University of Southern California Dissertations and Theses

Induction therapy in relapse adult acute lymphoblastic leukemia

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Induction therapy in relapse adult acute lymphoblastic leukemia

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Content i

INDUCTION THERAPY IN RELAPSE ADULT ACUTE
LYMPHOBLASTIC LEUKEMIA

By

Ravindra Patel

A Thesis Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements of the Degree
MASTER OF SCIENCE
(CLINICAL AND BIOMEDICAL INVESTIGATIONS)

December 2013

ii

DEDICATION

To my family, mentor and patients

iii

ACKNOWLEDGEMENT
The work in this thesis has been made possible by the great help from my mentor Dr. Vinod
Pullarkat, Dr. Ibrahim Aldoss and Dr. Stanley Azen. Thank you so much for your kind help.

iv

TABLE OF CONTENTS
Dedication ii
Acknowledgement iii
List of Tables vi
List of Figures vi
Abbreviations vii
Abstract viii
Introduction 1
- Background 1
- Diagnosis, Treatment and Prognostic Factors 4
Methods 7
- Study Patients 7
- Therapy 8
- Statistical Consideration 14
Results 15
- Patients Characteristics 15
- Response to Therapy 15
- Toxicity 17
- Outcomes of Patients Treated Off the Study 18
v

Discussion 19
Bibliography 22

vi

LIST OF TABLES
Table 1: Chemotherapy Protocol (Induction phase I and II) 9
Table 2: Chemotherapy Protocol (Consolidation and maintenance) 11
Table 3: Recommended Chemotherapy Dose Adjustments for Induction Phase 12
Table 4: Recommended Chemotherapy Dose Adjustments for Consolidation Blocks 13
Table 5: Patients Characteristics 16
Table 6: Results of Induction Therapy in Prospective and Retrospective Study 17

LIST OF FIGURES
Figure 1: Incidence rates by age 2
Figure 2: Mortality rates by age 3
Figure 3: Survival rates by age 4
Figure 4: ALL Blood smear 5
Figure 5: ALL Bone marrow biopsy 5

vii

ABBREVIATIONS
ALL Acute Lymphoblastic Leukemia
Allo-HSCT Allogeneic Hematopoetic Stem Cell Transplant
BMT Allogenic bone marrow transplant
CR Complete Remission
CR2 Complete Remission 2
Ph Philadelphia Chromosome
SEER Surveillance Epidemiology and End Results
BFM Berlin-Frankfurt-Muenster
LFS Leukemia Free survival
OS Overall Survival
HSCT Hematopoietic stem cell transplant
ANC Absolute neutrophil count

viii

ABSTRACT
Background Currently available chemotherapeutic treatment for relapse/refractory acute
lymphoblastic leukemia (ALL) helps to achieve complete remission (CR) in only one third of the
patients. The definitive treatment for ALL is allogeneic hematopoietic stem cell transplant
(HSCT) which can be used only in patients who achieved complete remission with the
chemotherapy. We did the study to explore possibilities for better survival by using other
possible chemotherapeutic regimens in relapsed/refractory ALL patients.
Methods Patients with ALL who relapsed or were refractory to chemotherapy, age range of 17
to 55 years, Karnofsky performance status of > 50%, and adequate hepatic and renal function
were eligible for the study. The primary objective of the study was to achieve higher CR rate
after the two phases of induction therapy as compared to standard of care. Secondary objectives
were to achieve longer LFS (Leukemia free survival), measure regimen toxicity and decrease
number of days required for neutrophil count recovery after each cycle of induction as compared
to current chemotherapy for relapsed/refractory ALL patients. In an effort to improve the CR rate
in adults ALL cases, a modified regimen was derived from pediatric Berlin-Frankfurt-Muenster
(BFM)-85 protocol, with addition of a continuous infusional phase II induction followed by
consolidation with alternating monthly cycles.
Results In this study, we have included the outcome of 19 patients treated prospectively on the
study, as well as a subsequent cohort of 31 patients treated off the study. Thirteen out of nineteen
(68%) patients from the initial prospective study achieved CR, and the median overall survival of
these 13 CR patients was 10.3 months. The median survival and LFS of all 19 patients were 5.6
and 4.3 months respectively. The regimen was well-tolerated and no grade 4 non-hematological
ix

