h em a to lo g ic m a lig n a n c ie s. T h e o b jectiv e is to im prove th e o u tc o m e of allo g e n e ic h em ato p o ie tic cell tra n sp la n ta tio n for h e m ato lo g ic m alig n an cy . OVERLAP (Budaetuv. Scientific: See Section 26 In Aoollcitlon Picket) N one. NAME OF INDIVIDUAL(First Name. Middle Name. Last Name) DEGREE® D avid S . S n y d e r. M.D. STATUS: NONE ACTIVE PENDING PROJECT NUMBER (Principal Investigator) NIH P O 1 C A 3 0 2 0 6 -2 0 (J e n s e n ) SOURCE TITLE TOTAL DIRECT COSTS NIH/NCI B one M arrow T ra n sp la n ta tion P ro g ra m P ro je ct, H em atologic M alig n an cies $ 1 8 5 ,8 2 6 I PERCENT EFFORT I 5% THE OBJECTIVES OF THIS STUDV P roject VI: Clinical a n d biological s tu d ie s of b lo o d /m arro w tra n sp la n ta tio n for h em a to lo g ic m a lig n a n c ie s. T h e o b jective is to im prove th e o u tc o m e of allo g e n e ic h e m a to p o ie tic cell tra n sp la n ta tio n b y ta rg e tin g m a lig n a n t B C ells in L ym p h o m a a n d L eukem ia w ith g en e tica lly m odified T cell clo n es. OVERLAP (Budgetary. Scientific: See Section 26 In Application Picket) N one. P a g e 28 233 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): J o y cely n n e M, P a lm e r Other Support (continued) NAME OF INDIVIOUAL(First Name. Middle hiame, Last None) D avid S . S n y d e r. M.D. STATUS: | NONE | ACTIVE | X | PENDING | PROJECT NUMBER (Principal Investigator) NIH P O 1 C A 3 0 2 0 6 -2 0 (S lovak) SOURCE NIH/NCI TITLE B one M arrow T ra n sp lan tatio n P ro g ra m P ro jec t, H em ato lo g ic M alig n an cies TOTAL DIRECT COSTS $ 1 3 7 ,7 4 3 | PERCENT EFFORT | 5 % THE OBJECTIVES OF THIS STUDY C o re C: C linical a n d biological s tu d ie s of blo o d /m arro w tra n sp la n ta tio n for h em a to lo g ic m a lig n a n c ie s. T h e ob jectiv e is to im p ro v e th e o u tc o m e of allo g e n e ic h e m a to p o ie tic cell tra n sp la n ta tio n th ro u g h th e investigation o f cellular a n d m o lecu lar c h a n g e s . OVERLAP (Budgetary, Scientific: See Section 26 In Application Packet) N one. P a g e 29 234 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): J o y cely n n e M. P a lm e r Other Support (continued) NAME OF INDIV1DUAL(First Name. Middle Name, Last Name) DEGREE(S) S u s a n P resto n -M artin , P h.D . STATUS: NONE ACTIVE | X PROJECT NUMBER (Principal Investigator) P 0 1 C A 1 7 0 5 4 (R o ss) SOURCE TOTAL DIRECT COSTS N IH /N C I________________ Iatro g en ic c a u s e s of c a n c e r. S u b -P ro je c t D: E x p o su re to m e d ical rad iatio n a n d A cu te M yeloid L eu k em ia FAB su b ty p e $ 1 ,1 9 2 ,3 0 2 (S u b -P ro je c t I p e r c e n t e f f o r t 1 25% THE OBJECTIVES OF THIS STUOV T h e m a jo r g o al of th is s tu d y is to e x a m in e ionizing rad iatio n a s a risk fa c to r for sp ecific A cu te M yeloid L eu k em ia FAB s u b ty p e s. OVERLAP (Budgetary. Scientific: 8 — Stction 26 In Application Packet) N one. NAME OF INDMDUAL(First Name. Middle Name. Last None) OEGREE(S) S u s a n P resto n -M artin . P h.D . STATUS: | NONE I ACTIVE I X I PENDING | PROJECT n u m b e r (Principal Investigator) 8 U 0 1 H D 32632-03 (L evine) SOURCE NIH/NIAID TITLE S o u th e rn C alifornia W o m e n ’s In te ra g e n c y HIV S tu d y (W IH S) TOTAL DIRECT COSTS $ 1 ,8 5 5 ,7 1 8 | PERCENT EFFORT | 2 0 % THE OBJECTIVES OF TH S STUDY T h e S o u th e rn C alifornia W o m e n 's In te ra g e n c y HIV S tu d y (W IH S) C o n so rtiu m h a s b e e n e s ta b lis h e d to p articip ate in th e n atio n al W IH S /H E R S p ro ject in o rd e r to defin e th e sp e c tru m a n d c o u rs e of HIV infection in w o m e n . OVERLAP (Budgetary, Scientific: See Section26 In Aoollcatlon Packet) N one. P a g e 30 235 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): J o y cely n n e M. P a lm e r Other Support NAME OF INDIVIDUAL(First Name, Middle Name, Last Name) DEGREE(Sf" S u s a n P resto n -M artin , P h.D . STATUS: NONE ACTIVE p r o j e c t n u m b e r (Principalinvestigator) 2 R 0 1 C A 1 4 7 0 3 -1 8 (F ra s e r) SOURCE TITLE TOTAL DIRECT COSTS NIH/NCI C a n c e r E pidem iology in A d v en tists - a Low R isk G roup $ 9 9 3 .7 6 6 _________________ | PERCENTEFFORT [ 25% THE OBJECTIVES OF TH S STUDY T his p ro je ct will e x a m in e th e c a n c e r risk in S e v e n th D ay A d v en tists b a s e d on e x p o s u re to a v a rie ty o f d ie tary a n d o th e r facto rs. OVERLAP (Budgetary. Scientific: S a t Stction 26 In Application Packtfl N one. P a g e 31 236 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): J o y cely n n e M. P a lm e r FORM 12 Required for all applications. S ee Section 25 in Application P acket for further instructions._______ Facilities and Resources FACILITIES: List the facilities to be u sed and briefly indicate their capacities, pertinent capabilities, relative proximity, and extent of availability for the project. U se ‘other* to describe the facilities at any of the other perform ance sites listed on Face P age for all aw ard m echanism s. Using continuation p ag e s if necessary, num bered sequentially. Include an explanation of any consortium /contractual arrangem ents with other organizations. LABORATORY Not A pplicable CLINICAL T h e C ity of H o p e N ational M edical C e n te r is a te rtia ry c a re c e n te r sp ecializin g in th e tre a tm e n t of p a tie n ts with chronic d is e a s e s , including c a n c e r a n d le u k em ia. T h e blo o d /m arro w tra n sp la n ta tio n p ro g ra m at City of H ope is o n e of th e la rg e st in th e nation. ANIMAL N ot A pplicable COMPUTER T h e P i's office is e q u ip p e d with a P en tiu m c o m p u te r run n in g on M icrosoft W in d o w s NT S e rv e r 4 .0 a n d M icrosoft S Q L S e r v e r 7 .0 . T h e D e p a rtm e n t of B io statistics will pro v id e all n e c e s s a r y statistic al so ftw a re a n d g rap h ical s o ftw a re re q u ire d to a n a ly z e a n d su m m a riz e th e p a tie n t clinical a n d o u tc o m e s d a ta . All c o m p u te rs h a v e th e n etw ork v ersio n of O ffice 9 7 c o m p le te with th e M icrosoft su ite of so ftw are p ro d u c ts (e.g . M icrosoft W ord a n d Excel). All c o m p u te rs h a v e a c c e s s to th e Intern et, em ail, a n d M edline/P ubM ed._____________________ OFFICE T h e PI is p ro v id e d w ith 8 0 s q u a r e fe e t of office s p a c e in th e D ivision of Inform ation S c ie n c e s . T h e office is e q u ip p e d w ith a P en tiu m b a s e d P C a n d m o d e m , te le p h o n e a n d c o n n e ctio n to a la s e r p rinter. T h e PI h a s av a ilab le full-tim e skilled se c re ta ria l staff with p h o to c o p ie r a n d fax m a c h in e s. OTHER P a g e 32 237 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M. P a lm e r FORM 12 (Continued) Required for all applications.__________________________________________________________________ MAJOR EQUIPMENT: List the most Important equipment Items already available for this project, noting the location and pertinent capablitles of each. M ajor e q u ip m e n t in th e P rincipal In v e stig a to r's office include: a p e rs o n a l c o m p u te r w orkstation, p e rs o n a l la s e r printer, s to ra g e p la c e fo r b o o k s, tw o 4 -d o o r lateral file c a b in e ts with lock. Division r e s o u rc e s a s s e s s a b le to th e P rincipal In v estig ato r in clu d e a p h o to c o p ier, facsim ile m a c h in e a n d color printer. ADDITIONAL INFORMATION: Provide any othor Information describing the environment for the project. Identify support services such as consultants, special arrangements, secretaries, machine shop, electronics shop, and the extent to which they w ill be available to the project. See Section 25 In Application Packet for forther Information. '___________________________________________________ T h e C ity of H ope N ational M edical C e n te r o c c u p ie s a 9 3 a c re site in D u arte C alifornia, a su b u rb a n co m m u n ity in th e S a n G abriel valley, a b o u t 25 m iles n o rth e a s t of dow ntow n L os A n g e le s. T h e institution c o n s is ts o f th e C ity of H ope N ational M edical C e n te r, w hich is an N C I-d esig n ated C o m p re h e n s iv e C a n c e r C e n te r, a n d th e B ec k m an R e s e a rc h Institute. Dr. S u s a n P resto n -M artin , a te n u re d faculty m e m b e r in E pidem iology, is th e P rincipal In v e stig a to r's d isse rta tio n ch a ir for h e r d octoral d e g re e in E pidem iology. Dr. P resto n -M artin a s a g r e e d to provide g u id a n c e re la te d to E pidem iologic m e th o d o lo g y on th is p ro ject alth o u g h is not re q u e stin g c o m p e n sa tio n . P a g e 33 238 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M. P a lm e r________ FORM 13 Required for all applications. S ee S ections 4 and 25 in trie Application P acket for additional instructions and form at requirem ents.______ R e s e a r c h P la n A. S p e c if ic A im s T h e overall o b jectiv e of th is p ro p o s a l is to e x a m in e fa c to rs th a t m a y s e rv e a s p ro g n o stic in d icato rs of cy to g e n e tic re la p s e a n d /o r d e a th in p a tie n ts w h o h a v e u n d e rg o n e allo g e n e ic blo o d o r m arrow tra n sp la n ta tio n (Allo-BMT) for tre a tm e n t of ch ro n ic m yeloid le u k em ia in ch ro n ic p h a s e (C M L-C P). T h e clinical c o u rs e f a p a tie n ts d ia g n o s e d with C M L -C P is h e te ro g e n e o u s . P re v io u s s tu d ie s h a v e d e m o n s tra te d th a t p ro g n o s is v a rie s w idely d e p e n d in g on th e risk p rofiles of p a tie n ts; h is ta ic a lly risk p rofiles w e re b a s e d on d e m o g ra p h ic c h a ra c te ristic s, clinical fe a tu r e s at p re s e n ta tio n a n d prior th e ra p y (ty p e, a m o u n t a n d du ratio n ). M ultivariate risk c lassificatio n s a n d s c a i n g s y s te m s b a s e d o n p re tre a tm e n t fe a tu re s h a v e b e e n th e su b je c t of n u m e ro u s p ro g n o stic s tu d ie s (T ura, 1981: C e rv a n te s , 1982; S o k al, 1984; S o k al, 1985: K antarjian, 1985; K antarjian. 1990: Italian G ro u p , 1991: T hiele, 1991; H eh lm an n . 1992; O z e r, 1993: T hiele. 1993: Italian G roup, 1994; C a t e s , 1997; H a s f a d , 1998). [In m o s t c a s e s , th e s e e a rlier s tu d ie s w e re lim ited to e v a lu a tin g th e relative im p act of p re tre a tm e n t fe a tu re s on overall survival.] A s a resu lt, se v e ra l m o d e ls h a v e b e e n e s ta b lis h e d th a t c a te g a i z e p a tie n ts into different g ro u p s with distinctive survival c h a ra c te ris tic s (S o k al, 1984: H a s f a d , 1 998), h o w ev er, th e reproducibility a n d g en e ra liz ab ility o f m o s t of th e s e sta g in g s y s te m s h a v e b e e n re p e a te d ly q u e s tio n e d b e c a u s e th e s e s y s te m s w e re g e n e ra lly re s tric te d to ce rta in th e ra p e u tic re g im e n s. A pplication of th e v a rio u s risk m o d e ls a n d s c a i n g s y s te m s to c o h o rts with o th e r tre a tm e n t m o d a lities, in p articu lar Allo-BM T, freq u e n tly d e m o n s tra te a significant lack o f p ro g n o stic efficiency with o v erlap p in g risk discrim ination (G ratw ohl, 1998; C lark. 2001; M ichallet. 