Clinical outcomes of allogeneic hematopoietic stem cell transplant in acute lymphoblastic leukemia patients: a quality improvement project and systematic review meta-analysis

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Content 1

Clinical outcomes of Allogeneic Hematopoietic Stem cell
Transplant in Acute Lymphoblastic Leukemia patients:
A quality improvement project and Systematic review
Meta-analysis

By
Pooja Parikh, MBBS
A Thesis Presented to the Faculty of the Graduate School

UNIVERSITY OF SOUTHERN CALIFORNIA

In Partial Fulfillment of the Degree

MASTER OF SCIENCE
IN
Clinical, Biomedical and Translational Investigations
December2014

2

Table of Contents

Acknowledgement ....................................................................................................................3
List of Abbreviations .................................................................................................................4
List of Figures ...........................................................................................................................5
List of Tables.............................................................................................................................6
CHAPTER – 1: A quality improvement project of survival and prognostic factors in
predominantly Hispanic adult Acute Lymphoblastic Leukemia patients undergoing
Allogeneic Hematopoietic Stem cell Transplant at Norris Cancer Hospital ……………………….7
1.1 Abstract ...........................................................................................................................7
1.2 Introduction .....................................................................................................................8
1.3 Methods ........................................................................................................................10
1.4 Results ..........................................................................................................................11
1.5 Discussion.....................................................................................................................13
1.6 Conclusion ....................................................................................................................14
1.7 Reference .....................................................................................................................23
CHAPTER – 2 : TKI plus Chemotherapy versus Allogeneic SCT to prevent relapse in
newly diagnosed Ph+ALL adolescent and adult patients who achieve first complete
remission with TKI plus Chemotherapy – A Systematic review and Meta-analysis .........25
2.1 Abstract .........................................................................................................................25
2.2 Introduction ...................................................................................................................27
2.3 Methods ........................................................................................................................28
2.4 Results ..........................................................................................................................30
2.5 Discussion.....................................................................................................................31
2.6 Conclusion ....................................................................................................................33
2.7 Reference .....................................................................................................................40

3

Acknowledgement
This thesis project was a very crucial learning experience for me. By this project I was
able to apply what I have learned in my master program in to the real world experiences.
This thesis project would not be possible without extremely valuable conceptual
guidance of Dr. Chaudhary throughout this study. I would like to thank Dr. Chaudhary for
being a director of my thesis committee and enrich me with his knowledge and expertise
in hematology and stem cell transplant. In addition, I highly value the guidance provided
by my two other committee members Dr. Patino-Sutton and Dr. Azen. Being an
epidemiologist, Dr. Patino-Sutton has provided me crucial direction regarding conducting
systematic review and meta-analysis. She also provided me insight in to various
guidelines for writing a paper, epidemiological study types and various statistical
methods. Dr. Azen, as a biostatistician and a director of our master program has always
guided me regarding thesis writing format and statistical methods. I would also like to
thank our librarian Lynn Kysh at Norris medical library who helped me in establishing
extremely useful search strategies to find out relevant articles and proving knowledge
regarding endnote to manage searched articles. I heartily appreciate my colleague Payal
Shah for helping me in sorting out searched articles and in data abstractions with meta-
analysis. I would also like to thank bone marrow transplant team members Sosy, Vicky
and Ellison for their support in providing information related to data abstraction for
transplant patients. Lastly I would like to thank my family members for their continuous
support in this expedition.

4

List of Abbreviations
AlloSCT – Allogeneic hematopoietic stem cell transplant
Auto – Autologous stem cell transplant
TKI – Tyrosine Kinase Inhibitors
HSCT- Hematopoietic stem cell transplant
Chemo - Chemotherapy
ALL- Acute lymphoblastic leukemia
Ph+ - Philadelphia Chromosome Positive
Ph- - Philadelphia chromosome negative
GVHD – Graft versus host disease
GVL – Graft versus leukemia effect
CR- Complete remission
CR1 - First complete remission
CR2 - Second complete remission
NCCN - National Comprehensive Cancer Network
DFS - Disease free survival
OS - Overall survival
RR – Relative risk

5

List of Figures

Figure-1.1: Blood cell development ……………………………………… ………. …… ……………… …. …..9
Figure-1.2: Philadelphia chromosome………………………………………..…….....9
Figure-1.3: Disease Free Survival (DFS) in ALL patients …………………………………... …15
Figure-1.4: Overall Survival (OS) in ALL patients …………………………… ……. . … …………....15
Figure-1.5: OS among Ph+ and Ph-ALL patients…………………………………...16
Figure-1.6: DFS according to GVHD developed or not………………………….…16
Figure-1.7: DFS according to Donor type…………………………………………....17
Figure-1.8: DFS according to disease remission status……………………….…..17
Figure-1.9: OS according to disease remission status………………………….…18
Figure-1.10: DFS according to Ethnicity………………………………………….…18
Figure-1.11: OS according to Ethnicity………………………………………….…..19
Figure-1.12: Estimated Hazard for relapse………………………………………...……19
Figure-1.13: Estimated Hazard rate among Ph+ and Ph- ALL……………..……20
Figure-2.1: Flow diagram for study selection……………………………………….34
Figure-2.2: Forest plot showing relative risk for relapse……………………….….38
Figure-2.3: Forest plot showing relative risk for death………………………….…39

6

List of Tables
Table-1.1: Pre-Transplant Patients' characteristics ………………………….… 21
Table-1.2: Post-Transplant Outcomes…………………………………………….22
Table-1.3: Post-Transplant survival analysis results…………………………….22
Table-2.1: Characteristics of studies included in systematic review….………..35
Table-2.2: Patients' data according to remission status & treatment division…36
Table-2.3: Post treatment outcomes in GR1 and GR2…………………………..37
Table-2.4: Meta-analysis: Relative risk for Relapse……………………………..38
Table-2.5: Meta-analysis: Relative risk for Death………………………………..39

7

CHAPTER – 1
A quality improvement project of survival and
prognostic factors in predominantly Hispanic adult
Acute Lymphoblastic Leukemia patients undergoing
Allogeneic Hematopoietic Stem cell Transplant at Norris
Cancer Hospital

1.1 Abstract:
We studied a total of 18 adults (78% Hispanics) with Acute Lymphoblastic Leukemia
patients who underwent allogeneic hematopoietic stem cell transplantation at Norris
Cancer Hospital from January2011 to March 2014. Overall 100 day survival (OS) was
94% (Cumulative Hazard=0.11) and overall relapse free survival (RFS) was 89 %
(Cumulative Hazard=0.06). At the same time one year RFS was 23 %( Cumulative
Hazard=1.3) and OS was 69 %( Cumulative Hazard=0.36). 83% of patients had either
relapse or death within 24 months of transplant. OS and RFS was inferior in Hispanic
adult ALL patients than other ethnicity. Possible explanation of our high relapse rate is
that Hispanics may have high risk disease that has higher tendency for relapse and
lower response to allograft. Out of total death, 92% were in Ph-ALL while 8% was in Ph+
ALL. OS was better in Ph+ adult ALL patients than Ph- Adult ALL patients after six
months of transplant. This could be explained by the recent use of newer targeted
therapy such as Tyrosine kinase inhibitors that are effective against Ph+ALL.
8