toxicity was observed. Of the 31 patients treated off the study and analyzed retrospectively, 16
(52%) achieved CR. After including all 50 patients, 29 achieved CR (58%).
Conclusion The regimen used in this trial helps to achieve higher CR than the current
chemotherapeutic regimen for relapse/refractory ALL and helps to use allogeneic-HSCT as a
definitive treatment in these patients.
KEYWORDS: Acute lymphoblastic leukemia, adult, relapse, reinduction

1

INTRODUCTION
Acute Lymphoblastic Leukemia (ALL) is a serious health problem in all ages. ALL is a
hematological neoplasm involving cells of lymphoid lineage characterized by Lymphoblasts.
These malignant blast cells continuously multiply and occupy the bone marrow space by
overcrowding that leads to underproduction of normal hematological cells and causes various
clinical manifestations such as anemia, infection, and bleeding. Advanced technology in
diagnosis and treatment for ALL helps to minimize the side effects and improve survival rates.
ALL incidence and cure rates are much higher in children (90%) as compared to adults,
primarily because of relapses in adults. (Pui et al., 2011) According to the previous studies, less
than 33% of relapsed cases in adults achieve remission and become long term survivors (Rowe et
al., 2005). We performed this study to evaluate the efficacy of the newer regimen derived from
Berlin-Frankfurt-Muenster (BFM)-85 German Cooperative Group trial which proved to be
highly effective in relapsed pediatric ALL (Gökbuget et al., 2012) .
Background
ALL has bimodal distribution on the incidence graph. In children, ALL occurs during 2-5 years
of age and in adults it usually occurs in old age. It is estimated that 6,070 patients (3,350 men
and 2,720 women) will be diagnosed and 1,430 patients will die due to ALL in 2013. The
median age at diagnosis for ALL was 14 years during 2006-2010. Approximately 59.5% were
diagnosed under age 20; 10.5% between 20 and 34; 5.5% between 35 and 44; 6.7% between 45
and 54; 7.0% between 55 and 64; 5.3% between 65 and 74; 4.0% between 75 and 84; and 1.5%
85+ years of age. The age-adjusted incidence rate was 1.7 per 100,000 men and women per year.
The above information is based on cases diagnosed from 18 SEER geographic areas during
2

2006-2010. According to the data from 2008-2010, 1 in 784 men and women will be diagnosed
with acute lymphocytic leukemia during their lifetime.
Figure 1: Incidence Rates by Age

3

Figure 2: Mortality Rates by Age

The median age at death for acute lymphocytic leukemia was 52 years of age during 2006-2010.
Approximately 18.1% died under age 20; 16.2% between 20 and 34; 8.7% between 35 and 44;
10.8% between 45 and 54; 13.6% between 55 and 64; 13.6% between 65 and 74; 12.7% between
75 and 84; and 6.4% 85+ years of age. The age-adjusted death rate was 0.5 per 100,000 men and
women per year. These rates are based on patients who died in 2006-2010 in the US.

4

Figure 3: Survival Rates by Age

According to the data from 18 SEER geographic areas, 66.0% of cases survived during 2003-
2009. (SEER website, 2013)
Diagnosis, Treatment and Prognostic factors
Diagnosis of ALL begins with history, physical exam, and initial laboratory tests such as CBC
(complete blood count) and blood smear. The gold standard diagnostic test for ALL is bone
marrow biopsy. Other tests such as X-Ray, CT scan, Ultrasound, and CSF examination may help
to determine whether cancer has spread to the brain and spinal cord or other parts of the body.
Recently, special tests are also being considered such as Ph chromosome, immunophenotyping,
TdT (terminal deoxynucleotidyl transferase), and CALLA (common ALL antigen).
5

