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Relapse Prevention with Tyrosine Kinase Inhibitors after Allogeneic

Transplantation for Ph+ ALL, A Systematic Review

Zabih Warraich , Pavan Tenneti , Theresa Thai , Anne Hubben ,

Hina Amin , Ali McBride , Sami Warraich , Abdul Hannan ,
Faiza Warraich , Navneet Majhail , Matt Kalaycio , Faiz Anwer

PII: S1083-8791(19)30633-0
DOI: https://doi.org/10.1016/j.bbmt.2019.09.022
Reference: YBBMT 55733

To appear in: Biology of Blood and Marrow Transplantation

Received date: 10 June 2019

Accepted date: 18 September 2019

Please cite this article as: Zabih Warraich , Pavan Tenneti , Theresa Thai , Anne Hubben ,
Hina Amin , Ali McBride , Sami Warraich , Abdul Hannan , Faiza Warraich , Navneet Majhail ,
Matt Kalaycio , Faiz Anwer , Relapse Prevention with Tyrosine Kinase Inhibitors after Allogeneic
Transplantation for Ph+ ALL, A Systematic Review, Biology of Blood and Marrow Transplantation
(2019), doi: https://doi.org/10.1016/j.bbmt.2019.09.022

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© 2019 Published by Elsevier Inc. on behalf of the American Society for Transplantation and Cellular
Therapy
Title page:
Title: Relapse Prevention with Tyrosine Kinase Inhibitors after Allogeneic Transplantation for Ph+
ALL, A Systematic Review

Authors: Zabih Warraich1, Pavan Tenneti2, Theresa Thai3, Anne Hubben4, Hina Amin5, Ali McBride6,
Sami Warraich7, Abdul Hannan8, Faiza Warraich9, Navneet Majhail10, Matt Kalaycio10 and Faiz Anwer10.

Author Affiliation:
1. Department of Internal Medicine, United Health Services Wilson Memorial Regional Medical Center |
Johnson City, NY 13790
2. Hematology Oncology, Levine Cancer Institute, Charlotte, NC 28204
3. The University of Arizona, College of Medicine, Tucson, AZ 85719
4. Department of Internal Medicine, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195
5. Clinical research, Hematology Oncology, Cleveland Clinic, 10201 Carnegie Ave | Cleveland, OH
44195
6. College of Pharmacy, The University of Arizona, Tucson, AZ 85719, USA
7. Department of Internal Medicine, Sisters of Charity Hospital, 2157 Main Street Buffalo, NY 14214
8. Hospice and Palliative Medicine Fellow, University of Missouri Health Care, One Hospital Drive
M226 Medical Sciences Building, DC032.00, Columbia, MO 65212
9. Department of Internal Medicine, McLaren Flint Hospital, 401 S. Ballenger Hwy, Flint, MI 48503
10. Cleveland Clinic, Taussig Cancer Center | 10201 Carnegie Ave | Cleveland, OH 44195

Key words: Tyrosine Kinase Inhibitors, Acute Lymphoblastic Leukemia, Philadelphia chromosome,
relapse.

ACKNOWLEDGMENTS: Financial disclosure statement: This work was not supported by any grant.
Conflict of interest statement: Authors declare that there is no conflict of interest with this manuscript.
The authors have no relevant affiliations or financial involvement with any organization or entity with a
financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants
or patents received or pending, or royalties. No writing assistance was utilized in the production of this
manuscript.

Authorship statement: ZW, PT, FA designed the study. All authors performed the study, contributed to
data extraction, analyzed the data, wrote the paper, and approved manuscript.
*Both authors contributed equally for this manuscript.

Corresponding Author
Faiz Anwer M.D., F.A.C.P.
Staff Physician, Taussig Cancer Center
Hematology, Oncology, Stem Cell Transplantation
Multiple Myeloma Program
ANWERF@ccf.org
Cleveland Clinic | 9500 Euclid Ave, CA60 | Cleveland, OH 44195
Taussig Cancer Center | 10201 Carnegie Ave | Cleveland, OH 44195
Fax: 216-444-9464
Abstract:

Background: Relapse after stem cell transplantation for Philadelphia chromosome (Ph) positive

acute lymphoblastic leukemia (ALL) remains a significant challenge. In this systematic review,

we compare survival outcomes of second-generation tyrosine kinase inhibitors (TKIs) nilotinib

and dasatinib with first generation imatinib when these agents are used after allogeneic

hematopoietic stem cell transplantation (allo-HSCT) in Ph-positive ALL. In addition, we review

the literature on TKI use to prevent relapse in patients who proceed to allo-HSCT beyond first

complete response (>CR1).