2 0 0 1 ; R adich. 2001; G ratw ohl, 2 003). W hile a n u m b e r of p ro g n o stic m o d e ls f a non-B M T p a tie n ts h a v e b e e n d e v e lo p e d a n d a re well d o c u m e n te d in th e literature, a u sefu l s c a i n g sy ste m /p ro g n o stic m odel h a s n o t b e e n d e v e lo p e d f a C M L -C P p a tie n ts th a t u n d e rg o Allo-BM T. T h e p u rp o s e of th is a n a ly s is is to e v a lu a te th e p ro g n o stic sig n ifican ce of p atien t, d is e a s e , a n d tre a tm e n t c h a ra c te ris tic s f a p a tie n ts w h o h a v e u n d e rg o n e Allo-BMT f a tre a tm e n t of C M L-C P. An ex a m in atio n of th e role of p atien t, clinical a n d tre a tm e n t f a c t a s co llected bah at th e tim e of d ia g n o sis a n d Allo-BM T will b e d o n e to a s s e s s th e predictive v a lu e of th e s e f a c t a s on a p a tie n t's risk f a d is e a s e re c u rre n c e a n d / a d e a th follow ing Allo-BMT. A n o n g o in g c a s e - s e r ie s of 3 9 3 C M L -C P p a tie n ts tr e a te d at th e City of H ope N ational M edical C e n te r with Allo-BM T from 1 9 8 1 -2 0 0 2 will b e u s e d f a th is an a ly sis. A s p a rt of th e b a c k g ro u n d f a th e statistic al a n a ly sis, an e x te n s iv e review of th e m e d ical literatu re (from 1 9 8 0 to 2 0 0 3 ) h a s b e e n co m p le te d . T his review h a s re v e a le d th e h is ta ic a lly significant p atien t, d is e a s e a n d tre a tm e n t f a c t a s th a t will b e u s e d in th is a n a ly sis. T his stu d y will a ls o e x p l a e th e pred ictiv e v a lu e of th re e g e n e ra lly a c c e p te d s c a i n g s y s te m s (S okal, H a s f a d a n d G ratw ohl) in th is la rg e sin g le c e n te r Allo-BM T pop u latio n . T h e q u e s tio n a n d sele ctio n of optim al tre a tm e n t d e p e n d s on m a n y f a c t a s , w hich in clu d e d is e a s e c h a ra c te ris tic s, p re v io u s tre a tm e n t, a n d individual p atie n t c o n s id e ra tio n s . T h e re s u lts of th is stu d y will co n trib u te to th e overall u n d e rs ta n d in g of C M L -C P p ro g n o s is in th e Allo-BMT settin g a n d cou ld a s s is t clinicians with tre a tm e n t d ec is io n s re la te d to Allo-BMT. O u r sp ecific a im s a re: 1: To. b a s e d on an identified c a s e - s e r i e s o f A llo-B M T C M L -C P p a t ie n t s , c o lle c t a n d s u m m a r iz e d a ta o n: 1) significant d is e a s e a n d p atie n t c h a ra c te ris tic s (re c o rd e d at d ia g n o sis a n d Allo-BM T); 2) p a tie n t's tre a tm e n t h istory ( r e c a d e d from d ia g n o sis to Allo- P a g e 3 4 239 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M. P a lm e r________ BMT): 3) poten tially re le v a n t m o lecu lar, c y to g e n e tic a n d clinical f e a tu r e s (at d ia g n o sis a n d Allo-BM T): a n d 4) c y to g e n e tic r e la p s e e v e n ts a n d /o r d e a th p o s t Allo-BMT (if app licab le). 2: T o u s e th e u p d a te d d a ta b a s e to a s s i g n w e ig h te d r is k s c o r e s for th e th re e m o s t w idely a c c e p te d sco rin g s y s te m s (S o k al, H asford a n d G ratw ohl) a n d t e s t t h e p r o g n o s tic r e p ro d u c ib ility in th is in d e p e n d e n t p a tie n t po p u latio n . 3: T o u s e th e u p d a te d d a ta b a s e to e x a m in e t h e p re d ic tiv e v a lu e o f m o le c u la r, c y to g e n e tic a n d c lin ic a l f e a t u r e s on survival a n d c y to g e n e tic re la p s e p o s t Allo-BMT [after ad ju stin g for 'a t d ia g n o sis' d is e a s e a n d p a tie n t c h a ra c te ris tic s] (d ev elo p in g a p ro g n o stic m odel). 4: T o c o m p a re th e p ro g n o stic fa c to rs s e e n a t d ia g n o sis with th o s e at Allo-BM T, th e re b y id e n tify in g th ro u g h statistic al a n a ly s is (p o te n tia lly ) n e w d i s e a s e a n d c lin ic a l f e a t u r e s at Allo-BM T th a t a re p red icto rs o f d is e a s e re c u rre n c e a n d /o r d e a th p o st Allo-BM T. P a g e 35 240 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M. P a lm e r B. B a c k g r o u n d a n d S ig n if ic a n c e W h y th e s tu d y o f C M L -C P r e q u ir e s a n o n - tr a d ltlo n a l a p p r o a c h . O verall, th e stu d y of CM L- C P d o e s n ot follow th e s ta n d a rd 'p o p u la tio n -b a s e d ' r e s e a r c h ap p ro a c h th a t h a s b e e n ap p lied to th e m ajority of ch ro n ic d is e a s e s th a t u n d e rg o e p id em io lo g ic investigation. T his d e p a rtu re is d u e in la rg e p a rt to th e lim ited n u m b e r of p a tie n ts d ia g n o s e d a n n u a lly with CML [ F o o tn o te 1], A s a resu lt, epidem io lo g ic effo rts fo c u s e d on p rev en tin g CM L b y rev ea lin g th e u n deriying c a u s e /s of d is e a s e th ro u g h c a se -c o n tro l. cohort, or eco lo g ic s tu d ie s a re le s s viable for th is p atien t p o p u la tio n . F o r m o re th a n 5 0 y e a rs , 'c la s s ic ' ep id em io lo g ic investigation h a s stu d ie d th e m o re in clusive leu k em ia d is e a s e co n stru c t. (L eu k em ia is m a d e up of four m a jo r s u b ty p e s : chronic m yeloid leu k em ia (CM L). ch ro n ic lym phocytic le u k e m ia (CLL), a c u te ly m p h o b lastic le u k em ia (ALL), a n d a c u te m yeloid le u k em ia (AML).) C o n sisten tly , th e re s u lts of th e s e s tu d ie s h a v e im p lic ated en v iro n m en tal a n d o c c u p atio n a l e x p o s u re s (e.g . ionizing rad iatio n , non-ionizing e le c tro m a g n e tic fields, b e n z e n e , ag ricultural e x p o s u re s re la te d to p o ultry a n d dairy farm ing, livestock p roduction a n d ce rtain cro p s) in th e etio lo g y a n d p a th o g e n e s is of th is h e m ato lo g ic m a lig n a n c y (S ch o tten feld . 1996). H ow ever, m o s t e x p e rts w ould a g r e e th a t o c c u p a tio n a l a n d e n v iro n m en tal e x p o s u re to radiation or c h e m ic a ls a r e re s p o n s ib le for only a sm all n u m b e r of le u k em ia c a s e s , a n d a re m o re re le v a n t to a c u te le u k em ia th a n chronic le u k em ia. For th e p a s t 20 y e a rs , th e g o a ls of CML ep id em io lo g ic re s e a rc h h a v e b e e n to: 1) identify a n d u n d e rs ta n d a p p ro p ria te d is e a s e m e a s u re s/in d ic a to rs , 2) stu d y th e s tre n g th o f e v id e n c e reg ard in g th e b e n e fits a n d risk s of av a ilab le tre a tm e n t o p tio n s. 3) h elp identify th e optim al tim ing of th e in terv en tio n a n d m onitoring o f d is e a s e b a s e d on d is e a s e a n d p atien t c h a ra c te ris tic s, a n d 4) identify p ro g n o stic in d icato rs of d is e a s e re la p s e a n d d e a th . In a n effort to im prove th e lo n g -term survival for C M L -C P p a tie n ts, th is r e s e a rc h p ro p o sa l s e e k s to stu d y rem ain in g q u e s tio n s in th e a r e a of p ro g n o s is for p a tie n ts th a t u n d e rg o a llo g e n e ic blood or m a rro w tra n sp la n ta tio n . T his p ro je ct will build on th e c u rren t b o d y of literatu re re la te d to risk m od elin g (pred ictio n ) of re la p s e a n d /o r d e a th e v e n ts follow ing tre a tm e n t. C u r r e n t lim ita tio n s o f CM L r is k c l a s s if ic a tio n . B e c a u s e of th e highly v a ria b le clinical c o u rs e of C M L-C P. m e th o d s w e re d e v e lo p e d to p red ict th e biological b e h a v io r of individual c a s e s b a s e d on clinical fe a tu re s at d ia g n o sis. S tu d ie s of p atie n t a n d tu m o r c h a ra c te ris tic s by u n iv a riate a n d m u ltiv ariate a n a ly s is h a v e h e lp e d in u n d e rs ta n d in g d is e a s e h e te ro g e n e ity a n d in d e v e lo p in g clinical prediction ru le s (or p ro g n o stic m o d e ls) th a t c a te g o riz e p a tie n ts into different risk g ro u p s b a s e d on p re tre a tm e n t p ro g n o stic fa c to rs (T u ra. 1981; C e rv a n te s , 1982: S okal. 1984; S o k al. 1985; K antarjian. 1985: K antarjian. 1990: Italian G ro u p . 1991; T hiele, 1991; H eh lm an n . 1992: T hiele. 1993; Italian G roup. 1994: C o rte s. 1997; H asford. 1998). O v er th e p a s t 20 y e a rs s e v e ra l distinct s c o rin g s y s te m s h a v e b e e n d e v e lo p e d , a n d n u m e ro u s predictive m o d e ls h a v e b e e n d eriv ed b a s e d on o n e or m o re clinical p a r a m e te rs a t p re s e n ta tio n . T h e m o s t g en e ra lly a c c e p te d p ro g n o stic s c o r e s a re th e S o k a l (S o k al. 1984). H asfo rd (or E u ro p e a n ) (H asfo rd , 1998), a n d G ratw ohl (G ratw ohl, 1 998) risk s c o r e s (D ein in g er a n d D ruker, 2003). T h e s e sco rin g s y s te m s a re b a s e d on p a r a m e te rs with an e s ta b lis h e d u n fa v o ra b le effect on survival, th e p a ra m e te r s in clude: (at d ia g n o sis) a g e , s p le e n size , p la telet co u n t, b la st % . b aso p h il % . eo sin o p h il % . (at tra n sp la n t) d is e a s e p h a s e , tim e from d ia g n o sis to tra n sp la n t, an d p a tie n t-d o n o r g e n d e r co m b in atio n . F ootnote 1: Annual^ CML constitutes about 0 3% ( 0033) of all incident cancers in tho United States, accounting for 13-?0% of jli ca ses of leukemia (Perkins. 2000. Ries. 2001) CML has an annual incidence of 1-2 ca ses per 100.000 per year and affects about 4,500 Americans each yeai (465 annually m California) (American Cancer Society, 2001) Although CML occurs m all decade: of life, it is mainly a disease of adults Incidence rises slowly with age until the mid-forties when if s ta ts to rise more rapidly resulting m a median age of onset between 50 and 60 years of age Age-adjusted incidence rates reported by SEEP (Surveillance. Epidemiology and End Results) for all races from 1994-1998 w ere 0 7 and 7 2 per 100.000 for persons diagnosed <65 years and £65 years respectively (Ries. 2001) Males have a rate 1 7 times as hicji as females P a g e 36 241 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): J o y cely n n e M. P a lm e r________ An ev a lu atio n of th e literatu re s h o w s th a t th e d iversity in re le v a n t fa c to rs fo u n d by in v e stig a to rs ca n b e linked to h e te ro g e n e o u s p a tie n t s a m p le s , d iffe re n c e s in front line tre a tm e n t, a n d d iffe re n c e s in d is e a s e m a n a g e m e n t s tra te g ie s . T h e fact th a t th e s e d iffe re n ces ex ist h a s b e e n an e n o rm o u s im p ed im en t to th eir applicatio n . A lthough th e s e s c o r e s a re c a p a b le of identifying p a tie n ts in low . in te rm e d ia te a n d high-risk g ro u p s, th e y a re relatively c ru d e in d icato rs th a t h a v e lim ited v a lu e in o u tc o m e prediction for individual p a tie n ts (D eininger a n d D ruker. 