Figure 4: ALL blood smear (Source: Webpath)

Figure 5: ALL Bone marrow biopsy (Source: Wikipedia)

6

Earlier diagnosis will have better treatment outcomes. Chemotherapy is the initial treatment of
choice. Chemotherapy of ALL contains three phases: Induction, Consolidation and Maintenance
phase. Various regimens have been approved for the treatment of ALL. Definitive therapy for
ALL is Allogeneic hematopoietic stem cell transplantation (HSCT). This treatment is effective if
it is used in those patients who have achieved complete remission (CR) by chemotherapy
(Gökbuget et al., 2012). Prognosis of relapsed cases is generally poor. Only 31 to 44% of
relapse/refractory patients treated with currently available chemotherapeutic regimens achieves
CR. Median survival is less than one year and less than one-quarter of patients survives three
years (uptodate.com). In this trial, we have used a modified pediatric BFM-85 regimen to
improve the CR2 rates in relapse/refractory adult ALL patients so that more patients can be
treated with allogeneic-HSCT. The BFM-85 pediatric trial, included induction with high-dose
methotrexate and cytosine arabinoside, followed by post-remission therapy consisting of
2 alternating multi-agent treatment blocks, and achieved in heavily pretreated children, a CR rate
of 90% with an event-free survival at 5 years of 30% (Henze et al., 1991). We modified this
pediatric protocol by adding a second induction cycle of continuous infusion of vincristine,
adriamycin, and dexamethasone (VAD) with ifosfamide in all patients regardless of whether they
achieved a CR after the first cycle of induction therapy (Aldoss et al., 2013).

7

METHODS
This was a phase II, single arm, single-institution, prospective clinical trial. The primary
objective of the study was to determine the Complete Remission (CR) rate after the two phases
of induction therapy (table 1). Secondary objectives were Leukemia free survival (LFS),
medication toxicity, and number of days for neutrophil count recovery after each cycle of
induction. CR was defined as less than 5% lymphoblasts in normocellular bone marrow
(cellularity >20%), normal peripheral and differential counts including neutrophils >1500/mcl,
and platelet counts >100,000/mcl. Relapse was defined as greater than 5% blasts in the bone
marrow, presence of leukemic blasts in the peripheral blood, or extra-medullary leukemia on
biopsy. Treatment failure was defined as either resistant disease or persistence of bone marrow
aplasia. Patients who did not respond even after both phases of induction therapy were
considered as resistant disease cases. We included all the patients for response and toxicity
assessment. Patients with relapse were selected and data (ph chromosome status, prior treatment,
date of relapse, site of relapse BM or CNS or Both, date of relapse treatment started, date of
CR2, date of other relapse, date of last contact, vital status, H/O bone marrow transplant, cause
of death) were obtained. Leukemia-free survival (LFS) was calculated from the time of CR to the
time of relapse, last follow-up, or death. We calculated the Overall survival (OS) from the
beginning of treatment to the time of death. The survival analysis was based on standard Kaplan-
Meier method (Aldoss et al., 2013).
Study Patients
The eligibility criteria included patients with ALL who relapsed or were refractory to
chemotherapy, age range of 17 to 55 years, Karnofsky performance status of > 50%, and
8

adequate hepatic and renal function. The diagnosis of relapsed ALL was based on bone marrow
morphology, and immunophenotypical analysis. Cytogenetic characterization was not required
for study entry. Because of the intensity of our study regimen, we limited our study to adults
younger than 55 years of age. Patients with central nervous system (CNS) involvement were
eligible for this protocol.
Exclusion criteria were congestive heart failure or ejection fraction < 45%, other severe medical
or psychiatric conditions, positive HIV test, or known hypersensitivity to E coli-derived proteins.
No patient had received high-dose cytosine arabinoside or high-dose methotrexate at any time
prior to enrollment in this trial. The trial consisted analysis of prospective and retrospective
analysis and both analysis were approved by the Institutional Review Board of the Keck School
of Medicine of the University of Southern California.
Therapy
The induction protocol is summarized in Table 1 and was derived from the BFM-85. It consisted
two induction phases. The first phase included high dose cytosine arabinoside followed two
weeks later by high dose methotrexate; E. Coli Asaparginase was given for two days after each
agent. The second induction phase was initiated irrespective of whether or not the patients
achieved a CR and included vincristine, adriamycin, dexamethasone (VAD) and intensified with
addition of ifosfamide (Henze et al., 1991; Kantarjian et al., 2000).