Development of GVHD was associated with increase in RFS after six months of
transplant. Among the patients with GVHD, those with chronic GVHD survived longer
than the patients with acute GVHD. Similarly, transplant from sibling donor and in first
complete remission are associated with better RFS after six months of transplant.
Median disease free survival was 233 (95% CI 180 -330) days. Newer therapeutic
modalities, such as use of total body irradiation for conditioning and use of tyrosine
kinase inhibitors and JAK inhibitors for treatment of Ph-like ALL are needed to improve
the outcome of Hispanics with ALL.
1.2 Introduction:
Acute Lymphoblastic Leukemia (ALL) is an aggressive type of leukemia characterized by
an excess of lymphoblasts or immature lymphocytes in peripheral blood or bone marrow.
ALL presumably arises from malignant transformation of B- or T-cell progenitor cells that
arise from lymphoid stem cell (Fig1.1). For adults, the prognosis of ALL is not as good as
children. Most common cytogenetic abnormality in ALL patient is Philadelphia
chromosome(Ph)which occurs due to reciprocal translocation that fuses bcr gene from
chromosome 22 to abl gene from chromosome 9(fig-1.2). About 20-30% of adult patients
with ALL have bcr-abl fusion gene which is identical to Ph chromosome
7-10
. Treatment
and prognosis of ALL is different according to presence or absence of bcr-abl fusion
gene. As per 2014 NCCN guidelines, treatment strategy for adults less than 65 year of
age with Ph+ALL is Allogeneic hematopoietic stem cell transplant (AlloSCT) after
achieving complete remission; while for Ph-ALL patients either chemotherapy or
AlloSCT is recommended.
9

Figure-1.1: Blood cell development. A blood stem cell goes through several steps to become a red
blood cell, platelet, or white blood cell . Figure taken from www.cancer.gov

Figure-1.2: Philadelphia chromosome. A piece of chromosome 9 and a piece of chromosome 22
break off and trade places. The bcr-abl gene is formed on chromosome 22 where the piece of
chromosome 9 attaches. The changed chromosome 22 is called the Philadelphia chromosome
Different studies have suggested various predictors for survival in ALL patients
undergoing AlloSCT. These includes followings: 1)Younger age and first remission are
associated with improved survival and disease free survival, while receiving cyclosporine
alone as GVHD prophylaxis is associated with lower disease free survival
1
. 2) Patients in
10

first CR or subsequent CR have better clinical outcome than those in relapse
1-3
. 3) In
Ph+ALL patients, MRD(Minimal residual disease) positive status at the time of transplant
is associated with high relapse while matched related donor has high risk of relapse than
unmatched or unrelated donor, and patients with significant chronic GVHD are
associated with lower risk of relapse
2
. 4) One study reported that bone marrow
transplant at CR1, age<35 and grade1/2 acute GVHD have better OS and DFS while
Ph positive status, high leukocyte count and B cell phenotype were not associated with
lower survival
4
. 5) Ph+ ALL patients in first complete remission have similar survival after
reduced intensity and myeloablative allogeneic transplantation
5
.
According to CIBMTR data, 100 days mortality in unrelated donor transplant ranges from
10-20%, while it is 8-19% in HLA matched sibling transplants. 3 year survival was
between 21 %( advanced disease) and 54 %( early disease) in HLA matched sibling
transplants and 16-51% in unrelated transplants. At our Norris cancer institute, we
observed relapse in majority of our ALL patients undergoing AlloSCT. Allogeneic stem
cell transplant is associated with significant short- and long-term transplant related
complications and is expensive. Therefore, it is necessary to find out reasons behind
high relapse to improve patient's survival and decrease health care cost burden. Our
objective for this study is to find disease free survival, overall survival, cumulative
hazards and risk factors that affect survival by conducting a retrospective observational
analysis of adult ALL patients undergoing AlloSCT at the Norris Cancer Hospital.
1.3 Methods:
We conducted a quality improvement project at Norris cancer hospital during March
2014- June 2014. Informed consents were obtained from patients to use their data
before start of the project. Data until June 2014 were collected. Data from all adult ALL
11

patients undergoing allogeneic SCT at Norris cancer hospital from year January, 2011 -
March, 2014were abstracted to find out survival parameters. Data including age, sex,
BMI, ethnicity, type of ALL, chromosomal abnormalities, family history, other medical
history, White Blood Counts (WBC) at the time of diagnosis, induction regimen used,
number of induction cycles needed before transplant, central nervous system
involvement, conditioning regimen used, time to transplant, type of donor, any
complication before or after transplant, date of transplant, date of relapse, time to
relapse and, patient's status at the time of collecting data were collected in Microsoft
excel. All the collected data were checked twice to avoid any human error. Follow up
time was counted in days. In patients with loss to follow up, time until last follow up was
considered. Data was represented in form of tables and survival curves. Kaplan-Meier
survival curve, log-rank test, survival probabilities and cumulative hazard were obtained
using SAS 9.4 data analysis software.
1.4 Results:
Total 18 adult ALL patients underwent allogeneic stem cell transplant during January,
2011-March, 2014 at Norris Cancer hospital. Pre-transplant patients' characteristics are
shown in table-1.1. Out of 18 patients 14 patients were Hispanic, 3 Caucasian whites
and 1 Korean. 50% of patients were less than 25year of age, while remaining 50% were
between 26-65 years of age. Median BMI was 25 Kg/m2. Six patients had Ph+ ALL. 15
patients had pre-B subtype ALL, while one patient had ambiguous leukemia. 14 patients
were in CR1, 2 were in CR2 and 2 were in relapse state at time of transplant, while all of
six Ph+ ALL patients were in CR1. 12 patients had matched sibling donor and 6 had
matched unrelated donor transplant. Median time to transplant from diagnosis was 5
months, with a range of 3-41 months. In approximately50% of patients, conditioning
regimen used was cytoxan and busulfan, while in others fludrabine was used instead of
12