2 003). M oreover, it is n ot cle a r th a t a n y of th e s e sco rin g s y s te m s retain th e ir pred ictiv e v alu e th ro u g h th e p a tie n t's tre a tm e n t c o u rs e , e sp e c ia lly in p a tie n ts th a t re c e iv e th e ra p ie s know n to alter th e u n derlying n atu ral c o u rs e of th e d is e a s e (e .g .. b lo o d or m arro w tra n sp la n ta tio n a n d Imatinib M esy late). G iven th a t th e m ajority of th e s e s tu d ie s m o d e le d c h a ra c te ris tic s re c o rd e d at d ia g n o sis a n d did not in c lu d e significant p atien t, d is e a s e a n d clinical fe a tu re s a t Allo-BM T p a tie n ts, scientific q u e s tio n s re m a in re la te d to th e validation of th e s e ris k -s c o re s in AJIo-BMT p a tie n ts. B e c a u s e th e scientific co m m u n ity a c k n o w le d g e s th e lim itations of th e existing sco rin g s y s te m s a n d p ro g n o stic m o d e ls , re s e a rc h is fo c u s e d o n th e d e v e lo p m e n t of a re v ise d risk sco re/risk m o d el th a t is e x p a n d e d to include tre a tm e n t histo ry a n d cy to g en etic /m o le c u la r fe a tu r e s for Allo-BM T p a tie n ts. E x p e rts a g r e e th a t th e a n a ly s is a n d valid atio n o f an e x p a n d e d list of p ro g n o stic fa c to rs is n e c e s s a r y fo r th e d e v e lo p m e n t a n d applicatio n o f risk -a d ju ste d th e ra p ie s , im p ro v ed d is e a s e /p a tie n t m a n a g e m e n t, a n d im p ro v ed survival (o u tc o m e). L ite r a tu re R ev iew . A s p a rt of th e b a c k g ro u n d for th e d a ta collection effort a n d statistical a n a ly sis, a review of th e m e d ical litera tu re (from 1 9 8 0 to 2003) w a s c o m p le te d to identify th e ap p ro p ria te p atien t, d is e a s e a n d tre a tm e n t fa c to rs th a t w e re e ith e r sh o w n to b e m e an in g fu l by u n iv a riate a n a ly sis or u s e d in a m ultivariate p ro g n o stic sco rin g s y ste m /m o d e l fo r p a tie n ts d ia g n o s e d with C M L-C P. T his review of th e litera tu re in cluded a n a s s e s s m e n t of th e p a tie n t p op u latio n (e.g .. d ia g n o sis period, prior th e ra p y ), statistic al m e th o d s , stu d y d esig n (e.g .. o b se rv a tio n a l s tu d ie s, s a m p le s iz e , duration of follow -up), a n d m e th o d u s e d to d efin e m odeling fac to rs. T h e resu lt of th is ev a lu atio n s h o w s th a t n o t all of th e s e p a p e rs d e a l with th e ac tu a l d e v e lo p m e n t of a p ro g n o stic m o d el. S o m e fo c u s on n e w fa c to rs th a t a re of in d e p e n d e n t p ro g n o stic im p o rta n c e w ithout specifying a n a c tu a l m o d el. O th e rs u s e p ro g n o stic fa c to rs to d efin e s u b g ro u p s of p a tie n ts with g o o d or b a d (low. m e d iu m , high-risk) p ro g n o s is . (M odels p re s e n te d in th e litera tu re a re often a c o m p ro m ise b e tw e e n th e e x tre m e s of th e statistic al ideal a n d th e clinical id eal.) G en erally , c o v a riate inform ation w a s e ith e r u s e d b y defining a p ro g n o stic ind ex a s a w e ig h te d m e a n of th e p ro g n o stic v a ria b le s or b y defining s o m e ru le s for g ro u p in g of p a tie n ts. S tra n g e ly e n o u g h , th e c o n c e p t of a p ro g n o stic m o d el is far from w ell d efin ed . S o m e a u th o rs u s e th e te rm to in d icate th e s e le c tio n of p ro g n o stic fa c to rs in clu d ed in th e m o d e l, w hile o th e rs a re satisfie d to re p o rt th a t fa c to r X is of in d e p e n d e n t p ro g n o stic v alu e, s u g g e s tin g th a t it ca n b e a d d e d to an a lre a d y long list of re le v a n t a n d g e n e ra liz a b le p ro g n o stic facto rs. In terestin g ly e n o u g h m a n y s tu d ie s d o not rep o rt b a s ic d a ta on th eir p a tie n t po p u latio n , su c h a s a g e . d is e a s e p h a s e , d is e a s e c h a ra c te ris tic s, a n d duratio n of follow -up. S o m e lo n g -term survival d a ta w e re b a s e d on th e o b s e rv a tio n s of v e ry few p a tie n ts. In o th e r c a s e s , th e inclusion criteria w e re v a g u e a n d s a m p le s iz e s w e re sm all, providing in a d e q u a te statistic al p o w e r to e v a lu a te d iffe re n c e s in o u tc o m e s , a n d w ide 9 5 % c o n fid e n c e in terv als for th e e s tim a te of relativ e risk. T h e s e d eficien c ies p o s e a s e rio u s p ro b le m a s h e a lth c a re pro v id e rs a tte m p t to d e c ip h e r a n d ap p ly th e o u tc o m e of th e s e s tu d ie s to th e m e d ical d e c is io n s ab o u t th e ir p a tie n ts. T h e s e initial findings a re a call to r e s e a r c h e rs a n d clinicians to u s e rig o ro u s stu d y d e s ig n s a n d statistic al m e th o d o lo g y w h en d e v e lo p in g or applying th e s e p ro g n o stic sco rin g s y s te m s a n d to o b s e rv e g re a te r scientific d ilig en c e in th e ev alu atio n of th e s e d a ta . T h e s e findings h e lp explain th e v ariation in th e re p o rte d risk fa c to rs b e tw e e n s tu d ie s a n d will g u id e th e a n a ly s is p ro p o s e d h ere. P a g e 37 242 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M. P a lm e r________ C. P re lim in a ry R e s u lts Id e n tifie d A llo-B M T C M L -C P P a tie n t P o p u la tio n . In 2 0 0 2 , L eukem ia c o n tin u e d to b e th e s e c o n d le ad in g c a n c e r d ia g n o sis for new ly d ia g n o s e d c a s e s or tre a te d c a n c e rs at th e C ity of H o p e N ational M edical C e n te r, b re a s t c a n c e r w a s first (C a n c e r N et, 2 0 0 2 ). C ity of H o p e is th e w o rld 's 3r0 la rg e s t p ro v id e r of b lo o d o r m a rro w tra n sp la n ta tio n : s in c e th e first tra n sp la n t in M ay of 1981 th ro u g h th e e n d o f 2 0 0 2 , a to tal of 3 9 3 p a tie n ts h a v e u n d e rg o n e Allo-BM T for tre a tm e n t o f C M L-C P. T h e p a tie n t p o pulation u s e d fo r th is re tro sp e c tiv e a n a ly sis will b e draw n from this identified c a s e - s e rie s . R e s u lt s o f th e L ite r a tu re R ev iew . A s p a rt of th e b a c k g ro u n d for th e d a ta collection effort a n d statistic al a n a ly sis, a rev iew of th e m ed ical litera tu re (from 1 9 8 0 to 2 003) w a s c o n d u c te d to identify th e rele v a n t p atien t, d is e a s e a n d tre a tm e n t fa c to rs th a t will b e c o llected a n d a n a ly z e d for th is re s e a rc h p ro p o sa l. T h e final list of ‘a t d ia g n o sis' a n d 'a t tra n sp la n t' fe a tu r e s th a t will b e u s e d for th is a n a ly s is a re o u tlin ed in T a b le 1 a n d w a s c o n s tru c te d from fa c to rs th a t w e re sh o w n in th e literatu re to b e e ith e r 1) significantly predictive o f overall survival b y u n iv a riate a n a ly s is or 2) u s e d in a m ultivariate p ro g n o stic sco rin g s y ste m /m o d e l. S p ecial c o n s id e ra tio n w a s giv en to th o s e p ro g n o stic fa c to rs th a t w e re identified or c o rro b o ra te d b y th e N ational C o m p re h e n s iv e C a n c e r N etw ork (N C C N ) E xpert P a n e l fo r CM L in lieu of form al r e s e a rc h stu d ie s. (T h e p a n e l's ev a lu atio n of existing tre a tm e n t o p tio n s a n d fa c to rs b e lie v e d to in flu en ce re s p o n s e /o u tc o m e a r e s u m m a riz e d in th e N CCN Q in ical P ra c tic e G u id e lin e s fo r CML -v ersion 0 1 .2 0 0 4 .) T a b le 1 : F a c to r s s h o w n t o b e p r e d ic tiv e o f o v e ra ll s u rv iv a l F e a tu re s at D iag n o sis F e a tu re s at T ra n sp lan t Aqe (years)' ” Time from diagnosis to transplant (m onths)1 Spleen size (cm )' " Age patient (years)” W hite blood cell count (10a/liter) Patient-D onor gender combination 1 Platelet count (10J/liter)' “ Donor type (syngeneic-sibling vs. related-unrelated)” Eosinophils in blood (%)" Material type (bone m arrow vs. peripheral blood stem cells) Basophils in blood (%)“ Preparative regim en Blasts in blood (%)” G raft vs. Host D isease (GvHD) prophylaxis Initial therapy type A cute - Chronic GvHD (yes/ho) M olecular data (qualitative and quantitative PCR results) Cvtogenetic data (clonal evolution from baseline) : P aram eter used in Sokal S core P aram eter used in Hasford S core c: P aram eter used in Gratwohl Score S u m m a ry o f D a ta C o lle c tio n E ffo rts a n d Initial R e s u lts . P a tie n t c h a ra c te ris tic s re c o rd e d at d ia g n o sis' a re s u m m a riz e d in T a b le 2. P a tie n t d e m o g ra p h ic s h a v e b e e n c o lle c te d a n d s u m m a riz e d for all p a tie n ts a n d a re c o n s id e re d c o m p le te . A s e x p e c te d , a slight m a le p re d o m in a n c e (55% ) c a n b e s e e n in th is p a tie n t p o p u la tio n , w hich is c o n s is te n t w ith sta tistic s p u b lish e d b y S E E R (S u rv eillan ce . E pidem iology a n d E n d R e s u lts P ro g ram ) (R ie s. 2 001). A ge tre n d s a ls o follow n atio n a l sta tistic s with v e ry few c h ild re n /a d o le s c e n ts ( a g e < 1 8 .0 y e a rs ) d ia g n o s e d with th is d is e a s e . T h e n u m b e r o f c a s e s ris e s slow ly with a g e until th e early -fo rties w h en it s ta rts to rise m o re rapidly. W h ile th e a g e tr e n d s a re c o n s is te n t w ith w h at h a s b e e n re p o rte d , th e m e d ian a g e o f o n s e t for th is c a s e - s e r ie s is 35. w hich is fifteen y e a rs below th e n atio n al m e d ian of 5 0 -6 0 y e a rs of a g e . T h e m e a n in g /p o ss ib le im p act of th is finding will b e e x p lo re d a s part of th e a n a ly sis. A s for th e d is e a s e fe a tu re s at d ia g n o sis (e .g .. w hite blood P a g e 38 243 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M. P a lm e r________ ce ll/p late let co u n t, % eo sin o p h ils, % b a so p h ils, % b la sts, s p le e n s iz e a n d initial th e ra p y ) a n d tre a tm e n t h istory prior to tra n sp la n t, o v er 5 0 % of th e s e d a ta a re m issin g a n d will b e co lle c te d a s p art of th is re s e a rc h p ro p o sal. T h e s a m e is tru e for th e 'a t tra n sp la n t' c h a ra c te ris tic s (T a b le 3) a n d o u tc o m e s (T a b le 4). W hile th e s o u rc e s of th e s e d a ta h a v e b e e n identified a n d a c c e s s h a s b e e n g ra n te d , a su b sta n tia l d a ta collection effort will b e n e e d e d to c o m p le te th is project. P a g e 39 244 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Table 2: Allogeneic Bone Marrow Transplantation for Treatment of CM L In CP Summary of Patient Characteristics Pre-Transplant Patients Transplanted 05.May.1981 to 31.D ecem ber.2002 TOTAL PATIENTS ' (N=393) SIBLING/ SYNGENEIC * (n=266) ^ 5 " ^ O Q CM ill P ‘ Y ear o f D iag n o sis £ 1985 4 7(12.0) 46(1 7 .3 ) 1 ( 0.8) < .0001 1986-1990 70(17.8) 54 (20.3) 16(12.6) 1991-1995 128(32.6) 72 (27.1) 56(44.1) 1996-2000 133 (33.8) 84(31.6) 49 (38.6) 2001-2002 15 ( 3.8) 10 ( 3.8) 5 ( 3.9) P a tie n t G en d er Male 216(55.0) 153(57.5) 63 (49.6) .16 Fem ale 177(45.0) 113(42.5) 64 (50.4) A ge at D iag n o sis (Y ears) Mean ± Std 35.3 ± 1 0 .4 35.1 ± 10.2 35.8 ± 1 0 .7 .55 Median (Range) 35.4(4.9-71.1) 34.3(6.5-71.1) 36.7 (4.9-55.6) R ace-E thnicity A merican Indian 1 ( 0.3) 1 ( 0.4) 0 ( 0) < .0001 Asian 40(1 0 .2 ) 29(10.9) 11 ( 8.7) Black Non-Hispanic 15 ( 3.8) 13 ( 4.9) 2 ( 1.6) Hispanic 113(28.8) 96 (36.1) 17(13.4) W hite Non-Hispanic 222 (56.5) 125 (47.0) 97 (76.4) Other/Unknown 2 ( 0.5) 2 ( 0.8) 0 ( 0) M arital S ta tu s a t D iag n o sis Single 104(26.5) 71 (26.7) 33 (26.0) .48 Married 241 (61.3) 167 (62.8) 74 (58.3) S eparated 11 ( 2.8) 7 ( 2.6) 4 ( 3.2) Divorced 29 ( 7.4) 15 ( 5.6) 14(11.0) W idowed 6 ( 1 5 ) 4 ( 1.5) 