9

Table 1. Chemotherapy protocol (Induction phase I and II)
Induction phase I
Allopurinol 300 mg/day PO days 1 to 15
Prednisone 100 mg/m
2
PO days 1 to 8, 15 to 21
Vincristine 1.5 mg/m
2
(max 2 mg) intravenously (IV) on days 1, 8, 15, 22
Cytarabine 3 g/m
2
IV over 3 h bid for 4 doses on days 1, 2
Methotrexate 1 g/m
2
continuous IV infusion (CIV) over 36 h on day 15 (10% is
given in the first h, 90% over next 35 h)
Leucovorin 30 mg PO or IV starting 42 h after starting methotrexate every 6 h for
6 doses
L-Asparaginase 10,000 units/m
2
/dose IV on days 3, 4, 16, 17
Filgrastim 5 mcg/kg/day IV or SC injections were started 24 h after the end of
cytosine arabinoside until 24 h before methotrexate, and then resumed
at 24 h after the end of methotrexate. Filgrastim was continued until
post nadir ANC ≥ 10 x 10
9
/L through the administration of vincristine
and L-asparaginase.
Induction phase 2 Starting on day 28 to 30
Dexamethasone 40 mg/day PO on days 1 to 4, 9 to12
Ifosfamide 500 mg/mg/m
2
/day IV on days 1 to 4
Mesna 500 mg/m
2
/day IV immediately before ifosfamide on days 1 to 4
Vincristine 0.4 mg/m
2
(max 2 mg) CIV on days 1 to 4
Adriamycin 12 mg/m
2
CIV on days 1 to 4
Filgrastim 5 mcg/kg/day IV or SC injections were started on day 5, 24 h after the
end of the cytosine arabinoside and continued until post nadir ANC
≥ 10 x 10
9
/L.
Intrathecal Therapy Prophylaxis starting on day 1 or 2 of phase II. If CNS involvement
was diagnosed, then IT prophylaxis administered 2 times weekly in
both phases I and II until CSF sterilization. Then, IT therapy
continued on a weekly basis for 1 month.
10

Prophylactic filgrastim 5 mcg/kg/day was given 24 hours after administration of each of the
induction phases. Consolidation consisted of alternating blocks of multi-agent chemotherapy
(Table 2). Filgrastim 5 mcg/kg was administered daily in the consolidation blocks when the
neutrophil count was < 500/mcl. We wanted to refer all patients in CR to allogeneic HSCT if
patients achieve CR. Intrathecal (IT) prophylaxis was administered on days 1 or 2 of induction
phase II and on day 8 of each consolidation block (Tables 2 and 3). If the CNS was involved
prior to induction, IT therapy was administered twice weekly until CSF sterilization, then weekly
for 1 month, followed by cranial radiotherapy with 18 Gy (if not given during first remission).
After the eighth consolidation block, patients continued with maintenance chemotherapy (Table
2). In all treatment phases, except for the maintenance phase, chemotherapy doses were not
modified for hematological toxicity. For non-hematologic toxicity the doses were modified as
described in Tables 3 and 4.