Methods: We performed database searches (inception to Jan 2018) using PubMed, Cochrane

Library, and Embase. After exclusions, seventeen articles were included in this analysis.

Results:

Imatinib was used post-transplant either prophylactically or pre-emptively in 12 studies, of

which 7 were prospective studies and 5 being retrospective studies. The overall survival (OS) for

most prospective studies at 1.5-3 and 5 years ranged between 62-92% and 74.5-86.7%. The

disease-free survival (DFS) at 1.5-5 years was 60.4-92%. Additionally, imatinib failed to show

survival benefit in patients who were in >CR1 at the time of Allo-HSCT. The cumulative OS for

most retrospective studies using Imatinib at 1-2 and 3-5 years was 42-100% and 33-40%

respectively. The event free survival (EFS) at 1-2 and 3-5 years was 33.3-67% and 20-31%

respectively.

Dasatinib was used as maintenance treatment in three retrospective studies (n=34). The OS for

patients with Ph+ ALL with utilization of dasatinib as maintenance regimen after Allo-HSCT at
1.4- 3 years was 87-100% and DFS at 1.4-3 years was 89- 100%. 93% of patients with minimal

residual disease (MRD) positive status after allo-HSCT became MRD negative.

Three prospective studies used Nilotinib. In two studies where investigators studied patients with

advanced chronic myeloid leukemia and Ph-positive ALL, the cumulative OS and EFS at 7.5

months- 2 years was 69-84% and 56-84% with nilotinib. In another study (n=5) with Ph+ ALL,

nilotinib use resulted in OS at 5 years of 60%.

Conclusions:

Our review showed utilization of TKI (all generations) post allo-HSCT for patients in CR1

improved OS when given as prophylactic or pre-emptive regimen. Limited data suggests that

second generation TKI (Dasatinib) has better OS especially in patients with MRD positive status.

Imatinib did not improve OS in patients that were in >CR1 at time of allo-HSCT; for this

population, no data was available with newer generation TKI. The evaluation of survival benefit

with newer generation TKI and their efficacy in >CR1 patients needs further study in large

randomised clinical trials.

Introduction:

Acute lymphoblastic leukemia (ALL) represents 75-80% of acute leukemias in children and

about 20% of all leukemias in adults [1, 2]. The overall survival (OS) from ALL decreases with

advancing age [3]. The presence of the Philadelphia chromosome is a well-established adverse

prognostic marker, and it is one of the most common cytogenetic abnormalities in adult-onset

ALL [4]. The emergence of tyrosine kinase inhibitors (TKI) given frontline along with

chemotherapy followed by allogenic stem cell transplant(allo-HSCT) has shown to improve

survival in Ph+ ALL. One of the first large phase II studies using upfront TKI in combination

with multiagent chemotherapy was conducted by Yanda et al.2006(n=77) which resulted in CR

of 96.2%. The patients(n=49) who subsequently underwent allo-HSCT had 1-year OS of 73.3%.

The 3 year OS was 65% compared to 44% in historical controls without imatinib based

chemotherapy regimens [5]. Similarly in another study (GRAPH-2003) (n=45) imatinib when

given with mitoxantrone and intermediate dose cytarabine, resulted in improved long term OS

compared to chemotherapy alone (4 yr. OS, 52% vs 20%,p=0.0001) [6, 7]. TKI when given

along with hyper-CVAD (cyclophosphamide, vincristine, adriamycin, dexamethasone) regimen

has also shown long term survival benefit in a study by Thomas et al.2010 (n=45,3 yr OS=

54%)[8]. TKI containing multi-agent chemotherapy regimens decreased the relapse incidence at

3 years by two folds after allo-HSCT(38% vs 81%) even if low intensity conditioning

regimen(n=67) was used compared to non TKI consisting induction regimens [9]. TKI has also

shown benefit in older patients (>55 years) in combination with steroids for induction (LAL-

0201-B, n=29, 1 yr. DFS and OS=48% and 74%)[10]. National cancer consortium network

(NCCN version 2,2019) has recommended usage of frontline TKI based chemotherapy regimens

in newly diagnosed Ph+ALL.