2 ( 1.6) Unknown 2 ( 0.5) 2 ( 0.8) 0 ( 0) O ccu p atio n at D iag n o sis D ata Available | Classification 3 59(91.3) 245 114 * A ge <18.0 years 19(4.8) 12 7 D ata Not Reported 15(3.8) 9 6 1 : Descriptive results are m ean ± std/m edian (range) or num ber (percent) b: p-value obtained from Fisher’s exact te st, S tudent t-test, or Wilcoxon Rank Sum T est w hen appropriate *: This research proposal will fund the collection of th e se data Page 39a 245 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Table 2: (continued) Allogeneic Bone Marrow Transplantation for Treatment of CM L In CP Summary of Patient Characteristics Pre-Transplant P atients Transplanted 05.May.1981 to 31.Decem ber.2002 TOTAL PATIENTS * (N=393) SIBLING/ SYNGENEIC * (n=266) MUD/ MRD * (n=127) P ‘ W hite B lood Cell C ount (109/liter) at D iag n o sis Median (R ange) Mean ± Std 124.5(2.6-1136.0) 161.0 ±138.1 129.0(2.6-1136.0) 164.6 ± 14 0 .3 104.0(3.5-555.0) 149.7 ± 1 3 1 .8 * Data Complete Records to be investigated 336 57 229 37 107 20 % E o sin o p h ils in th e B lood at D iag n o sis Median (Range) Mean ± Std 1.0 (0.0-91.6) 4.8 ± 1 2 .2 2.0 (0.0-91.6) 6.54 ± 1 6 .3 1.0 (0.0-11.0) 2.6 ± 2 .3 * Data Complete R ecords to be investigated 303 -9 0 200 66 103 24 % B a s o p h ils in th e B lood at D iag n o sis Median (Range) Mean ± Std 1.0 (0.0-19.0) 3.4 ± 3 .7 2.0 (0.0-16.0) 3.6 ± 3.4 3.0 (0.0-19.0) 3.1 ± 4 .0 * Data Complete Records to be investigated 303 -9 0 200 66 103 24 P la te le ts (109/liter) a t D iag n o sis Median (Range) Mean ± Std 377 (7.2-2000) 456.6 ± 3 0 8 .9 384 (55-2000) 485.7 ± 332.8 314.5 (7.2-888) 366.7 ± 1 9 5 .5 * Data Complete Records to be investigated 313 -8 0 212 54 101 26 % B la sts in th e B lood at D iag n o sis Median (Range) Mean ± Std 1.0(0.0-10.0) 1.8 ± 2.3 2.0 (0.0-10.0) 1.8 ± 2 .3 3.0 (0.0-8.0) 1.8 ± 2 .4 * Data Complete R ecords to be investigated 313 -8 0 212 54 101 26 *: Descriptive results are m ean ± std/m edian (range) or num ber (percent) b: p-value obtained from Fisher's exact te st, S tudent t-test, or Wilcoxon Rank Sum T est w hen appropriate *: This research proposal will fund the collection of th e se data Page 39b 246 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Table 2: (continued) Allogeneic Bone Marrow Transplantation for Treatment of CML In CP Summary of Patient Characteristics Pre-Transplant Patients Transplanted 05.May.1981 to 31.Deeem ber.2002 TOTAL PATIENTS * (N=393) SIBLING/ SYN G EN EIC' (n=2B6) MUD/ MRD * (n=127) P ‘ S p len o m eg aly at D iag n o sis Yes — — — * No — — — Data Complete 313 212 101 R ecords to be investigated -8 0 54 26 S p lee n S ize (cm ) at D iag n o sis Median (R ange) — — — * Mean ± Std — — — Data Complete 303 200 103 R ecords to b e investigated -9 0 66 24 S p len e c to m y (prior to BMT) Yes — — — * No — — — Data Complete 323 220 103 Records to be investigated -7 0 46 24 Initial T h e ra p y (City of H ope) No 137 (34.9) 90 (33.8) 47 (37.0) .52 Y es, Single Agent 93 (23.6) 59 (22.2) 34 (26.8) Y es, Multiple A gents 147 (37.4) 105 (39.5) 4 2 (3 3 .1 ) Y es, NOS 16 ( 4.1) 12 ( 4.5) 4 ( 3.1) Initial T h e rap y Type Busulfan — — — * Hydroxyurea — — — IFN-a — — — Allo-BMT (Sibling/Syngenic) — — — Allo-BMT (Related/U nrelated) — — — G leevec — — — O ther — — — Data Complete 323 220 103 R ecords to b e investigated -7 0 46 24 ‘ : Descriptive results are m ean ± std/m edian (range) or num ber (percent) b: p-value obtained from Fisher’s exact te st, S tudent t-test, or Wilcoxon Rank Sum T est w hen appropriate *: This research proposal will fund the collection of th e se data Page 39c 247 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Table 3: Allogeneic Bone Marrow Transplantation for Treatment of CM L In CP Summary of Patient Characteristics at Transplant P atients Transplanted 05.May.1981 lo 31.D ecem ber.2002 TOTAL PATIENTS 1 (N=393) SIBLING/ SYNGENEIC * (n=266) MUD/ MRD ' (n=127) P ‘ Y ear of T ra n sp lan t s 1985 1986-1990 1991-1995 1996-2000 2001-2002 35 ( 8.9) 51 (13.0) 127 (32.3) 148 (37.7) 32 ( 8.1) 35 (13.2) 49 (18.4) 8 0(30.1) 86 (32.3) 16 ( 6.0) 0 ( 0) 2 ( 1.6) 47 (37.0) 62 (48.8) 16(12.6) < .0001 D uration o f C P: Tim e from D iag n o sis to T ra n sp lan t (Y ears) Median (R ange) Mean ± Std 0.8 (0.1-10.8) 1.3 ± 1.4 0.6 (0.1-10.8) 1.2 ± 1.4 1.4 (0.3-7.9) 1.7 ± 1 .4 <.001 A ge a t T ra n sp la n t (Y ears) Median (Range) M ean ± Std 36.7 (5.9-71.5) 36.6 ± 1 0 .3 35.6(8.6-71.5) 36.1 ± 10.1 37.5(5.9-60.1) 37.5 ± 1 0 .8 * A ge at T ra n sp lan t < 4 0 Y ears > 4 0 Years 237 (60.3) 156(39.7) 167(62.8) 99 (37.2) 7 0(55.1) 57 (44.9) .15 K am o fsk y P erfo rm an c e S ta tu s at T ra n sp lan t 90-100 £ 8 0 — — — - R ecords to be investigated (Infer) -7 0 46 24 D o n o r M atch-M ism atch (Patient-Donor) Match (Male-Male) Match (Fem ale-Fem ale) M ismatch (M ale-Fem ale) M ismatch (Female-M ale) 83 51 39 44 53 35 37 32 30 16 2 12 * Data Com plete R ecords to be investigated 217 176 157 109 60 67 *: Descriptive results are m ean ± std/m edian (range) or num ber (percent) b: p-value obtained from Fisher’s exact test, S tudent t-test, or Wilcoxon Rank Sum T est w hen appropriate *: This research proposal will fund the collection of th e se data Page 39d 248 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Table 3: (continued) Allogeneic Bone Marrow Transplantation for Treatment of CML In CP Summary of Patient Characteristics at Transplant Patients Transplanted 05.May.1981 to 31 .Decem ber.2002 TOTAL PATIENTS ’ (N =39 3) SIBLING/ SYNGENEIC ‘ (n=266) MUD/ MRD * (n=127) P ‘ D onor Type Syngeneic Sibling M atched R elated M atched Unrelated 4 ( 1.0) 262 (66.7) 9 ( 2.3) 118(30.0) 4 ( 1.5) 262 (98.5) 9 ( 7.1) 118(92.9) — T ra n sp lan t S o u rce M aterial Type Bone Marrow (BM) Peripheral Stem Cells (PSC ) PSC+BM 329 (93) 23 ( 6) 1 ( 1) 222 (91) 22 ( 8) 1 ( 1) 107 (99) 1 ( 1) 0 * R ecords to be investigated 40 21 19 P rep a ra tiv e R egim en Busulfan/Cytoxan Etoposide/FTBI Cytoxan/ FTBI Other --- --- --- * Data Com plete R ecords to be investigated 323 -7 0 220 46 103 24 GVHD P ro p h y lax is C yclosporine/PSE Cyclosporine/MTX Cyclosporine/PSE/M TX O ther — --- --- * Data Complete R ecords to be investigated 323 -7 0 220 46 103 24 ' : Descriptive results are m ean ± std/m edian (range) or num ber (percent) b: p-value obtained from Fisher’s exact te st, S tudent t-test, or Wilcoxon Rank Sum T est w hen appropriate *: This research proposal will fund the collection of th e se data Page 39e 249 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Table 4: Allogeneic Bone Marrow Transplantation for Treatment of CML in CP Summary of Outcomes P atients Transplanted 05.May.1981 to 31.Decem ber.2002 TOTAL PATIENTS * (N=393) SIBLING/ SYNGENEIC * (n=266) MUD/ MRD * (n=127) P * Tim e to E ng raftm en t (D ays) Absolute Neutrophil Count — — — * (> 500x103 /pL) U ntransfused Platelet Count — — — (> 25x10a/liL) Data Com plete 323 220 103 Records to be investigated ~70 46 24 A cute GVHD (Clinical G rade) 0-I — — — * II III , _ _ IV — — — Data Com plete 323 220 103 Records to be investigated -70 46 24 C hronic GVHD (M axim um G rade) Limited — — — * Extensive — — — Data Com plete 323 220 103 Records to be investigated -70 46 24 S e c o n d T ra n sp lan t Yes — — — * No — — — Data Com plete 323 220 103 Records to be investigated -7 0 46 24 ‘ : Descriptive results are m ean ± std/m edian (range) or num ber (percent) b: p-value obtained from Fisher's exact te st, S tudent t-test, or Wilcoxon Rank Sum T est w hen appropriate *: This research proposal will fund the collection of th e se data Page 39f 250 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Table 4: (continued) Allogeneic Bone Marrow Transplantation for Treatment of CML in CP Summary of Outcomes P atients Transplanted 05.May.1981 to 31 .Decem ber.2002 TOTAL P A T IEN TS' (N=393) SIBLING/ MUD/ SYNGENEIC* MRD * P ‘ (n=268) (n=127) C y to g e n etic R e la p se (P o st Allo-BMT) Y es * No Vital S ta tu s Alive * Dead Lost to Follow-up P rim ary C a u s e o f D eath Infection * AGVHD CGVHD V eno-occlusive D isease O ther C a u se of D eath (T ran sp lan t R elated) Yes No M edian S urvival 1-Y ear S urvival P robability 5-Y ear S urvival P robability 10-Y ear S urvival P robability 1 : D escriptive results are m ean ± std/m edian (range) or num ber (percent) b: p-value obtained from Fisher's exact test, Student t-test, or Wilcoxon Rank Sum T est w hen appropriate *: This research proposal will fund the collection of th e se data P age 39g 251 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): J o y cely n n e M. P a lm e r D. R e s e a r c h D e s ig n a n d M e th o d s P a tie n t P o p u la tio n . T h e p a tie n t pop u latio n h a s b e e n identified a s a c a s e - s e rie s of p a tie n ts th a t h a v e u n d e rg o n e Allo-BM T for tre a tm e n t o f C M L -C P a t th e C ity of H o p e N ational M edical C e n te r. B etw e en M ay 1981 a n d D e c e m b e r 2 0 0 2 , 3 9 3 c o n s e c u tiv e C M L -C P p a tie n ts re c e iv e d an Allo-BM T from e ith e r a h isto c o m p atib le sibling d o n o r or u n re la te d d o n o r identified th ro u g h th e N ational M arrow D o n o r P ro g ram . All p a tie n ts w h o w e re o th e rw ise eligible w e re in c lu d ed in th e stu d y re g a rd le s s of th e ir g e n d e r or eth n ic identity. Eligibility criteria fo r p a tie n ts in c lu d e y e a r of tra n sp la n t, d ia g n o sis a t tra n sp la n t, p h a s e of d is e a s e a t tra n sp la n t, a n d ty p e of tra n sp la n t. T h e d a te s of inclusion for sele c tio n of th e p a tie n t pop u latio n w a s p ro je cted to e n s u re th a t e a c h p atie n t w ould h a v e a m inim um of 12 m o n th s of follow -up (for p a tie n ts surviving to th e d a te of an a ly sis). T h e d ia g n o sis o f CML w a s b a s e d on biopsy; all b io p sy s p e c im e n s w e re rev iew e d a n d co n firm ed by an e x p e rt h e m a to p a th o lo g is t at C ity of H ope. W ritten in form ed c o n s e n t w a s o b ta in e d from e a c h p a tie n t a n d th e City of H o p e Institutional R eview B o ard h a s a p p ro v e d this stu d y (protocol # 0 0 1 2 0 ). F o r all p a tie n ts re g iste re d o n to th is stu d y , d a ta on eligibility s ta tu s , in form ed c o n s e n t d a te , d ia g n o sis, d a te s of tre a tm e n t, follow -up interval, la st c o n ta c t d a te , re la p s e a n d survival s ta tu s a re c o m p u te riz e d in B ITS ( s e e d a ta b a s e m a n a g e m e n t se c tio n of th e r e s e a rc h p ro p o sal). T h e c a s e rep o rt fo rm s for th is s tu d y h a v e b e e n d ra tte d a n d in clu d e th e stu d y sp ecific d a ta (all of th e n e c e s s a r y e le m e n ts req u ire d to c o n d u c t th is study). T w o d a ta e n try c le rk s w ithin th e D ivision of Inform ation S c ie n c e s will e n te r th e d a ta into BITS, a n d th e Q uality A s s u ra n c e A nalyst will run c o m p u te riz e d logic c h e c k s a n d distrib u te e rro r re p o rts to th e d a ta m a n a g e r fo r rectification. At th e tim e of a n a ly sis, th e d a ta will b e e x p o rte d from BITS to S A S (a statistic al so ftw are p a c k a g e ) for p ro g ram m in g b y th e B iostatistician. U p d a tin g t h e d a t a b a s e , d a t a c o lle c tio n . A