11

Table 2. Chemotherapy Protocol (Consolidation and Maintenance)
Consolidation block I
Prednisone 100 mg/m
2
PO days 1 to 5
6-Mercaptopurine 100 mg/m
2
/day PO on days 1 to 5
Vincristine 1.5 mg/m
2
(max 2 mg) intravenously (IV) on day 1
Cytosine
arabinoside
300 mg/m
2
IV on day 1
VP-16 100 mg/m
2
/day PO on days 1 to 5
Methotrexate 500 mg/m
2
IV infusion over 4 h on day 8
Leucovorin 30 mg PO or IV starting 42 h after starting methotrexate every 6 h for 6
doses
Filgrastim 5 mcg/kg/day IV or SC injections if ANC < 0.5 x 10
9
/L until an ANC of
≥ 10 x 10
9
/L
Consolidation block II
6-Thioguanine 100 mg/m
2
/day PO on days 1 to 5
Dexamethasone 20 mg/m
2
/day PO on days 1 to 5
Ifosfamide 1.33 g/m
2
IV on day 1
Mesna 1.33 g mg/m
2
IV immediately before ifosfamide
Vincristine 1.5 mg/m
2
(max 2 mg) CIV on days 1
Methotrexate 500 mg/m
2
IV infusion over 4 h on day 8
Leucovorin 30 mg PO or IV starting 42 h after starting methotrexate every 6 h for 6
doses
Filgrastim 5 mcg/kg/day IV or SC injections if ANC < 0.5 x 10
9
/L until ANC of
≥ 10 x 10
9
/L
Intrathecal
Therapy
Prophylaxis starting on day 8 of block I and block II. If CNS involvement,
then 2 times weekly until CSF sterilization. Then, IT therapy continued on a
weekly basis for 1 month.
Methotrexate 12 mg on day 8
Cytosine
arabinoside
30 mg on day 8
Hydrocortisone 15 mg on day 8
12

Maintenance Therapy Only given to those patients who achieve a complete remission
Methotrexate 50 mg/m
2
PO once weekly for 2 years
6-thioguanine 50 mg/m
2
PO on daily basis for 2 years.

Table 3. Recommended Chemotherapy Dose Adjustments for Induction Phases
Induction phase I

Prednisone Reduce or discontinue as indicated for steroid psychosis, gastric
ulceration, or severe myopathy
Vincristine Withhold for major muscle weakness, cranial nerve palsy, or severe
ileus
Cytosine arabinoside Place on hold for grade 3 or 4 encephalopathy or cerebellar ataxia of
any grade
Methotrexate Place on hold if creatinine > 2 mg/dl; reinstitute with resolution of renal
dysfunction
L-Asparaginase Withhold for pancreatitis, grade 3 or 4 liver toxicity, deep vein
thrombosis, pulmonary embolism, or major hemorrhage
Induction phase II
Dexamethasone Reduce or discontinue as indicated for steroid psychosis, gastric
ulceration, or severe myopathy
Ifosfamide Discontinue for hemorrhagic cystitis
Vincristine Withhold for major muscle weakness, cranial nerve palsy, or severe
ileus
Adriamycin Adjust for liver dysfunction: Give 50% dose when bilirubin is 1.5 to
3 mg% or SGOT between 3 to 5 times normal; discontinue for
congestive heart failure, ejection fraction < 45%, or symptomatic
cardiac arrhythmias

13

Table 4. Recommended Chemotherapy Dose Adjustments for Consolidation Blocks
Consolidation block I
Prednisone Reduce or discontinue as indicated for steroid psychosis, gastric
ulceration, or severe myopathy
6-Mercaptopurine Reduce dose to 50% for grade 2 liver toxicity. Withhold for grade 3 or
4 liver toxicity and resume at 50% dose when liver toxicity resolves.
VP-16 Withhold for grade 4 cutaneous reaction
Methotrexate Place on hold if creatinine > 2 mg/dl; reinstitute with resolution of renal
dysfunction
Consolidation block II
6-Thioguanine Reduce dose to 50% for grade 2 liver toxicity. Withhold for grade 3 or
4 liver toxicity and resume at 50% dose when liver toxicity resolves.
Dexamethasone Reduce or discontinue as indicated for steroid psychosis, gastric ulceration,
or severe myopathy
Ifosfamide Discontinue for hemorrhagic cystitis
Vincristine Withhold for major muscle weakness, cranial nerve palsy, or severe ileus
Maintenance Therapy
Methotrexate Place on hold if creatinine > 2 mg/dl; reinstitute with resolution of renal
dysfunction
6-thioguanine Reduce dose to 50% for grade 2 liver toxicity. Withhold for grade 3 or
4 liver toxicity and resume at 50% dose when liver toxicity resolves.