Relapse after allo-HSCT is still the most common reason for treatment failure, and these are

particularly high in Ph+ALL. Minimal residual disease (MRD) which is defined as presence of

0.01% or more ALL cells in the body, increases the likelihood of relapse post allo-HSCT [11].

Polymerase chain reaction(PCR) assays are beneficial in detecting BCR-ABL transcripts on

chromosome 22, which is an indicator for MRD[12]. There is a need for additional therapeutic

interventions in presence of MRD to prevent full blown relapse [12]. NCCN, Version 2. 2019

recommendations favor the use of post-transplant maintenance therapy with a TKI. These

recommendations are based on the results of two prospective studies showing imatinib

maintenance after allo-HSCT further improved EFS and OS [17, 18]. They can be administered

prophylactically to all patients (irrespective of MRD status) after allo-HSCT once hemopoietic

stability is achieved or pre-emptively on appearance of MRD. It is unclear which mode of

administration has greater survival and relapse prevention benefit. In recent years, second

generation TKIs are also being investigated in prospective and retrospective studies as

maintenance therapy after allo-HSCT.

In this systematic review, we compared survival outcomes of second generation TKIs with first

generation imatinib maintenance therapy after allo-HSCT. In addition, we examined TKI use as

a relapse prevention strategy in patients who proceed to allo-HSCT beyond first complete

response (>CR1). We also compared prophylactic and pre-emptive strategies for their efficacy

and tried to determine the optimal agent, dosage, initiation time, and duration of treatment after

allo-HSCT.
Materials and Methods:

Eligibility criteria: All studies involving adult patients with Ph-positive ALL who underwent

bone marrow or peripheral blood stem allo-HSCT followed by the post-transplant use of a TKI

were included. Studies with exclusively chronic myeloid leukemia (CML) patients, Philadelphia

chromosome negative ALL (Ph- ALL) and individual case reports were excluded.

Literature Search: We performed a systematic literature search (from inception until January

2018) using the following databases: PubMed, Wiley Cochrane library central, and Embase. The

search strategies included various combinations of text words and controlled vocabulary, when

available. There were no language or year limits placed on the search. Two reviewers (Z.W. and

T.T.) independently applied the inclusion and exclusion criteria to the articles identified by the

search strategy and extracted data using a standardized form. Potentially relevant studies were

reviewed in full to confirm their eligibility. Any discrepancies were resolved by consensus with a

third collaborator (F.A.).

Data Extraction and Analysis: The following data were extracted from each study: number of

patients in the study, type of transplant received, donor source, number of patients on TKIs post-

transplant, the type of TKI used, treatment start date, TKI dosage, duration of treatment, adverse

effects, and outcomes. Where not explicitly stated, we calculated outcomes and other data based

on information included within the published record; if this was not possible, “not reported” was

listed in the resulting tables. Data are presented as the mean or median (range) and all values are

expressed to 1 decimal place unless the original article did not provide this degree of accuracy.

Study outcomes were overall survival (OS), disease-free survival (DFS), leukemia or relapse free

survival (LFS/RFS) and relapse rates.

Search Criteria

A total of 868 articles were identified by our search strategy. Seven duplicate articles were

excluded. The remaining 861 articles were screened for relevance based on their titles and

abstracts. Of these, 86 articles were potentially eligible and full manuscripts were retrieved for

review. 68 of these articles were subsequently excluded for the following reasons: case reports,

no intervention, exclusively CML patients, TKIs use only prior to transplant, review articles, and

insufficient data. 18 articles met inclusion criteria. The review process is depicted in the flow

diagram (Figure 1).

Study Demographics

All studies (n=462) included adult patients (age >18 years) with Ph+ ALL who underwent allo-

HSCT with initiation of a TKI following transplant. Imatinib was studied in seven prospective

trials (n=224) and five retrospective studies (n=188). Second generation TKIs were studied in six

trials: three prospective case series of nilotinib (n=16) and three retrospective studies of dasatinib

(n=34). Details of individual study design and patient characteristics are included in the

accompanying tables.