cytoxan. Three patients had pre-transplant complication in form of fever, abscess or
heart failure. Three patients had CNS involvement before transplant. Five patients had a
chromosomal abnormality other than Philadelphia chromosome. Most patients (78%)
had tacrolimus and sirolimus for GVHD prophylaxis.
Post- transplant results are shown in Table-1.2 and Table-1.3. 15 patients (83%) had
relapse. Among three patients who didn't have relapse, two were 2014 transplant
patients while one didn't have relapse for more than 24 months. Time to relapse was
between 2-22 months. Post-transplant disease free survival (DFS) and overall survival
(OS) for ALL patients are shown in Fig.1.3 and Fig.1.4 respectively. Overall 100 days
survival was 94%(Cumulative Hazard=0.06) and Relapse free survival was 89%
(Cumulative Hazard=0.11) while 1 year OS was 69%(Cumulative Hazard=0.36) and
RFS was 23%(Cumulative Hazard=1.3). Overall survival ranged between 3- 25+months.
Median disease free survival was 233 (CI: 180 -330) days. 7(39%) patients died, 2 were
lost to follow up while 9 were alive at time of completion of data collection. 13 patients
(72%) develop GVHD, among them majority had acute GVHD while a few patients had
chronic GVHD. 10 (56%) patients had one or more of other complications such as CMV
reactivation, C.difficilediarrhea, mucositis and neutropenic fever. In Ph+ALL patients, 3
out of six patients (50%) had relapse, and 1 patient(17%) died due to ARDS and
possible GVHD, while in Ph-ve ALL patients 11 of 12 patients (92%) patients had
relapse and 6 (50%) patients died. Ph+ALL patients had better OS than Ph-ALL
(p=0.428)(Fig-1.5). Ph+ALL patients had lower estimated hazard for death than Ph-ALL
(Fig-1.13).Patients who developed GVHD had better RFS after six months of transplant
as compared to patients without it (Fig-1.6). Similarly, patient who had matched sibling
donor transplant had better DFS after six months of transplant (Fig-1.7). Patients with
chronic GVHD survived longer than others. Survival was higher in patients who were in
13

first complete remission than those in second or in relapse (p=0.088) (Fig-1.8,1.9).
Hispanics had lower OS and DFS than other ethnicities (P=0.0680)(Fig-1.10,1.11).
Estimated hazard for relapse increased around 200 days post AlloSCT (Fig.1.12). Age,
conditioning regimen, high WBC count, BMI and time to transplant did not affect survival
in our patient population.
1.5 Discussion:
In study by Chim CS et al
4
, Disease-free survivals (DFS) at 15 years for transplant
patients at CR1 and beyond CR1 were 45.8 and 15.9% respectively. In comparison,
83% of our ALL patients relapsed within two years. Possible explanation could be the
following: 1) 91% patients in the study by Chim CS et al had total body irradiation as the
conditioning regimen. 2) It was conducted in Hong Kong, so patients were most likely
Asians, while our population was mainly Hispanics. High relapse in Hispanics adult ALL
patients can be due to the natural history of disease or different underlying genetic
abnormalities. Our 100 days survival was 94 % compared to 80-92% in CIBMT data,
which shows good acute care management at our hospital. Patient with GVHD and
especially with chronic GVHD survived more than those without GVHD. While this could
support the theory of graft versus leukemia effect, there are alternative explanations that
need to be considered. In particular, steroids are the first line treatment for almost all
patients with GVHD. Steroids also have strong anti-ALL activity as reflected by the fact
that they are one of the components of almost all ALL chemotherapy regimens.
Therefore, the possibility cannot be ruled out that the association between chronic
GVHD and lower relapse in ALL is at least in part due to the confounding effect of
steroids and not due to a GVL effect.50% of patients relapsed during 150-250 days after
transplant. As shown in Fig-1.12, weighted hazard for relapse increased around 200
days. This is also around the time that immunosuppressant are usually discontinued.
14

This again supports the intriguing possibility that immunosuppressant are actually
helping to prevent disease relapse by exerting an anti-ALL effect (as in the case of
steroids). Additionally, immunosuppressant drugs could also prevent or delay relapse
indirectly by preventing rejection of donor cells by regenerating host hematopoiesis.
Previous studies show similar survival in Ph+ ALL and Ph-ALL patients, while our
analysis shows better survival in Ph+ ALL patients. This can be explained by better
remission with newer Tyrosin Kinase Inhibitors (TKI). 100% of our Ph+ patients were in
first CR and were treated with TKI. There was only one patient out of 18 patients, who
was alive for more than two years without relapse. He was 58 year Caucasian white who
had Ph + ALL and was in complete molecular remission before transplant. Further
studies are needed to determine if in the era of TKI continuing TKI with chemotherapy is
better as compared to AlloSCT to prevent relapse in adult Ph+ ALL patients. In addition,
larger studies are needed to confirm that Hispanic adult ALL patients have poor outcome
than other ethnicities.
Limitation of Project: Sample size was very small
1.6 Conclusion:
Hispanic ALL patients seem to have high relapse rate and lower survival than other
ethnicities. Development of GVHD, especially chronic GVHD, may increase survival in
adult ALL patients. As shown in other studies, allogeneic transplantation in first complete
remission and transplant from sibling donor improve survival outcome. Ph+ ALL patients
have better survival outcome than Ph- ALL patients in era of TKI. These results will be
used to develop new quality improvement initiatives for our allogeneic bone marrow
transplant program.
15

Figure-1.3 : Disease Free Survival (DFS) in ALL patients

Figure-1.4: Overall Survival (OS) in ALL patients

16

Figure-1.5: OS among Ph+ and Ph-ALL patients

Figure-1.6: DFS according to GVHD developed or not

17

Figure-1.7: DFS according to Donor type

Figure-1.8: DFS according to disease remission status

18

Figure-1.9: OS according to disease remission status

Figure-1.10: DFS according to Ethnicity

19

Figure- 1.11: OS according to Ethnicity

Figure- 1.12: Estimated Hazard for relapse

20

Figure1.13. Estimated Hazard rate among Ph+ and Ph- ALL

21

Table: 1.1 Pre-Transplant Patients' characteristics (N=18)

Characteristics: n (%),[M]
Age:
18-25 years
26-50 years
51-65 years

9 (50)
5 (28)
4 (22)
Sex:
Female
Male

7(39)
11(61)
Ethnicity:
Hispanic
Caucasian White
Korean

14 (78)
3 (17)
1 (5)
BMI (Range) kg/m2 (21-34) [25]
Presence of other medical co-morbidities 4 (22)
History of smoking /alcohol 2 (11)
Family history of cancer 5 (28)
Type of ALL:
Ph + ve ALL
Ph +ve ALL(Hispanics)
PreB or B ALL
Ambiguous
Type not known

6 (43)
4 (66)
15 (83)
1 (5)
2 (11)
CNS involvement 3 (17)
Wbc Counts > 30,000 7 (39)
Chromosomal abnormalities other than Ph+ status 5 (28)
Disease Status at transplant:
CR1
CR2
Relapsed

14 (78)
2 (11)
2 (11)
CR1 at Transplant in Ph+ patients: 6 (100)
Type of Donor:
Matched sibling
Matched unrelated

12 (66)
6 (43)
Type of Induction regimen used:
USC ALL
BMF+/-other
Other

4
7
7
Conditioning regimen used:
Cytoxan+Busulfan
Fludrabine+busulfan
Fludrabine+Melphalan
Fludrabine

9(50)
6(43)
2(11)
1(5)
Time to transplant: (range)months (3-41) [5]
Infection/complication before transplant 3 (17)
GVHD prophylaxis:
Tacrolimus+Methotrexate
Tacrolimus+Sirolimus
Tacrolimus+ Cellcept