14

Statistical Considerations
This was a phase II, single-institution, prospective clinical trial. The primary objective of the
study was the CR rate after the two phases of induction therapy. Secondary objectives were LFS,
regimen toxicity and number of days required for neutrophil count recovery after each cycle of
induction. CR was determined by morphologic evaluation of the bone marrow and defined as
cellularity greater than 20%, maturation of all cell lines, less than 5% marrow blasts, peripheral
ANC > 1.5 x 10
9
/L, and a platelet count of > 100 x 10
9
/L. We defined relapse from CR as the
occurrence of any of the following: (1) greater than 5% blasts in the bone marrow, not
attributable to the regeneration of bone marrow following chemotherapy induced aplasia, (2)
reappearance of leukemic blasts in the peripheral blood, or (3) biopsy-proven extra-medullary
leukemia. We defined treatment failure as either resistant disease or persistence of bone marrow
aplasia. Resistant disease was defined as the lack of CR in surviving patients despite receipt of
both phases of induction therapy. All patients were considered eligible for response and toxicity
assessment. We calculated Leukemia-free survival (LFS) from the time of CR to the time of
relapse, last follow-up, or death. Overall survival (OS) was calculated from the beginning of
treatment to the time of death. The survival and remission duration curves were calculated using
standard Kaplan-Meier methodology (Aldoss et al., 2013).

15

RESULTS
Patient Characteristics
Nineteen patients (14 males and five females) were enrolled in the study. Patient characteristics
are summarized in Table 5. The median age of the patients was 25 years (range 19-51 years).
Among 19 patients, 16 patients were diagnosed with Precursor B cell ALL and three patients
were diagnosed T-cell ALL. The median time of the first relapse was 10.5 months (range 3-60
months) from the initial diagnosis. The median white blood cell count (WBC) at the time of
relapse was 1300/mcl (range 200-7030/mcl).
Response to Therapy
Table 6 summarizes the results of the induction therapy in all 19 patients. Thirteen of the
nineteen patients (68%) achieved a CR (95% CI, 43% to 87%). Among those 13 patients, 11
patients (85%) achieved CR after receiving the initial phase of the induction therapy. The median
time to achieve CR from the start of the induction therapy was 28 days (range, 20 to 94). Six
patients (31%) who failed to achieve CR; one had primary refractory disease, while the others
died of treatment-related infections or hemorrhage. Only one patient was treated with allogeneic
HSCT. Other patients were not treated with Allogeneic HSCT because of early relapse, lack of
suitable donor or socioeconomic reasons. All the patients who achieved CR were treated for
post-remission phase of the protocol. Only seven patients completed between 1 to 3
consolidation blocks; no patients completed all of the consolidation blocks. The median overall
survival (OS) of all 19 patients was 5.6 months.

16

Median survival time of patients who achieved CR was 10.3 months. Eighteen out of nineteen
patients (95%) died during the trial and the causes were as follows: 11 patients died of disease
progression, five patients died of infection, one patient died of bleeding, and one patient died of
unrelated causes. One patient was successfully treated with Allogeneic-HSCT and become a long
term survivor. The median LFS was 4.3 months.
Table 5. Patient Characteristics
Prospective cohort Retrospective cohort
Number of patients 19 31
Period of cohort enrollment 1993 to 1999 2004 to 2013
Median Age, years (range) 25 (19 to 51) 36 (18 to 53)
Cell Type, No
Precursor B cell
T-cell

16
3

29
2
Median WBC at relapse (range), 10
9
/L 13 (2 to 70.3) 5 (1.5 to 116)
Median previous CR duration, months
(range)
10.5 (3 to 60) 16(1 to 79)
Median prior lines of therapy, No (range) 1 (1) 1 (1 to 2)
Disease status
Relapsed/refractory