n initial draft of th e c a s e rep o rt fo rm s h a v e d e v e lo p e d . All d a ta co lle c te d will u n d e rg o a p eriodic a u d it b y th e p hysician on th is s tu d y a n d th e q uality a s s u r a n c e co m m ittee (th e c o s t a s s o c ia te d with th e q uality a s s u r a n c e c o m m itte e will b e pro v id e d b y City of H ope). T h e p rim ary g o al of th e au d it p ro c e d u re is to a s s u r e a c c u ra te d a ta collection a n d in terp reta tio n . In addition to collecting th e inform ation a b o u t th e p a tie n ts d is e a s e a n d tre a tm e n t history, follow u p will b e c o n d u c te d o n all p a tie n ts from d ia g n o sis to la st c o n ta c t or d e a th , to d e te rm in e th e ir c a n c e r s ta tu s a n d vital s ta tu s: c o m p le te d e a th inform ation including d a te a n d c a u s e o f d e a th will b e c a p tu re d fo r all ex p ired p a tie n ts. C ity of H o p e Institutional R eview B o ard a p p ro v al h a s b e e n o b ta in e d to review th e m e d ical re c o rd s for th e s e p a tie n ts to a b s tra c t tum or, tre a tm e n t, g e n e tic , clin ic al/tran sp lan t c h a ra c te ristic s, r e la p s e a n d vital s ta tu s d a ta . D a ta b a s e M a n a g e m e n t a n d D a ta M a n a g e m e n t. At C ity of H ope all c a n c e r c e n te r stu d y d a ta a r e e n te r e d into th e B io statistics Inform ation T racking S y ste m (BITS), a c e n tra liz e d relational r e s e a rc h d a t a b a s e d e v e lo p e d w ithin th e Division o f Inform ation S c ie n c e s o v e r 15 y e a rs a g o u sin g th e A d v a n c e d R evelation (A REV ) so ftw are s y ste m . BITS is d e p lo y e d o n a n NT s e rv e r a n d is m a in ta in e d within th e Division of Inform ation S c ie n c e s . T h e s y ste m is p a s s w o rd p ro te c te d to restrict a c c e s s to re s e a rc h staff a n d in v e stig a to rs. S ecu rity c a n b e s e t to "re a d o n ly ' or "write" priv ileg es b a s e d on th e u s e r 's p erm issio n to view , e n te r a n d /o r ed it d a ta . B ITS in c o rp o ra te s all d a ta req u ire d for stu d y ad m in istratio n , statistic al a n a ly sis, a n d h a s e lectro n ic in te rfa c e s for im porting d e m o g ra p h ic , d is e a s e , la b o ra to ry a n d tre a tm e n t d a ta from o th e r institutional s y s te m s . T h e k e y p e rs o n n e l fo r th is s tu d y (with th e ex c e p tio n of th e off-site c o n s u lta n t) h a v e g a in e d a c c e s s to th is d a ta b a s e a n d th e a p p ro p ria te p e rm is sio n s h a v e b e e n s e t b a s e d on stu d y role. S ta tis tic a l M e th o d s . D em o g ra p h ic a n d d is e a s e c h a ra c te ris tic s will b e su m m a riz e d for all p a tie n ts u s in g d escrip tiv e statistic s. T h e W ilcoxon ra n k -su m te s t will b e u s e d w h e n c o m p arin g m e d ia n s for c o n tin u o u s d a ta , a n d F is h e r's e x a c t te s t to c o m p a re ca te g o ric a l d a ta . P age40 252 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M. P a lm e r________ Survival e s tim a te s will b e c a lc u la te d b a s e d on th e product-lim it m e th o d (K aplan a n d M eier. 1958), a n d 9 5 % c o n fid e n c e in terv als will b e c a lc u la te d u sin g th e logit tra n sfo rm atio n with G re e n w o o d 's v a ria n c e e s tim a te (B reslow a n d D ay, 1980). T h re e e n d p o in ts will b e stu d ie d : overall survival (O S ), d is e a s e fre e survival (D F S ) a n d r e la p s e . F a c to rs a s s o c ia te d with overall survival, d is e a s e fre e survival a n d re la p s e will b e e x a m in e d s e p a ra te ly b y u n iv a riate C ox re g re s s io n a n a ly s is (C ox. 1972). T h e a s s u m p tio n of proportionality of th e h a z a rd ratio will first b e te s te d on e a c h v ariab le. T h e p ro portional h a z a rd s a s s u m p tio n will b e c h e c k e d u s in g a form al te s t p ro c e d u re d e s c rib e d b y M arubini & V alsecchi (1 9 9 4 ). T h e v a ria b le s to b e te s te d w e re d e te rm in e d from th e litera tu re review . T h e risk ratio will b e c a lc u la te d fo r e a c h v aria b le alo n g w ith th e 9 5 % c o n fid e n c e limits. T o d ev e lo p a m ultivariate m o d el, s te p w is e C ox re g re s s io n will b e p erfo rm e d to d e te rm in e in d e p e n d e n t p re d ic to rs of survival a n d re la p s e : all v a ria b le s with a p- v a lu e < 0.1 0 b y u n iv a riate a n a ly s is will b e in c lu d ed a s c a n d id a te s in this a n a ly sis. All ca lcu la tio n s will b e d o n e u s in g S A S v ersio n 8.2. P o w a r J u s t if ic a ti o n f o r S u rv iv a l A n a ly s is . F o cu sin g on th e prim ary e n d p o in t (survival), this a n a ly s is w a s a im e d at ev a lu atin g th e m inim um h a z a r d ra te ratio s th a t ca n b e d e te c te d given th e e x p e c te d n u m b e r of e v e n ts u n d e r th re e different s c e n a rio s . T h e s c e n a rio s in c lu d ed in th is a n a ly s is w e re s e le c te d to s h o w th e ra n g e of p o w e r giv en a s e t of m eaningful h a z a r d ra tio s (1.4, 1.6 a n d 1.8). (W h en survival is th e o u tc o m e of in te re s t it a p p e a r s to b e co m m o n p ra c tic e to c o m p a re th e survival tim e b e tw e e n g ro u p s; th is is w h a t w a s d o n e h e re .) T his p o w e r a n a ly s is w a s c o n d u c te d to te s t for an a s s o c ia tio n b e tw e e n o verall survival tim e a n d c o v a ria te s in a re tro sp e c tiv e cohort of 3 9 3 BM T p a tie n ts. P o w e r re s u lts fo r a tw o -g ro u p 'su rv iv al tim e' c o m p a riso n a re p re s e n te d in T a b le 5. F o r e x a m p le , w h en th e sa m p le s iz e s in a g e g ro u p s > 40 a n d <40 a r e 1 5 6 a n d 237, resp ectiv ely , a .05 level tw o -sid e d log-rank te s t will h a v e 9 1 % p o w er to d e te c t th e survival tim e d iffe re n ce for a h a z a rd ratio (H R) of 1.8, w hich is m u c h low er th a n th e HR of 2.9 in th e o b s e rv e d d a ta . T able S: R e su lts of P o w e r A n aly sis -C om paring su rv iv al tim e b etw e en tw o g ro u p s ; tw o -sid ed log-rank te s t, a-lev el .05, to tal sa m p le size 393 p a tie n ts S c e n a rio s S am p le S ize by C o m p a riso n G roup* H azard Ratio" b e tw e e n g ro u p s P o w e r1 ' A ge group: >40 vs. £40 years 156 vs. 237 1.4 42 1.6 73 1.8 91 2.9* 99 T ransplant Type: MUD/MRD vs. S ibling/S yngeneic: 127 v s. 266 1.4* 52 1.6 83 1.8 96 2.0 99 Tim e from Diagnosis to Allo-BMT: >12 m onths vs. £12 m onths 196 vs. 197 1.4 49 1.6 80 1.8 95 1.9* 98 a Sam ple sizes in groups of high vs low survival risks 0 H azaid ratio in observed data was marked with an asterisk (*} c Power estim ated by nQuery A dvisa 5 0 software using 2000 simulations Page41 253 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M. P a lm e r T h e s e d a ta s h o w th a t, u n d e r th e s c e n a rio s te s te d , a .0 5 level tw o -sid ed log-rank te s t will h a v e > 8 0 % p o w e r to d e te c t th e survival d iffe re n ce th a t c o rre s p o n d s to a h a z a rd ratio (H R) of 1.6-2.9. W ith th e ex cep tio n of p a ra m e te rs with m o re h eav ily u n b a la n c e d s a m p le s iz e sp lits (e.g ., tra n s p la n t ty p e ) th is a n a ly s is s h o w s th a t th e r a n g e of h a z a rd ra tio s th a t a re d e te c ta b le giv en th e d a ta is g e n e ra lly go o d . 3 -Y e a r P r o je c t S c h e d u le . T h e follow ing p ro je ct s c h e d u le ite m iz e s th e m a jo r ta s k s a n d g ran t d e liv e ra b le s by fiscal y e a r. F is c a l Y e a r 01 (7 /1 /0 2 -6 /3 0 /0 3 ) 1. D raft rev iew p a p e r, m a n u sc rip t #1 2. G ain a c c e s s to identified s o u rc e s of m o le c u la r a n d c y to g en etic d a ta 3. B egin d a ta collection a n d finalize th e a n a ly s is s tra te g y 4. S u b m it m a n u sc rip t #1 for publication T h e first 3 m o n th s of th e fu n d in g p erio d will b e d e v o te d to finalizing a draft of th e review p a p e r on C M L-C P p ro g n o s is (m a n u sc rip t #1 ). T h e rem ain in g n in e m o n th s of fiscal y e a r 01 will b e d e v o te d to th e d a ta collection effort a n d finalizing th e a n a ly s is stra te g y . F is c a l Y e a r 02 (7 /1 /0 3 -6 /3 0 /0 4 ) 1. C o n tin u e d a ta collection a n d beg in p ro g ram m in g of statistic al p ro g ra m s 2. D raft re s u lts of statistic al a n a ly s is (m a n u sc rip t # 2 ) F is c a l Y e a r 03 (7 /1 /0 4 -6 /3 0 /0 5 ) 1. F inalize d a ta collection a n d co m p le te statistical a n a ly s is 2. S ubm it re s u lts of statistic al a n a ly sis, m a n u sc rip t # 2 C ollecting th e re q u ire d d a ta will b e a la b o r-in ten siv e p ro c e s s th a t is p ro je c te d to ta k e 2 y e a rs to c o m p lete. B e c a u s e n o t all p a tie n ts w e re initially d ia g n o s e d or tre a te d at C ity of H ope a n d m a y h a v e b e e n d ia g n o s e d 1 5-25 y e a rs ag o . obtain in g s o u rc e d o cu m e n ta tio n o n th e s e p a tie n ts will ta k e s o m e tim e to re triev e a n d is d e p e n d e n t o n th e co o p e ra tio n of o u ts id e h o s p ita ls a n d clinics. P age42 254 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M. P a lm e r E. R e f e re n c e s A m erican C a n c e r S o cie ty . C alifornia D ivision, a n d P ublic H ealth Institute. C alifornia C a n c e r R eg istry . C alifornia C a n c e r F a c ts a n d F ig u re s 2002. O ak la n d . C A A m erican C a n c e r S ociety. C alifornia D ivision. S e p te m b e r 20 0 1 . B onifazi F, D e Vivo A, R osti G . et al. T e stin g S o k a l's a n d th e new p ro g n o stic s c o re for chronic m yeloid le u k e m ia tre a te d with alp h a-in terfero n . British Jo u rn al of H em a to lo g y 1 1 1 :5 8 7 -5 9 5 . 2000 . B reslow N E a n d D ay NE. S tatistical m e th o d s in c a n c e r re s e a rc h , vol 1: T h e a n a ly s is o f c a s e - control s tu d ie s. Lyon, F ra n c e . W H O Intern atio n al A g en cy for R e s e a rc h in C a n c e r. 1980. C e rv a n te s F, R o zm an C . A m ultivariate a n a ly s is of p ro g n o stic fa c to rs in ch ro n ic m yeloid le u k em ia. B lood 6 0 :1 2 9 8 -1 3 0 4 .1 9 8 2 . C lark R E. H e rm a n s J . M adrigal A. N a c h b a u r D. K ro p sh o fer G , G ratw ohl A A p p erley J. a n d N ied e rw ie se r D for th e C h ro n ic L e u k aem ia W o rking P a rty of th e E u ro p e a n G ro u p of B lood a n d B o n e M arrow T ra n sp la n ta tio n . HLA-A3 in c re a s e s a n d HLA-DR1 d e c r e a s e s th e risk of a c u te g ra ft-v e rsu s -h o s t d is e a s e after H L A -m atched sibling b o n e m a rro w tra n sp la n ta tio n for ch ro n ic m y e lo g e n o u s le u k a e m ia . British Jo u rn al of H aem a to lo g y 114(1): 3 6-41. 