14 (78)
3 (17)
1 (5)
22

Table-1.2 Post- Transplant outcomes (N=18)

Outcome: n (%),[M]
No. of patients having relapse (HR)
Ph+ALL
Ph-ALL
15 (83)
3 (50)
11(92)
No. of total ALL patient died:
Ph+ALL
Ph-ALL
7 (39)
1 (17)
6 (92)
Relapse within 1 year :
Hispanics (14)
Other ethnicity (4)

12 (86)
2 (50)
Time to relapse (months) (2-22) [6.5]
Overall survival (months)
100 days survival
Overall mortality
Lost to follow up
No. of people alive
3-25+
17(94)
7 (39)
2 (11)
9 (50)
Development of GVHD:
Yes
No
Acute Liver (Grade1-2)
Acute skin (Grade1-3)
Chronic GVHD

13 (72)
5 (28)
2
7 (1GR3,6GR1)
4 (2liver,1skin,1oral)
Other complications:
CMV Reactivation
C.DiffDiarrhea
Mucositis
Neutropenic fever/ sepsis
10 (56)
3
3
4
4

Table 1.3: Post transplant survival analysis results

Time
RFS (Relapse
free survival)
OS (Overall
Survival)
Cumulative HR for
relapse
Cumulative HR for
Death
100 days 0.89 0.94 0.11 0.06
200 days 0.64 0.82 0.42 0.19
250 days 0.39 0.69 0.90 0.36
400 days/1year 0.23 0.69 1.3 0.36
735days/2 year 0.07 0.55 2.13 0.56

23

1.7 Reference:

1. Doney K, Hagglund H, Leisenring W, Chauncey T, Appelbaum FR, Storb R.
Predictive factors for outcome of allogeneic hematopoietic cell transplantation for
adult acute lymphoblastic leukemia. Biol Blood Marrow Transplant. Jul
2003;9(7):472-481.
2. Stirewalt DL, Guthrie KA, Beppu L, et al. Predictors of relapse and overall
survival in Philadelphia chromosome-positive acute lymphoblastic leukemia after
transplantation. Biol Blood Marrow Transplant. Mar 2003;9(3):206-212.
3. Doki N, Ohashi K, Oshikawa G, Kobayashi T, Kakihana K, Sakamaki H. Clinical
outcome of hematopoietic stem cell transplantation for Philadelphia
chromosome-positive acute lymphoblastic leukemia (Ph + ALL): experience from
a single institution. Pathol Oncol Res. Jan 2014;20(1):61-66.
4. Chim CS, Lie AK, Liang R, Au WY, Kwong YL. Long-term results of allogeneic
bone marrow transplantation for 108 adult patients with acute lymphoblastic
leukemia: favorable outcome with BMT at first remission and HLA-matched
unrelated donor. Bone Marrow Transplant. Aug 2007;40(4):339-347.
5. Bachanova V, Marks DI, Zhang MJ, et al. Ph+ ALL patients in first complete
remission have similar survival after reduced intensity and myeloablative
allogeneic transplantation: impact of tyrosine kinase inhibitor and minimal
residual disease. Leukemia. Mar 2014;28(3):658-665.
6. Moorman AV, Harrison CJ, Buck GA, et al. Karyotype is an independent
prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of
cytogenetic data from patients treated on the Medical Research Council (MRC)
24

UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. Blood 2007;
109:3189.
7. Swerdlow SH, Campo E, Harris NL, et al. World Health Organization.
Classification of Tumours of Haematopoietic and Lymphoid Tissues, IARC Press,
Lyon 2008.
8. National Cancer Institute and Center for International Blood and Marrow
Transplant Research (CIBMTR)data
9. National cancer Institute: Adult Acute Lymphoblastic Leukemia Treatment
http://www.cancer.gov/cancertopics/pdq/treatment/adultALL/HealthProfessional
10. Li YN, Zou DH, Zhao YZ, Mi YC, Wang JX, Qiu LG. Clinical characteristics and
outcomes of adults with Philadelphia chromosome positive and/or bcr-abl
positive acute lymphoblastic leukemia: a single center study from China.
Leukemia & Lymphoma. Mar 2010;51(3):488-496

25

CHAPTER – 2
TKI plus Chemotherapy versus Allogeneic SCT to
prevent relapse in newly diagnosed Ph+ALL adolescent
and adult patients who achieve first complete remission
with TKI plus Chemotherapy – A Systematic review and
Meta-analysis

2.1 Abstract:
Background:
Philadelphia chromosome is the most common type of cytogenetic abnormality
characterized by presence of abr-bcl fusion gene in patients with acute lymphoblastic
leukemia. The prognosis of patients aged 15-65 years with Ph+ALL is worse compared
to children. According to National Comprehensive Cancer Network (NCCN) guidelines,
all Ph+ALL patients should be treated with Tyrosine Kinase Inhibitors (TKI) plus
chemotherapy to achieve complete remission and then continue with AlloSCT or with
TKI plus chemotherapy to prevent relapse. With the availability of targeted TKI therapy, it
is important to determine whether AlloSCT is better than TKI plus chemotherapy to
prevent relapse in this older group of patients

26

Methods:
We conducted a systematic search of relevant literatures using database search. Then
we finalized articles that included data for patients treated with TKI plus chemotherapy
and then underwent either AlloSCT or continued with the same treatment. Only patients
with newly diagnosed Ph+ALL were considered for our analysis. Data was abstracted for
study type, number of patients in each group, number of relapse and death. Relative
risks were calculated and meta-analysis of pooled RR was obtained for relapse and
death.
Results:
Out of 790 articles, In Ph+ALL patients with age range between 15-65 years, who
achieve CR1 status with chemotherapy and TKI, we found 8 published articles between
2004-2014 that have results for patients who then go to AlloSCT and who continue to
receive TKI plus chemotherapy. Meta-analysis for relapse was performed on data from 7
articles and for death was on data from 6 articles. Pooled RR for relapse was 0.45 (95%
CI: 0.336-0.602) (P<0.001) and for death was 0.62( 95% CI:0.447-0.823) (P=0.001),
between AlloSCT compared to TKI plus chemotherapy, suggesting significant less risk of
relapse and death post allogeneic hematopoietic stem cell transplant compared to TKI
plus chemotherapy as a continuous treatment.
Conclusion:
Based on the findings of this meta-analysis patients with Ph+ ALL aged 15-65 years
who achieve first complete remission status with TKI plus chemotherapy in induction
phase, are less likely to relapse and die compared to TKI plus chemotherapy, and
should be afforded Allogeneic stem cell transplant as soon as the donor is available.
27