19/0

28/3
Disease location at relapse
BM only
BM + CNS
Non-CNS extramedullary (+/- BM)

19

23
5
4
Cytogenetics [No] Unavailable Ph-positive [3], NK [18],
del(9) [1], del(1) [1],
der(11) [1], t(1;2) [1],
unknown [6]
Previous chemotherapy Unavailable Modified BFM regimen
=25
Unknown =6

17

Toxicity
After the induction therapy, all the patients experienced hematologic toxicities including
thrombocytopenia and neutropenia. Four patients (21%) died of infections and one patient died
of bleeding during bone marrow aplasia. Eighteen patients experienced fever (temperature
≥ 38.2°C for at least 4 hours). The median duration of recovery to absolute neutrophil count
(ANC) of greater than 0.5 x 10
9
/L during the first induction phase was 21 days (range, 14 to 78;
Table 6), and to platelet count greater than 20 x 10
9
/L was 28 days (range, 11 to 89). Grade 1 or
2 nausea/vomiting were seen in 10 patients (53%). Grade 1 or 2 liver toxicity was observed in 9
patients (47%). Grade 1 or 2 diarrhea observed in 5 patients (26%) and grade 3 diarrhea was
observed in one patient (5%). Six patients suffered from stomatitis, five (31%) of them had grade
1 or 2 and one (5%) had grade 3 stomatitis. Three patients (16%) suffered from grade 1 or 2 skin
rash.
Table 6. Results of induction therapy Prospective and Retrospective study
Prospective cohort Retrospective cohort
CR, N (%) 13 (68%) 16 (52%)
Transplanted patients, N (%) 1 (5%) 9 (29%)
Refractory disease, N (%) 1 (5%) 12 (39%)
Death during induction, N (%) 5 (26%) 3 (10%)
OS (months) 5.6 16.1

18

Outcomes of patients treated off the study
We closed the study prematurely because of slow accrual of participants and lack of funding
after enrolling 19 patients. We used the same regimen for other patients because of higher
remission in the prospective cohort. We recruited patients for the retrospective study from those
patients who were treated between 2004 and 2013. We reviewed medical records of 43 patients
treated with the same regimen off the study. All these patients were younger than 55 years and
had relapsed or refractory ALL. We excluded all the patients with exclusive CNS relapse and
patients with missing data regarding drug dosing and response assessment. Of these 31 patients,
16 patients (50%) achieved CR, three patients (10%) died during induction therapy with bone
marrow aplasia and 12 patients (39%) were refractory to induction therapy. Two patients
successfully completed all the cycles of consolidation therapy and continued on the maintenance
phase of the regimen. Rest of the 12 patients in CR was taken off the regimen either due to
relapse or when they proceeded to HSCT. Nine patients subsequently underwent allogeneic
HSCT. In our pooled analysis for 50 patients (study = 19, and off-study = 31), 29 patients (13 out
of 19 and 16 out of 31) (58%) treated with this regimen achieved a CR. Ten patients underwent
allogeneic HSCT. Above results were publicized before in a research paper: An Effective
Reinduction Regimen for First Relapse of Adult Acute Lymphoblastic Leukemia’ by Aldoss et
al., (2013).

19

DISCUSSION
With the currently available chemotherapeutic agents, CR rates for the first time disease are
much higher than the relapse or refractory diseases. There is no standard regimen available for
relapsed or refractory disease. Any regimen will provide CR in only one third of patients with
relapsed or refractory ALL cases (Gökbuget et al., 2012; Kantarjian et al., 2010; Henze et al.,
1991). Allogeneic HSCT is the definitive therapy for ALL and it is very successful if used in
patients who achieve CR. Low CR rates are the main obstacle for the usage of HSCT along with
donor availability and socioeconomic problems in ALL patients. In the study, we have used the
concept of intensive chemotherapy with high-dose methotraxate and cytarabine integrated with a
continuous infusional regimen followed by alternating blocks of consolidation therapy. Pediatric
trials have shown high success rate with this concept and our protocol has been adapted from
those trials (Kantarjian et al., 2010; Henze et al., 1991; Aldoss et al., 2013).