2001. C o rte s J , K antarjian HM, G iralt S . e t al. N atural histo ry a n d sta g in g of chronic m y e lo g e n o u s leu k em ia. B aillieres C linical H em a to lo g y 1 0 :2 7 7 -2 9 0 .1 9 9 7 . C ox D R. R e g re ss io n m o d e ls a n d life ta b le s . J o u rn a l of th e R oyal S tatistical S o c . S e r. B. 3 4 :1 8 7 , 1972. D ein in g er MWN a n d D ruker BJ. S p ecific ta rg e te d th e ra p y of ch ro n ic m y e lo g e n o u s le u k em ia with im atinib. P h arm a co lo g ical R ev iew s 55: 4 0 1 -4 2 3 , 20 0 3 . G ratw ohl A. H e rm a n s J , G o ld m a n JM , A rc e s e W . C a rre ra s E. D ev erg ie A F ra sso n i F, G ah rto n G . Kolb H J. N ied e rw ie se r D. R uutu T, V e rn a n t J P , d e W itte T. a n d A p p erley J. R isk a s s e s s m e n t for p a tie n ts with ch ro n ic m yeloid le u k a e m ia b e fo re allo g e n e ic blood or m a rro w tra n sp la n ta tio n . L a n cet 3 5 2 (9 1 3 4 ): 1 0 8 7 -1 0 9 2 , 1998. G ratw ohl A. P ro g n o stic fa c to rs in ch ro n ic m yeloid leu k em ia: A llografting. S e m in a rs in H e m a to lo g y 40(1): 13-21. 20 0 3 . H asfo rd J, A n sari H, P firrm ann M. e t al. A n aly sis a n d validation of p ro g n o stic fa c to rs for CML: G e rm a n CML S tu d y G roup. B one M arrow T ra n sp la n t 1 7 :S 4 9 -S 5 4 . 1996. H asfo rd J . P firrm ann M. H eh lm an n R, et al. A n e w p ro g n o stic s c o re for survival of p a tie n ts with ch ro n ic m yeloid le u k em ia tre a te d with in terfero n -alp h a: W riting C o m m itte e fo r th e C ollaborative CM L P ro g n o stic F a c to rs P ro jec t G roup. J o u rn a l of th e N ational C a n c e r Institute 9 0 :8 5 0 -8 5 8 , 1998. H eh lm an n R. H eim pel H, G rie s s h a m m e r M. e t al. C h ro n ic m y e lo g e n o u s leu k em ia: rec e n t d e v e lo p m e n ts in p ro g n o stic ev a lu atio n a n d c h e m o th e ra p y . L eukem ia 6 :1 1 0 S -1 1 4 S . 1992. P age43 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M. P a lm e r________ H eh lm an n R, A n sa ri H, H asfo rd J , e t al. C o m p a ra tiv e a n a ly s is of th e im p a c t o f risk profile a n d of d ru g th e ra p y on survival u sin g S o k a l's ind ex a n d a n ew s c o re : G e rm a n C h ro n ic M yeloid L eu k em ia S tu d y G roup. British Jo u rn al of H em a to lo g y 9 7 :7 6 -8 5 ,1 9 9 7 . Italian C o o p e ra tiv e S tu d y G ro u p o n ch ro n ic m yeloid le u k em ia. C onfirm ation a n d im p ro v em e n t of S o k a l's p ro g n o stic classificatio n of P h+ ch ro n ic m yeloid leu k em ia: T he v a lu e of ea rly ev alu atio n in th e c o u rs e of th e d is e a s e . A n n a ls of H e m a to lo g y 6 3 :3 0 7 -3 1 4 ,1 9 9 1 . Italian C o o p e ra tiv e S tu d y G ro u p on ch ro n ic m yeloid le u k em ia. In te rfe ro n -alp h a a s c o m p a re d w ith co n v e n tio n al c h e m o th e ra p y for th e tre a tm e n t of chronic m yeloid le u k e m ia . N ew E n g lan d Jo u rn al of M edicine 3 3 0 :8 2 0 -8 2 5 ,1 9 9 4 . K antarjian HM, S m ith TL, M cC redie KB. et al. C hronic m y e lo g e n o u s leu k em ia: a m ultivariate a n a ly s is of th e a s s o c ia tio n s of p atie n t c h a ra c te ris tic s a n d th e ra p y with survival. B lood 6 6 :1 3 2 6 - 1335, 1985. K antarjian HM. V ellekoop L, M cC red ie KB, K eating MJ. H e s te r J, S m ith T et al. In ten siv e co m b in atio n c h e m o th e ra p y (R O A P 10) a n d s p le n e c to m y in th e m a n a g e m e n t of chronic m y e lo g e n o u s le u k em ia. Jo u rn al of C linical O n co lo g y 3: 192 -2 0 0 . 1985. K antarjian HM, K eatin g M. S m ith TL. et al. P ro p o sa l for a sim p le s y n th e s is p ro g n o stic sta g in g s y ste m in ch ro n ic m y e lo g e n o u s le u k em ia. A m erican J o u rn a l of M edicine 8 8 :1 -8 ,1 9 9 0 . K antarjian HM. S m ith TL, O 'B rien S. B eran M, P ie rc e S . a n d T a lp az M. P ro lo n g e d survival in ch ro n ic m y e lo g e n o u s le u k em ia a fte r c y to g e n e tic re s p o n s e to in terfero n -alp h a th e rap y : th e le u k em ia se rv ic e . A n n u a ls of Internal M edicine 1 2 2 :2 5 4 -2 6 1 , 1995. K aplan G a n d M eier P . N o n -p aram e tric e s tim a tio n s from in c o m p le te o b s e rv a tio n s . Jo u rn al of th e A m erican S tatistical A sso ciatio n 53: 4 5 7 ,1 9 5 8 . M arubini E a n d V alsecc h i M G. A nalyzing survival d a ta from clinical trials a n d o b se rv a tio n a l s tu d ie s. Jo h n W iley a n d S o n s. 1994. M ichallet M. Bilger K. G a rb a n F red eric. A ttal M. H uyn A e t al. A llogeneic h e m a to p o ie tic s te m cell tra n sp la n ta tio n after n o n m y e lo ab lativ e p re p a ra tiv e re g im e n s: Im pact of p re -tra n sp la n ta tio n a n d p o s t-tra n sp la n ta tio n fa c to rs on o u tc o m e . J o u rn a l of C linical O n co lo g y 19(14): 3 3 4 0 -3 3 4 9 . 20 0 1 . N ational C o m p re h e n s iv e C a n c e r N etw ork, C linical P ra c tic e G u id elin es in O n cology: C hronic M y elo g e n o u s L eukem ia. V ersion 0 1 .2 0 0 4 . http://w w w .nccn.orci/D hvsician ols/f ou id elin es.h tm l O z e r H. G e o rg e SL, S chiffer CA. e t al. P ro lo n g e d s u b c u ta n e o u s a d m in istra tio n of re c o m b in a n t a lp h a -2 b interferon in p a tie n ts p rev io u sly u n tre a te d P h ila d elp h ia ch ro m o so m e-p o sitiv e chronic- p h a s e ch ro n ic m y e lo g e n o u s le u k em ia. Effect on rem issio n duration a n d survival: C a n c e r a n d L eu k em ia G ro u p B S tu d y 8 5 9 3 . B lood 8 2 :2 9 7 5 -2 9 8 4 . 1993. P erk in s C l, K w ong SL. M orris C R . C o h e n R. Allen M. S c h a lg R. a n d W right W E. C a n c e r in C alifornia, 2 0 0 1 . S a c ra m e n to . CA: C alifornia D ep artm en t of H ealth S e rv ic e s , C a n c e r S u rv e illa n c e S ectio n , D e c e m b e r 20 0 0 . R ad ich J P . G o o le y T. B ryant E, C h a u n c e y T. Clift R. B ep p u L. E d m a n d s S. F lo w ers MED. K erkof K. N elson R, a n d A p p elb a u m FR. T h e sig n ifican ce of bcr-abl m o le c u la r d etectio n in P age44 256 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M. P a lm e r ch ro n ic m yeloid le u k em ia p a tie n ts 'la te '. 18 m o n th s or m o re a fte r tra n sp la n ta tio n . B lood 98: 1 7 0 1 -1 7 0 7 . 20 0 1 . R ie s LAG, E isn e r MP. K osary CL. H an k ey BF. Miller BA. C legg L. E d w a rd s BK. (ed s). S u rv eillan c e, E pidem iology, a n d E n d R e s u lts (S E E R ) C a n c e r S tatistic s R eview . 19 7 3 -1 9 9 8 . N ational C a n c e r Institute. N ational C a n c e r Institute. B e th e s d a , MD. h ttp ://se e r.c a n c e r.g o v /P u b lic a tio n s /C S R 1 9 7 3 1 9 9 8 /. 2001. S ch o tten feld , D. a n d F rau m e n i, J.F . C a n ce r E p id e m io lo g y a n d P r e v e n tio n - S e c o n d Edition. N ew Y ork, NY: O xford U niversity P re s s . Inc.: 1996. S o k al JE . C ox EB, B a c c a ra n i M, et al. P ro g n o stic discrim ination in 'g o o d -risk ' chronic gran u lo cy tic le u k em ia. Blood 6 3: 7 8 9 -7 9 9 ,1 9 8 4 . S o k al J E , B a c c a ra n i M, T u ra S , e t al. P ro g n o stic discrim ination a m o n g y o u n g e r p a tie n ts with ch ro n ic g ran u lo cy tic le u k em ia: R e le v a n c e to b o n e m a rro w tra n sp la n ta tio n . B lood 6 6 :1 3 5 2 -1 3 5 7 . 1985. T hiele J . K vasnicka HM. Z a nkovich R, et al. P a r a m e te rs of predictive v a lu e in ch ro n ic m yeloid le u k em ia - t h e p ro g n o stic im p act of h isto p a th o lo g ical v a ria b le s in a m ultivariate re g re s s io n a n a ly sis. L eu k em ia L ym p h o m a 4 :6 3 -7 4 , 1991. T hiele J. K vasnicka HM. T itius BR. e t al. H istological f e a tu r e s of p ro g n o stic sig n ifican ce in CML: a n im m u n o h isto c h em ical a n d m o rp h o m etric stu d y (m ultivariate re g re s s io n a n a ly sis) on tre p h in e b io p s ie s of th e b o n e m arrow . A n n als of H em a to lo g y 6 6 :2 9 1 -3 0 2 . 1993. T ura S. B ac caran i M. Corbelli G , e t al. S ta g in g of ch ro n ic m yeloid leu k em ia. British J o u rn a l of H e m a to lo g y 4 7 :1 0 5 -1 1 9 ,1 9 8 1 . P a g e 45 257 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M. P a lm e r FORM 14 Required for all applications. S e e Section 25 in Application Packet for additional instructions.________________________________ Statem ent of Distinction from Other Funded Work (P lease limit to 12 pi. font text and 1 1nch m argins) 11/3/2003: B ased on feedback from Joycelynne Palm er's dissertation subcom m ittee', this item w as intentionally left blank. *: Drs. S usan Preston-M artin, W endy Mack, and Stan Azen (alternate for Dr. David Snyder) P age46 258 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M. P a lm e r FORM 15 This form is required ON LY for New Investigator Award, Clinical Scientist D evelopm ent Award, and the G raduate S tudent Award for Hum an Population-B ased R esearch. S ee Section 25 in Application P acket for additional guidelines.__________________________________________ C areer Plan (P lease limit to one page with 12 pi. font text and 1 Inch m arg h s) 11/3/2003: B ased on feedback from Joycelynne Palm er's dissertation subcom m ittee*, this item w as intentionally left blank. *: Drs. S usan Preston-M artin, W endy Mack, and Stan Azen (alternate for Dr. David Snyder) P age47 259 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M. P a lm e r FORM 16 Required for all applications.__________________________________________________________________ Hum an S u b jects S ee Section 25 in the Application Packet for Instructions on completing this form. All applications proposing hum an subjects research are required to ad d ress the sev en points listed In th ese instructions. | D oes not apply b ecau se the proposed research will NOT m ake u se of hum an subjects or hum an tissue/fluid sam ples IF THE PROPOSED RESEARCH WILL MAKE USE OF HUMAN SUBJECTS, CHECK THE APPROPRIATE BOX: X Men and W om en Included X Ethnically/Racially D iverse Populations Included W om en Excluded Ethnically/Racially D iverse Populations Excluded M en Excluded Children Excluded Include separate tables for A LL human sublects protocols to be used with the grant application If funded: IRB APPROVAL STATUS | E x em p t A p proved | X P e n d in g | PROTOCOL NUMBER 00120 PRINCIPAL INVESTIGATOR David S. Snyder, M.D. PROJECT TITLE Identifying Predictors of R elapse and D eath for Patients undergoing Allogeneic Transplantation for T reatm ent of Chronic Myeloid Leukemia in Chronic P hase. APPROVAL DATE 09/04/2003 Are you listed a s an approved investlaator on this protocol? Y es X No D oes your institution require annual (or m ore frequent) review of this protocol? Y es X Y e s If y es, w hen is the next review? 