2.2 Introduction:

American cancer society estimated about 6000 acute lymphoblastic leukemia patients in
2014. Most common cytogenetic abnormality in these patients is bcr-abl fusion gene.
Bcr-abl fusion gene which is cytogenetically indistinguishable from Philadelphia
chromosome, is seen in 20-30% of adult acute lymphoblastic leukemia patients
12
. These
patients are categorized as Ph+ALL. Outcome of Ph+ALL is better in children than in
adults. Before discovery of newer targeted therapy known as tyrosine kinase inhibitors
(TKI) for bcr-abl gene, prognosis of Ph+ALL patients was extremely poor. Even with
chemotherapy or allogeneic hematopoietic stem cell transplant (AlloSCT) complete
remission and overall survival was less than 70% and 20% respectively. With the
addition of TKI to initial chemotherapy, outcome of these patients has improved
significantly, resulting in about 95% complete remission and 50% overall survival with or
without AlloSCT
1
. TKIs such as Imatinib, Dasatinib and Nilotinib are now standard
therapy for Ph+ patients and consequential increase in initial remission rate has allowed
more patients to be eligible for AlloSCT
5
. Similarly we found in section A of this project
that in our small retrospective quality improvement analysis at Norris hospital, patients
with Ph+ ALL have better outcome post AlloSCT than Ph-ALL patients as all of our
Ph+ALL patients had received TKI plus chemotherapy before transplant. Therefore,
these results raise the question whether AlloSCT is better than TKI incorporated
chemotherapy to prevent relapse in Ph+ ALL patients aged 15-65 years.
Current research is now focusing on how to prevent relapse as improvement in post-
remission therapy is crucial
1
.Even after dramatic change in outcome with TKI combined
with chemotherapy, AlloSCT is still believed to be standard care in Ph+ALL patients due
to lack of larger comparison study
2
. According to National bone marrow transplant link,
28

average cost for AlloSCT is between 150000$-200,000$ for one patient and it is
associated high transplant related complications. Allogeneic stem cell transplant has
better outcome than autologous stem cell transplant and conventional chemotherapy in
the pre-TKI era
3-4, 6
.However, in this era of TKI, it is necessary to determine whether
AlloSCT or continuing TKI plus chemotherapy is better option to prevent relapse in
patient after complete remission with induction therapy with TKI plus chemotherapy. In
this systematic review and meta-analysis, we will compare results of AlloSCT versus TKI
plus Chemotherapy in newly diagnosed Ph+ ALL patients who have achieved complete
remission with TKI plus chemotherapy as an initial treatment, of all the studies to see
difference in outcomes in form of overall survival, disease free survival, disease relapse
and death.
2.3 Methods:
Study Design:
Our study was designed to examine outcomes in the form of relapse, death, overall
survival and disease free survival in newly diagnosed Ph+ALL patients age 15-65 years
of age who achieved first complete remission with chemotherapy combined with TKI and
underwent AlloSCT or continued chemotherapy combined with TKI to prevent disease
relapse. A protocol was developed according to PRISMA guidelines for systematic
review and meta-analysis available at: http://protocolall.blogspot.com. Original articles
for our study were obtained using pre-established search strategy for systematic
literature search. Observational studies, randomized and non -randomized clinical trials
were eligible. Articles that had information for Ph+ALL patients who were in remission
with TKI plus chemotherapy and who underwent AlloSCT or continued chemotherapy
plus TKI were included for review. Two groups were established to identify post
29

remission therapy: GR1 represented the group of patients who underwent AlloSCT post
achieving CR1 with TKI plus chemotherapy. GR2 represented patients who continued to
get TKI plus chemotherapy post achieving CR1 with TKI plus chemotherapy. Only
studies with data in the form of number of patients who relapsed or died in GR1 and
GR2 were included in final analysis.
Literature Search and data Extraction:
Literature search was done using the following databases: Pub Med/Medline, Web of
Science, Cochrane library database, Clinical trials.gov, Grey literature and references of
selected articles. Literature search was done using line by line search strategy for
different databases established with the help of Norris medical Librarian (LK). Last
search was done on May30, 2014. Among the searched articles, all the articles that did
not discuss Ph+ALL were excluded. Articles that talked about Ph+ALL in adolescent and
adults, discussed outcome of TKI plus chemotherapy and or AlloSCT after complete
remission were included. Studies that discussed regarding Ph+ALL in children, did not
have information regarding outcome of both AlloSCT and TKI plus chemotherapy, had
not included TKI plus chemotherapy in induction regimen, and were in language other
than English were excluded. Using pre-established inclusion exclusion criteria, searched
articles were further narrowed down after reading abstract of each article by (PP) and
(PS). Selected full articles were read by two investigators (PP and PS) for data
abstraction. Using references from selected articles, further search was done to find
other eligible articles. The following data was abstracted and entered into excel spread
sheet: study name, author, reference, study design, number patients with complete
remission, post CR treatment division, number of people in GR1 and GR2, number of
relapses and deaths in GR1 and GR2, molecular remission data, overall survival and
relapse free survival in each group, risk of bias and comment for each study. Abstracted
30

data were represented in form of tables. All the numbers were compared between two
abstract personnel and discrepancies were discussed.
Statistical Analysis:
Data for number of total patients, number of relapse and number of death in GR1 and
GR2 were used to calculate Relative Risk (RR) for each group. Using MedCalc statistical
data analysis software version 14.8.1, RR for each study was calculated separately for
relapse and death. Pooled Risk ratio for fixed effect model and random effect model
were calculated and represented in form of forest plots using same software. Under fixed
effect model it is assumed that studies share common true effect and summery effect is
an estimate of common effect size, while under random effect model true effect in
studies are assumed to vary and summery effect is an weighted average of the effect
reported in different studies
20
. The results of Relative risk meta-analysis included the
following: a) 95% confidence interval (CI) for individual study specific rates b) Meta-
analytic pooled rate with 95% CI, c) and standard indexes evaluating between study
heterogeneity including I
2
and Cochran's Q test.
2.4 Results:
A total of790 articles were identified using our search strategy. All articles were screened
and sorted using inclusion and exclusion criteria. Figure-1.1 shows flow diagram for
study selection. A total of 8 studies were included in our systematic review and 7 in
meta-analysis. Data were drawn mostly directly from the information available in these
articles. In articles that did not have direct information on number of relapse or death,
these were calculated from % relapse or % death information. We abstracted data
separately for GR1 and GR2 from each selected study. In most of the studies, patients
continuing TKI and chemotherapy to prevent relapse were those who did not have
31