Our prospective study showed very high CR rate of 68% which is very convincing as compared
to any other chemotherapeutic regimens for relapsed/refractory ALL. The result of the
retrospective cohort was slightly lower than the prospective cohort mainly because of less strict
eligibility criteria and we did not use the second cycle of induction in patients who did not
achieve CR with the first cycle. One out of 19 patient from the prospective and 9 out of 31
patients from retrospective study went under allogeneic-HSCT. The low transplant rate was due
to disease relapses and various socioeconomic factors but the main reason was timely availability
of suitable donors for HSCT. Nowadays obstacle of donor availability is readily avoidable
because of a larger pool of matched unrelated donors and other alternate donor sources such as
20

umbilical cord blood and haploidentical donors and due to this even though the patients get short
remission duration, all the patients who achieves CR can be treated with Allogeneic-HSCT.

According to the previous data, LFS and OS is very short in relapsed/refractory ALL patients
and our results (LFS = 4.3 months and OS = 5.6 months) are comparable to these data (Fielding
et al., 2007; Oriol et al., 2010; Kantarjian et al., 2010). Inability to perform allogeneic-HSCT in
patients who achieve CR2 is the main reason for these results. Past studies suggest that first time
or relapsed/refractory ALL cases would not become a long term survivor if they do not receive
allogeneic-HSCT (Gökbuget et al., 2012). Therefore, any chemotherapy regimen can only be
considered a bridge to allogeneic HSCT to achieve longer LFS and OS.

High CR rates and low disease resistance rate in our study can be due to an intense induction
therapy regimen that included high-dose cytarabine and methotraxate, use of L-asparaginase
immediately after cytarabine and methotraxate, and young age of patients in our study. Use of
methotraxate and cytarabine may be very helpful if the relapsed/refractory patient never had
these drugs before for their disease especially when the patients were treated with HyperCVAD
regimen for the first time disease. Hematological toxicities like neutropenia and
thrombocytopenia were observed because of bone marrow suppression after the induction
therapy. Non hematological toxicities like nausea/vomiting, liver toxicity, diarrhea, stomatitis
and rash were observed. Most of these toxicities were of grade 1 or 2, some of them were grade 3
but none of them were grade 4. Infection rates after the reinduction were lower than usual
because of prophylactic usage of filgrastim. 15% of study participants died during the induction
21

therapy which is in concordance with other studies (Kantarjian et al., 2010; Faderl et al., 2011).
Introduction of newer drugs and continuous improvement in salvage therapy regimens for
relapsed/refractory ALL are improving survival of these patients.

22

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Asset Metadata

Creator Patel, Ravindra (author)

Core Title Induction therapy in relapse adult acute lymphoblastic leukemia

School Keck School of Medicine

Degree Master of Science

Degree Program Clinical and Biomedical Investigations

Publication Date 11/18/2015

Defense Date 10/21/2013

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

Tag acute lymphoblastic leukemia,Adult,OAI-PMH Harvest,reinduction,relapse

Format application/pdf (imt)

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Pullarkat, Vinod (committee chair), Aldoss, Ibrahim (committee member), Azen, Stanley P. (committee member)

Creator Email drravindrapatel@gmail.com,ravindrp@usc.edu

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c3-346168

Unique identifier UC11296333

Identifier etd-PatelRavin-2155.pdf (filename),usctheses-c3-346168 (legacy record id)

Legacy Identifier etd-PatelRavin-2155.pdf

Dmrecord 346168

Document Type Thesis

Format application/pdf (imt)

Rights Patel, Ravindra

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 a...

Repository Name University of Southern California Digital Library

Repository Location USC Digital Library, University of Southern California, University Park Campus MC 2810, 3434 South Grand Avenue, 2nd Floor, Los Angeles, California 90089-2810, USA