09/03/2004 IRB APPROVAL STATUS | E xem pt A pproved j P en d in g | PROTOCOL NUMBER PRINCIPAL INVESTIGATOR PROJECT TITLE APPROVAL DATE Are you listed a s an approved Investlaator on this protocol? Y es No D oes your institution require annual (or m ore frequent) review o f this protocol? Y es Y e s If y es. w hen Is the next review? IRB APPROVAL STATUS | E x em p t A ppro v ed | P e n d in g | PROTOCOL NUMBER PRINCIPAL INVESTIGATOR PROJECT TTTLE APPROVAL DATE Are you listed a s a n approved Investlaator on this protocol? Y es No D oes your institution require annual (or m ore frequent) review of this protocol? Y es Y e s If yes, w hen Is the next review? P age48 260 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): J o y cely n n e M. P a lm e r FORM 16 (Continued) I Please address the seven points listed In Section 25 of the Application Packet. I 1: G e n d e r a n d M in o rity I n c lu s io n (M in o rity O u tr e a c h ) T h e City of H ope N ational M edical C e n te r is d e d ic a te d to e n s u rin g th a t w o m en a n d m e m b e rs of m inority g ro u p s a re in clu d ed in o u r clinical r e s e a rc h s tu d ie s fo r b lo o d /m arro w tra n sp la n ta tio n (BM T). For e a c h p ro p o s e d clinical s tu d y (trial), w e in c lu d e a se c tio n on th e e x p e c te d n u m b e r of en ro lled w o m en /m in o rity s u b je c ts (ta rg et a c c ru a l) th e re b y m axim izing th e ir inclusion to th e ex te n t p o ssib le . W e d o n o t p la n a n y ex clu sio n of th e s e p o p u la tio n s in th is re tro sp e c tiv e r e s e a r c h p ro je ct. M en, w o m en a n d all eth n ic m in o rities will b e in c lu d ed a s s u b je c ts in th is stu d y with n o re strictio n s b a s e d on g e n d e r or ra c e . T ab le 1 sh o w s th e (distribution) n u m b e r a n d p e rc e n t of p a tie n ts tra n s p la n te d at City of H ope from 1 9 7 6 th ro u g h 1999. b y g e n d e r a n d ra c e -e th n ic ity group. T a b le 1 T r a n s p la n t R e c ip ie n ts b y G e n d e r a n d R a c e -E th n ic ity G ro u p W hite S p a n is h S u rn a m e A sian Black A m erican Indian O th er Total F em a le 1273 349 137 76 7 56 189 8 n (% ) (6 7 )a (19) (8) (3) (<1) (3) [55]“ M ale 946 381 77 43 6 88 1541 n (% ) (62) (25) (6) (3) (<1) (4) [45] Total 221 9 730 216 119 13 144 3 4 3 9 n (% ) (65) (21) (6) (3) (1) (4) a( ) r e p r e s e n ts row p e r c e n ta g e “[ ] re p re s e n ts colum n p e rc e n ta g e M in o rity O u tr e a c h . Thirty-five p e rc e n t of o ur BMT p a tie n ts a r e from eth n ic m inority g ro u p s, including 21% H ispanic (overall). T h e C ity of H ope h a s m a d e a su b sta n tia l effort to in c re a s e th e recru itm e n t of m inority s u b je c ts to o u r re s e a rc h p ro g ra m s via o ur M inority O u tre a c h P ro g ra m . T h e M inority O u tre a c h P ro g ram at City o f H op e, e s ta b lis h e d in 19 9 5 , in c lu d e s a L atino su p p o rt g ro u p for p a tie n ts a n d th eir fam ilies; tra n sla tio n of inform ational m a te ria ls into S p a n ish ; a q uality of life s tu d y for BMT su rvivors w ith a S p a n is h in stru m en t: a n d a clinical trials o u tre a c h p ro g ram to in c re a s e m inority a c c ru a l to r e s e a rc h s tu d ie s. T h e D e p a rtm e n t of B io statistics is re s p o n s ib le for th e co ordination of th is p ro g ram . 2: I n c lu s io n o f C h ild re n a s P a r ti c ip a n ts in B lo o d /M a rro w T r a n s p la n t S tu d ie s B e c a u s e of th e in c re a s in g s iz e a n d im p o rta n c e of th e P ed ia tric B lood/M arrow T ra n sp la n t P ro g ram at th e City o f H ope, p la n s w e re d e v e lo p e d to include children on in v e stig atio n al tra n sp la n t p ro to c o ls. T h e Institutional R eview B oard h a s p ro v id e d g u id a n c e to all C ity of H o p e in v e stig a to rs for th e inclusion or ex clu sio n of children in clinical r e s e a rc h p ro to c o ls th e re fo re th e s e p rin cip les h a v e b e e n indirectly a p p lie d to th e a n a ly s is plan d e s c rib e d in th is g ra n t. In g e n e ra l, children a r e in clu d ed w h e n e v e r fe a s ib le , with th e ex c e p tio n of P h a s e I trials th a t a re in direct co m petition with re s e a rc h p ro to c o ls d e v e lo p e d b y th e C h ild ren 's C a n c e r G ro u p . P age49 261 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): J o y cely n n e M. P a lm e r________ 3: I n s titu tio n a l A p p ro v a l o f R e s e a r c h P r o p o s a l S in c e th e p ro p o s e d re s e a rc h will include h u m a n s u b je c ts th is re s e a rc h p ro p o s a l h a s a s e p a r a te Institutional R eview B o ard (IRB) a p p ro v e d pro to co l fo r u s e in th e institution (IRB # 0 0 1 2 0 ). P a tie n ts w h o a re particip atin g in th is stu d y h a v e b e e n info rm ed of th e in v e stig ativ e n a tu re of th is re tro sp e c tiv e c h a rt rev iew (p o o le d a n a ly sis) a n d a w ritten in form ed c o n s e n t h a s b e e n o b ta in e d fo r e a c h p atien t. In 1984, th e E x e cu tiv e C o m m itte e of th e M edical S taff a t th e C ity of H ope d ire c te d th e C linical C a n c e r C o m m ittee to o v e r s e e s tu d y d e v e lo p m e n t a n d c o n d u c t w ithin th e C a n c e r C e n te r for all s tu d ie s involving c a n c e r p a tie n ts. T o a c co m p lish th is, a pre-IR B review a n d protocol sign-off p ro c e s s w a s initiated in w hich all c a n c e r-re la te d s tu d ie s rece iv e a full review b y th e C linical P rotocol R eview a n d M onitoring C o m m ittee (C P R M C ). w h o s e m e m b e rs c o n s is t of th e h e a d s of e a c h clinical division, th e E xecu tiv e V ic e -P re s id e n t of th e M edical C e n te r, a n d th e D irector of B io statistics. Follow ing th e ap p ro v al by th e C P R M C . all p ro to c o ls a r e re v ie w e d by th e IRB at C ity of H ope. T h e c h a ra c te ris tic s of th e s u b je c t pop u latio n including n u m b e r, a g e ra n g e s a n d h e a lth s ta tu s a r e s u m m a riz e d in th e E x p e rim en tal D esign a n d M eth o d s. S pecifically, h o w ev er, f e tu s e s , p re g n a n t w o m e n , a n d p ris o n e rs a re n ot utilized in th is stu d y . M en, w o m e n a n d all eth n ic m in orities will b e in c lu d ed a s s u b je c ts in th is stu d y with n o re stric tio n s b a s e d on s e x or ra c e . 4 : S o u r c e ( s ) o f D a ta T h e d a ta th a t will b e u s e d for th is p ro ject is a co m b in atio n of p re s e n ta tio n d a ta , o n -stu d y d a ta , a n d lo n g -term follow -up (d is e a s e -fre e survival, a n a ly s is of co m p lic atio n s of b lo o d /m arro w tra n sp la n ta tio n ) d a ta . B e c a u s e th is stu d y involves th e u s e of p a tie n t m e d ical re c o rd s , th e p ro p o sa l for u s e of th e p a tie n t's m e d ical re c o rd w a s su b je c t to th e s a m e g u id e lin e s/re q u ire m e n ts a s d e s c rib e d in th e p a ra g ra p h a b o v e 5: P o te n tia l R is k s - P h y s ic a l, P s y c h o lo g ic a l, S o c ia l, L e g a l o r o th e r T h e re a re n o p o te n tia l risk s (physical, p sy ch o lo g ical, social, le g al or o th e r) to th e s u b je c ts involved in th is stu d y . 6 : P o te n tia l R is k s - C o n f id e n tia lity In o rd e r to m a in ta in or m inim ize p o tential risk s including confidentiality, p a tie n ts a r e identified for both IRB rev iew a n d publication b y a U n iq u e P a tie n t N u m b er w hich allow s p a tie n t e v e n ts to b e tra c k e d a n d p a tie n t d a ta to b e co lle c te d w ithout rev ea lin g th e ir identity. A s p art of th e c o n s e n t p ro c e d u re at C ity of H ope, th e d escrip tio n of a n d th e m e a n s involved in p ro te ctin g a g a in s t th e s e risk s a r e in c lu d ed within th e c o n s e n t. 7: P o te n tia l R is k s - B io lo g ic a l S p e c i m e n s T h e re a r e n o p o tential risk s a s s o c ia te d with th e collection of biological s p e c im e n s fo r th e s u b je c ts involved in th is stu d y . B e c a u s e th is stu d y d o e s n o t re q u ire th e d irect p articipation of th e p atien t, only a review of th eir m e d ical reco rd , a m e d ical intervention or collection of a biological s p e c im e n is n o t n e c e s s a ry . P a g e 50 262 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): J o y cely n n e M. P a lm e r FORM 17 Required for all applications.__________________________________________________________________ V ertebrate Anim als X 1. D oes not apply b ecau se the proposed research will NOT u se vertebrate animals 2 The proposed research will m ake u se of vertebrate anim als. Include sep arate tables for ALL vertebrate animal protocols to be used with the grant application If lUnded. VERTEBRATE ANIMAL iririrrtuaH APPROVAL STATUS A pproved P en d in g PROTOCOL NUMBER PRINCIPAL INVESTIGATOR PROJECT TITLE APPROVAL DATE Are you listed a s a n approved Investlaator on this protocol? Y es No D oes your Institution require annual (or m ore frequent) review of this protocol? Y es Y e s If y es. w hen Is the next review? VERTEBRATE ANIMAL APPROVAL STATUS A pproved P en d in g PROTOCOL NUMBER PRINCIPAL INVESTIGATOR PROJECT TITLE APPROVAL DATE Are you listed a s an approved investlaator on this protocol? Y es No D oes your Institution require annual (or m ore frequent) review of this protocol? Y es Y es if yes, w hen is the next review? VERTEBRATE ANIMAL APPROVAL STATUS A pproved P en d in g PROTOCOL NUMBER PRINCIPAL INVESTIGATOR PROJECT TTTLE APPROVAL DATE Are you listed a s an approved Investlaator on this protocol? Y es No D oes your Institution require annual (or m ore frequent) review o f this protocol? Y es Y e s If y es, w hen Is the next review? VERTEBRATE ANIMAL A f V ___ __ APPROVAL STATUS A pproved P en d in g PROTOCOL NUMBER PRINCIPAL INVESTIGATOR PROJECT TTTLE APPROVAL DATE Are you listed a s an approved Investlaator on this protocol? Y es N o D oes your Institution require annual (or m ore frequent) review of this protocol? Y es Y es If y es, w hen Is the next review? P a g e 51 263 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): J o y cely n n e M. P a lm e r FORM 17 (continued)________________________________________________________________________ If you marked Box 2, please address the five points listed In Section 25 of the Application Packet. This p age left blank intentionally. P a g e 52 264 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M. P a lm e r FORM 18 Required for all applications that include an Appendix._________________________________________ A ppendix C over Sheet P le a s e ch e c k item s s u b m itted a s A ppendix m aterial. I I S ubcontract budgets I I Letters of collaboration, com m itm ent(s) to provide research resources, subcontract agreem ent(s) and budgets, le tte rs) from co n su ltan ts). [ H Supporting m aterials (Note that the R esearch Plan m ust be self-contained and understandable without having to refer to the Appendix. Only those m aterials n ec essary to facilitate the evaluation of the research plan m a y b e included: the A ppendix is not to be u sed to circum vent p ag e limitations.) M anuscripts subm itted a s Supporting M aterials are limited to 3. ITEMIZE: 1) D ata collection fo rm s a n d in stru ctio n s 2) Institutional R eview B o ard A pproval 3) Institutional C ertification to C o n d u ct H um an S u b je c ts R e s e a rc h P a g e 53 265 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission. Appendix C: Continued Principal Investigator (First, Ml, Last): Jo y c e ly n n e M. P a lm e r FORM 19___________________________________________________________________________________ C o v e r S h e e t : For all applications proposing hum an or vertebrate anim al research P le a s e ch e c k item s su b m itted a s A ppendix m aterial. I~X] Copies of assu ran ces for hum an subjects and vertebrate anim als [~X| H uman subjects List O rganization N am e(s): City of Hope National Medicai C enter I I V ertebrate Animals List Organization N am e(s): P a g e 54 266 R eproduced with perm ission of the copyright owner. Further reproduction prohibited without perm ission.