matching donor available. Table-2.1 shows study name and source, study type, patients’
characteristics and risk of bias. Table-2.2 and 2.3 show number of patients in CR and
total in each group, number of relapse, death and overall or relapse free survival. Out of
8 studies, 5 were non- randomized clinical trials and 2 were retrospective cohort studies
and 1 was prospective cohort study. Relative risk meta-analysis for relapse and death
are depicted in Table-2.4 - 2.5, and forest plots with pooled effect are shown in Figure-
2.2 - 2.3. Data from all 7 studies were used for analysis. A total 164 patients were in
GR1 and 115 were in GR2.Test for heterogeneity was non-significant for relapse and
death (P=0.46 and 0.98 respectively) and I
2
test showed no variability suggesting
homogeneous nature of our selected studies; therefore were reported results for fixed
effect model. Pooled relative risk for relapse for AlloSCT versus TKI plus chemotherapy
was 0.45 (95% CI0.48-0.82, P<0.001). Only 6 out of 7 studies were included for pooled
analysis for death. Pooled RR for death between AlloSCT and TKI plus chemotherapy
was 0.627 (95% CI0.48-0.82, P=0.001).
2.5 Discussion:
Our results show that patients who undergo AlloSCT post CR1 status with TKI and
chemotherapy have less risk of relapse and death compare to those who continue TKI
plus chemotherapy. Our meta-analysis was able to include data from 7 different studies
for final analysis. All these studies were published studies. These included about total
164 patients in AlloSCT group and 115 patients in TKI +Chemotherapy group.
In De labrathe
9
patients were divided in to HAMI and DIV group according to good initial
response to steroid and standard chemotherapy and poor response. Imatinib was used
in induction or consolidation regimen. Tangayu-schmidt
16
was a long term follow up of
De labrathe
9
study which has more information available to abstract relevant data.
32

Results were collected after four year follow up. Four year DFS was 71% in AlloSCT
while it was 33% in TKI with chemotherapy group. So, De labrathe
9
was excluded from
final analysis. In Fielding A.K
10
, comparison was between pre Imatinib versus Imatinib
cohort. Imatinib was started in induction phase in Imatinib cohort. Relapse rate and
death rate were calculated from % survived at 4 years. Only patients undergoing
protocol AlloSCT were considered in GR1 for analysis. RFS was 69% at four year in
AlloSCT patients while it was 18% in chemo plus TKI group. In Lee K.H
11
, Imatinib was
given in induction regimen. 3 patients relapsed after achieving CR on TKI plus chemo
underwent allotransplant and were not included in GR1 instead were considered in GR2.
Only patients who are in first CR and underwent AlloSCT were considered in GR1 for
analysis. In Li
12
et al study only patients in the frontline group had Imatinib at the
beginning of treatment, so only these patients were considered for GR2. Patients in
AlloSCT group had continued TKI post-transplant. In Ravandi
13
et al, Dasatinib was
given with hyper CVAD as frontline treatment while in Thayagu
14
et al. Imatinib was
given in induction with a pediatric based ALL protocol. In Thomas Da
15
, they used
Imatinib with hyper CVAD as well. Only cases with de novo Ph+ ALL who received CR
with Imatinib and Chemotherapy were included in GR2 for our final analysis.
Strength and Limitation:
As Ph+ALL is a rare disease and there were no study directly examining effectiveness of
AlloSCT versus TKI plus chemotherapy to prevent relapse post achieving CR, our
study includes useful information from seven different studies. Although there are
chances of selection bias due to absences of randomization, results were suggestive of
AlloSCT as an important modality for preventing relapse post achieving CR status with
TKI combined chemotherapy.
33

2.6 Conclusion:
In absence of any randomized trial directly examining effect of AlloSCT versus
chemotherapy with TKI in patients who achieves CR1 status with chemotherapy with TKI
in induction phase, our meta-analysis suggests that AlloSCT is an effective modality to
prevent relapse in Ph+ALL patients aged 15-65 years.

34

Figure-2.1: Flow Diagram for Study selection


Data abstracted from Articles (N=8)
Articles excluded (N=52);
 Case reports (N=10),
 Review articles (N= 8),
 Study results not posted (N=4),
 Using exclusion criteria- articles that do
not have data for outcome of both
AlloSCT and TKI + chemo (N=31)

Exclusion Criteria:
 Patients age<15 years
 Studies that do not use TKI
+chemotherapy for induction
 Do not discuss AlloSCT and or
TKI+Chemo for preventing relapse

Articles remained after second screening (N=122);
 Clinical Trial. gov. (N=5)
 Medline (N= 54)
 Web of Science (N= 63)
 59 Duplicates Removed
 3 Full text articles not found
477 articles excluded: did
not discuss Ph+ALL

Full text articles assessed for eligibility (N=60)
195 articles excluded after
reading abstract: met
exclusion criteria

Articles added by
hand search (N= 1)
Articles remained after first Screening (N= 313);
 Clinical Trial. gov. (N=25)
 Cochrane (N=13)
 Medline (N= 109)
 Web of Science (N=166)

Total articles identified using pre-established search
strategy (N= 790);
 Clinical Trial. gov. (N=49)
 Cochrane (N=49)
 Grey Literature (N=17)
 Medline (N= 327)
 Web of Science (N=348)
35

Table-2.1: Characteristics of studies included in systematic review
Sr.
No
Study Title, author, year, source of
publication
Patients
characteristics in
Type of
Study
Risk of
Bias/Comment
1

de Labarthe, A. 2007; Imatinib combined
with induction or consolidation
chemotherapy in patients with de novo
Philadelphia chromosome-positive acute
lymphoblastic leukemia: results of the
GRAAPH-2003 study
All patients aged 15 to 59
years with newly
diagnosed ALL included in
the GRAALL-2003 phase
2 trial were eligible for
theGRAAPH-2003 study if
diagnosed with Ph+ALL
Non
randomize
d clinical
Trial
Only Patients
without donor
undergo Gr2
2 Fielding, A. K. et al,2014;
UKALLXII/ECOG2993: addition of
imatinib to a standard treatment regimen
enhances long-term outcomes in
Philadelphia positive acute lymphoblastic
leukemia
Pt with newly diagnosed
Ph+ ALL age 15-65
Non
randomize
d clinical
Trial
Patients in Gr2
was more older
than in GR1
3 Lee, K. H,2005;Clinical effect of imatinib
added to intensive combination
chemotherapy for newly diagnosed
Philadelphia chromosome-positive acute
lymphoblastic leukemia
Age 15and older with
newly diagnosed Ph+ ALL
Non
randomize
d clinical
Trial
2 patients in Gr 2
was more than
60 year age
4 Li, Y,2009Clinical characteristics and
outcomes of adults with Philadelphia
chromosome positive and/or bcr-abl
positive acute lymphoblastic leukemia: a
single center study from China
Age 15 or more newly
diagnosed ALL, 110
patients were with Ph+ALL
Retrospecti
ve cohort
study
Data from non-
frontline gr in ICT
not included as
they used TKI
post remission.
5 Ravandi F,2010; First report of phase 2
study of dasatinib with hyper-CVAD for
the frontline treatment of patients with
Philadelphia chromosome-positive (Ph+)
acute lymphoblastic leukemia
Age 18 or more
,previously untreated
Ph+ALL
Non-
randomize
d Clinical
Trial
phase2
Patients had
option to go to
AlloSCT
6 Thyagu, S,2012; Treatment of
Philadelphia chromosome-positive acute
lymphoblastic leukemia with imatinib
combined with a pediatric-based protocol
age 18–60 years with a
new diagnosis of BCR-
ABL1 positive precursor B
ALL
Retrospecti
ve cohort
study
Out of 12, 5
patients who did
not receive HSCT
due to rapid
relapse(3) and
poor performance
status(2)
7 Thomas, Da,2004; Treatment of
Philadelphia chromosome-positive acute
lymphocytic leukemia with hyper-CVAD
and imatinib mesylate
Adults (age 15 years or
older) with Ph-positive
ALL, newly diagnosed or
minimally treated without
imatinib.
Non-
randomize
d clinical
trial
Out of 4 patients
1 was ineligible, 2
don't have donor.
We only consider
de novo patients.
8 Tanguy-Shmidt,2013 Long-Term Follow-
Up of the Imatinib GRAAPH-2003
Study in Newly Diagnosed Patients with
De Novo Philadelphia Chromosome-
Positive Acute Lymphoblastic Leukemia:
A GRAALL Study
45 patients with newly
diagnosed de novo
Ph+ALL (median age, 45
years; range,16-59 years)
were included in the
GRAAPH-2003 study
Prospectiv
e cohort
study
19 patients didn't
have AlloSCT
due to age
>55yr(4pt), no
donor(10)

36

GR1: Patients undergoing AlloSCT after CR, GR2: Patients continuing
TKI+Chemotherapy after CR
Table-2.2: Patients' data according to remission status &treatment division
Study Patients in
CR/ total
Patients
inMolecular
Remission
Post induction
treatment
division
Total patients
in GR1
Total
patients
in GR2
de
Labarthe,
A.
43/45 (CR1) N/A Allo-22(8+14),
Auto-6 (2+4),
TKI+chemo=15
22 15
Fielding,
A. K.
125 (survived
in CR1 at day
84) /137
N/A Myloablativeallo-
82,non protocol
allo-11, Auto-5,
chemo+imatinib -
39
76(Myeloablative
MUD or sibling
donor) +11 non
protocol
38
Lee, K. H 19/20
3 patients
relapsed post
CR on
chemo+TKI,
among them 2
went to allo
N/A all went to
allotransplant
(15in CR1 and 2 in
CR2) except 2. 1
died before CR.
17 (15 CR1+
2CR2)

(15)
2
(4)
Li,Y 2009 22/22in Gr1,
37/41 in ICT,
19/20 in
frontline group
8/22in Gr1,
16/41in ICT
4/19 in Gr2
(frontline gr)
CT,ICT(frontline
group/non
frontline)and SCT
22 19
Ravandi F 33/35( 2 died
before CR due
to infection)
Complete
cytological
27,
undetected
by flow
cytometry17,
Complete
molecular7,
major
molecular 6,
N/A 4 (3 with major
molecular
response)
29
Thyagu, S 30/32, 28 in
intensification
phase( 2 early
death post
induction)
2 HSCT-16,
Chemo-12

16 in CR1 12
Thomas,
Da
20/20( 15 with
active disease,
5 in CR from
entry)
11/11 pt de
novo
12/20 VAD, HyperCVAD,
HyperCVAD +
Imatinib
7 (de novo)
(10 all)
4 (de
novo)
(10 all)
Tanguy-
Shmidt et
al
(14+19)
43/45
8 MRD -ve in
AlloSCT, 2 in
TKI+Chemo
10 auto,
24 AlloSCT ,
9 no SCT
,
(8+16) 24/43.
24 (15sibling
donor, 5MRD -
ve),(9MUD,3
MRD negative)
(3+6)= 9
(2 MRD
negative)
37

Table-2.3: Post treatment outcomes in GR1 and GR2
Study No.ofpatients
relapsed in
GR1
No.of
patients
relapsed
in GR2
No.ofpa
tients
died
inGR1
No.pati
ents
died in
GR 2
RFS and
OS in
GR1
RFS and
OS in
GR2
De Labarthe,
A.
4 /22(18%) 2/15 (13) 4(18%) N/A N/A N/A
Fielding, A.
K.
*calculated
from%
survived
* 24 *31 *38/76(3
8
survived
at 4 yr)
*31/38(7s
urvived)
50% (4year
OS),
46%(EFS),
69% (RFS)
at 4 years
19%(OS),
14% (EFS),
18%(RFS)
at 4 years
Lee, K. H (3/15)
5 (3CR1+2 CR2)
/17

(3/4)
1/2

(5)
6 (1 in
CR2)

(2)
1 if no
2nd allo

N/A N/A
Li,Y ,2009 8/22 10/19

9 N/A 48.2+/-
13.9(DFS),
53.1+/-
12.7(OS)
(2year)
30.1+/-
12.2(DFS),
41.6+/-16.2
(OS)
(2year)
Ravandi F 0/4 5+4=9/29 0 4+3=7 N/A 57%(95%C
I-34-74)
(EFS),64%
(38-81)
Thyagu, S Total=16
Alive-8,
Relapse=2,

Total=12
Alive=5
Relapse=
6
NRM=2 NRM=1 56(OS),
70%(EFS)
3year
50(OS),45(
EFS)-3year
Thomas, Da 1/7
(1/10)
0/4
(2/10)
(ask
MRD)
1/7
(1/10med
ian f/up
20
months)
1/4
(4/10)
OS: 9
months(me
dian 12
months, 1-
17
months)4
had
imatinib
post
AlloSCT
6months
Tanguy-
Shmidt et al
* calculated
from %
relapsed/died
All data at 4
year
27% Sibiling,
44% (URD)
* (4 +4) = 8/24
39%
* 3.5=4/9
7%
(Sibling),
44%
(URD)
*(1+4)=
5/24
28%
*2.52=3/9
4 year- OS
76%(sibling
)(95%CI=5
6-100%),
11%(URD)(
2-70), DFS
71%(51-
100, 11
%(URD)
(2-70)
4 year
DFS&OS,
33% (11-
98)

38

Table-2.4: Meta-analysis: Relative risk for Relapse
Study
AlloSCT
(GR1)
TKI+Chemo(
GR2)
Relative Risk
Estimate (95%CI)
Fielding,2014 24/76 31/38 0.387 (0.269 to 0.557)
Lee,2005 3/15 3/4 0.267 (0.084 to 0.850)
Li,2009 8/22 10/19 0.691 (0.344 to 1.389)
Ravandi,2010 0/4 9/29 0.316 (0.022 to 4.613)
Tanguy-Shmidt.2013 8/24 4/9 0.750 (0.298 to 1.889)
Thomas,2004 1/7 0/4 1.875 (0.094to 37.634)
Thyagu,2012 2/16 6/12 0.250 (0.061 to 1.029)
Overall (I
2
=0,P<0.001) 46/164 63/115 0.450(0.336 to 0.602)

Figure-2.2: Forest plot showing RR for Relapse. Marker size relative to study weight and diamonds
for pooled effects. The location of the diamond represents the estimated effect size and the width
of the diamond reflects the precision of the estimate. Note that the relative risks with 95% CI are
drawn on a logarithmic scale
39