Linked assets

University of Southern California Dissertations and Theses

Conceptually similar

PDF

Assessment of fatigue as a late effect of therapy among survivors of childhood leukemia

PDF

Effect of genetic factors in the development of childhood lymphocytic leukemia (ALL)

PDF

Recreational physical activity and risk of breast cancer

PDF

Dietary fats, fat metabolizing genes, and the risk of breast cancer

PDF

Genetic risk factors in breast cancer susceptibility: The multiethnic cohort

PDF

Determinants of the age at natural menopause: The multiethnic cohort

PDF

Physical activity and adenomatous polyps: Measures of association and impact

PDF

Risk factors, sequellae and intervention studies for the treatment of diabetes mellitus in Native American populations

PDF

Molecular and genetic epidemiology of Chlamydia trachomatis in the United States

PDF

Colorectal cancer risks in Singapore Chinese: Polymorphisms in the insulin-like growth factor-1 and the vitamin D receptor

PDF

Androgen receptor gene and prostate -specific antigen gene in breast cancer

PDF

A case/parental/sibling control study of Ewing's sarcoma/peripheral primitive neuroectodermal tumor (pPNET)

PDF

Breast cancer in the multiethnic cohort study: Genetic (prolactin pathway genes) and environmental (hormone therapy) factors

PDF

A large-scale genetic association study of prostate cancer in a multi-ethnic population

PDF

CYP17 polymorphism and risk for colorectal adenomas

PDF

The role of genetic variation in insulin -like growth factors in prostate cancer risk: The multiethnic cohort

PDF

A case-control study of passive smoking and bladder cancer risk in Los Angeles

PDF

The effects of dietary and other lifestyle behaviors on the risk of colorectal cancer among the Mexican -origin Latino population

PDF

Progression of subclinical atherosclerosis in type 2 diabetes: Therapeutic and metabolic influences

PDF

An intervention and program evaluation to determine the effectiveness of public health reforms on primary prevention practices by chiropractic interns

Asset Metadata

Creator Palmer, Joycelynne Michelle (author)

Core Title Identifying predictors of cytogenetic relapse and death for patients undergoing allogeneic blood or marrow transplantation for treatment of chronic myeloid leukemia in chronic phase: The City of...

School Graduate School

Degree Doctor of Philosophy

Degree Program Epidemiology

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag health sciences, oncology,OAI-PMH Harvest

Language English

Contributor Digitized by ProQuest (provenance)

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c16-464523

Unique identifier UC11336056

Identifier 3197572.pdf (filename),usctheses-c16-464523 (legacy record id)

Legacy Identifier 3197572.pdf

Dmrecord 464523

Document Type Dissertation

Rights Palmer, Joycelynne Michelle

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Access Conditions The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the au...

Repository Name University of Southern California Digital Library

Repository Location USC Digital Library, University of Southern California, University Park Campus, Los Angeles, California 90089, USA