Table-2.5: Meta-analysis: Relative Risk for Death
Study
AlloSCT
(GR1)
TKI+Chemo
(GR2)
Relative Risk
Estimate (95%CI)
Fielding,2014 38/76 31/38 0.613 (0.467 to 0.804)
Lee,2005 5/15 2/4 0.667 (0.198 to 2.244)
Ravandi,2010 0/4 7/29 0.400 (0.027 to 5.962)
Tanguy-Shmidt,2013 5/24 3/9 0.625 (0.187 to 2.094)
Thomas,2004 1/7 ¼ 0.571 (0.048 to 6.856)
Thyagu,2012 2/16 1/12 1.500 (0.153 to 14.677)
Overall (I
2
=0,P=0.001) 51/142 45/96 0.627 (0.477 to 0.823)

Figure-2.3: Forest plot showing RR for death. Marker size relative to study weight and diamonds for
pooled effects. The location of the diamond represents the estimated effect size and the width of the
diamond reflects the precision of the estimate. Note that the relative risks with 95% CI are drawn on
a logarithmic scale

40

2.7 Reference:

1. Ohno R. Treatment of Adult Patients With Philadelphia Chromosome-Positive
Acute Lymphoblastic Leukemia. Current Oncology Reports. Sep 2008;10(5):379-
387.
2. Abou Mourad YR, Fernandez HF, Kharfan-Dabaja MA. Allogeneic hematopoietic
cell transplantation for adult Philadelphia-positive acute lymphoblastic leukemia
in the era of tyrosine kinase inhibitors. Biol Blood Marrow Transplant. Sep
2008;14(9):949-958.
3. Gupta V, Richards S, Rowe J. Allogeneic, but not autologous, hematopoietic cell
transplantation improves survival only among younger adults with acute
lymphoblastic leukemia in first remission: an individual patient data meta-
analysis. Blood. Jan 10 2013;121(2):339-350.
4. Hunault M, Harousseau JL, Delain M, et al. Better outcome of adult acute
lymphoblastic leukemia after early genoidentical allogeneic bone marrow
transplantation (BMT) than after late high-dose therapy and autologous BMT: a
GOELAMS trial. Blood. Nov 15 2004;104(10):3028-3037.
5. Couban S, Savoie L, Abou Mourad Y, et al. Evidence-based guidelines for the
use of tyrosine kinase inhibitors in adults with Philadelphia chromosome-positive
or BCR-ABL-positive acute lymphoblastic leukemia: a Canadian consensus.
Current Oncology. Apr 2014;21(2):E265-E309
6. Messori A, Fadda V, Maratea D, Trippoli S. Acute lymphoblastic leukemia in first
complete remission: temporal trend of outcomes in studies comparing allogeneic
transplant with autologous transplant or chemotherapy. Ann Hematol. Sep
2013;92(9):1221-1228.
7. Couban S, Savoie L, Abou Mourad Y, et al. Evidence-based guidelines for the
use of tyrosine kinase inhibitors in adults with Philadelphia chromosome-positive
or BCR-ABL-positive acute lymphoblastic leukemia: a Canadian consensus.
Current Oncology. Apr 2014;21(2):E265-E309.

8. Messori A, Fadda V, Maratea D, Trippoli S. Acute lymphoblastic leukemia in first
complete remission: temporal trend of outcomes in studies comparing allogeneic
transplant with autologous transplant or chemotherapy. Ann Hematol. Sep
2013;92(9):1221-1228.

9. de Labarthe A, Rousselot P, Huguet-Rigal F, et al. Imatinib combined with
induction or consolidation chemotherapy in patients with de novo Philadelphia
chromosome-positive acute lymphoblastic leukemia: results of the GRAAPH-
2003 study. Blood. Feb 15 2007;109(4):1408-1413.

10. Fielding AK, Rowe JM, Buck G, et al. UKALLXII/ECOG2993: addition of imatinib
to a standard treatment regimen enhances long-term outcomes in Philadelphia
positive acute lymphoblastic leukemia. Blood. Feb 6 2014;123(6):843-850.

41

11. Lee KH, Lee JH, Choi SJ, et al. Clinical effect of imatinib added to intensive
combination chemotherapy for newly diagnosed Philadelphia chromosome-
positive acute lymphoblastic leukemia. Leukemia. Sep 2005;19(9):1509-1516.

12. Li YN, Zou DH, Zhao YZ, Mi YC, Wang JX, Qiu LG. Clinical characteristics and
outcomes of adults with Philadelphia chromosome positive and/or bcr-abl
positive acute lymphoblastic leukemia: a single center study from China.
Leukemia & Lymphoma. Mar 2010;51(3):488-496.

13. Ravandi F, O'Brien S, Thomas D, et al. First report of phase 2 study of dasatinib
with hyper-CVAD for the frontline treatment of patients with Philadelphia
chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood. Sep 23
2010;116(12):2070-2077.

14. Thyagu S, Minden MD, Gupta V, et al. Treatment of Philadelphia chromosome-
positive acute lymphoblastic leukaemia with imatinib combined with a paediatric-
based protocol. British Journal of Haematology. Aug 2012;158(4):506-514.

15. Thomas D, Faderl S, Cortes J, et al. Treatment of Philadelphia chromosome-
positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate.
Blood. 2004;103(12):4396-4407..

16. Tanguy-Schmidt A, Rousselot P, Chalandon Y, et al. Long-term follow-up of the
imatinib GRAAPH-2003 study in newly diagnosed patients with de novo
Philadelphia chromosome-positive acute lymphoblastic leukemia: a GRAALL
study. Biol Blood Marrow Transplant. Jan 2013;19(1):150-155.

17. Foa R, Vitale A, Vignetti M, et al. Dasatinib as first-line treatment for adult
patients with Philadelphia chromosome-positive acute lymphoblastic leukemia.
Blood. Dec 15 2011;118(25):6521-6528.

18. Towatari M, Yanada M, Usui N, et al. Combination of intensive chemotherapy
and imatinib can rapidly induce high-quality complete remission for a majority of
patients with newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia.
Blood. Dec 2004;104(12):3507-3512.

19. Yanada M, Takeuchi J, Sugiura I, et al. High complete remission rate and
promising outcome by combination of imatinib and chemotherapy for newly
diagnosed BCR-ABL-positive acute lymphoblastic leukemia: A phase II study by
the Japan Adult Leukemia Study Group. Journal of Clinical Oncology. Jan
2006;24(3):460-466.
20. Borenstein M, Hedges LV, Higgins JPT, Rothstein HR (2009) Introduction to
meta-analysis. Chichester, UK: Wiley

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Creator Parikh, Pooja (author)

Core Title Clinical outcomes of allogeneic hematopoietic stem cell transplant in acute lymphoblastic leukemia patients: a quality improvement project and systematic review meta-analysis

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Publication Date 11/13/2014

Defense Date 10/26/2014

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