Results:

Overview of prospective trials with imatinib:

In seven prospective trials (n=224), imatinib was used post-transplant either prophylactically or

pre-emptively in the dose range of 200 – 600mg.

Wassmann et al. (2005) [13] demonstrated that imatinib, when given pre-emptively in 27 MRD-

positive patients (duration- 1 year from negative PCR), was associated with a 52% likelihood of
converting to MRD-negative status. Patients who achieved MRD-negative status after receiving

imatinib had improved OS (80-100%) and EFS (54.5-91%) at 1- 2 years [13]. Patients who

remained MRD-positive despite receiving imatinib had inferior outcomes with OS and DFS at 1

year of 23% and 8% respectively [13].

In studies by Carpenter et al. (2007) [14] (n=51) and Ram et al. (2011) (n=27) [15], patients who

received imatinib (duration – 1 year for both studies) prophylactically had an OS at 1.5-3 years

of 62-80%. A superior outcome with imatinib (OS at 3 yrs.= 62%) was achieved in the study by

Ram et al. following a non-myeloablative conditioning regimen[15]. Patients who were MRD-

negative prior to allo-HSCT had superior OS at 3 years (72%) when compared to the group

average (62%). Patients who were >CR1 prior to allo-HSCT had a 1.5-year OS of only 25%. The

average time to initiation of imatinib after allo-HSCT in patients studied by Carpenter et al. was

1 month. Grade 3 and 4 adverse effects occurred in 17% of patients; most of these patients (16%)

terminated treatment [14, 15]. Ottmann et al. (2009) [16] studied outcomes with imatinib used

prophylactically (n=17) and preemptively (n=10). Patients in CR1 at transplant did not relapse at

1.5 years of follow-up after transplant in either group. Patients who were >CR1 at the time of

transplant had a 60% relapse rate [16].

In a study conducted by Ribera et al. (2010)[17], the OS and DFS for 13 patients who received

prophylactic imatinib was only 30%(duration-9 months). Transplant and treatment-related

complications and patient selection may have contributed to poor outcomes in this small cohort.

Ten of twelve patients had interruptions in treatment for various reasons including relapse,

severe chronic graft versus host disease (GVHD), grade 3–4 toxicity, non-relapse death and

patient preference [17].

Chen et al. (2012) [18] reported superior outcomes for patients who received imatinib as

prophylactic or pre-emptive maintenance regimens (duration-3 months from negative PCR for

MRD) after allo-HSCT (n=62) when compared to those who did not receive post-transplant TKI

(n=20) (5 year- OS =86.7 vs 34.3%, p<0.001; EFS= 81.5 vs 33.5%, p<0.001). Additionally, 8 of

14 patients (57%) converted from MRD-positivity to negativity with imatinib [18]. Pfeifer et al.

(2013) [19] studied imatinib use either prophylactically (n=26) or pre-emptively (n=29) after

allo-HSCT (duration-scheduled for 1 year). They found prophylactic use of imatinib resulted in

lower incidence of molecular recurrence as compared to use at first detection of BCR-ABL

transcripts (40% vs. 69%; P=0.046) [19]. The long-term outcomes of OS and EFS at 5 years for

the two groups were 80.1% vs 74.5% (p=0.84) and 72.1% vs 53.7% (p=0.89) respectively,

however these results did not reach statistical significance [19].

To summarize, the OS for these prospective trials of imatinib at 1.5-3 and 5 years ranged

between 62-92% and 74.5-86.7%. The DFS at 1.5-5 years was 60.4-92%. Imatinib failed to show

a survival benefit in patients who were in >CR1 at the time of allo-HSCT.

Overview of retrospective studies with imatinib:

In five retrospective studies [28-32] 178 patients received imatinib post-transplant either

prophylactically or pre-emptively in doses ranging from 300 – 600mg.

Burke et al. (2009) [20] compared outcomes for patients who received prophylactic imatinib

(duration- 1 year) to patients who did not receive post-transplant TKI. OS at 2 years for patients

with imatinib (n=2) and without (n=17) were 100% and 41% with a corresponding relapse-free

survival (RFS) of 100% and 35% [20]. In their comparative study, Nishiwaki et al. (2010) [21]

showed superior outcomes for patients who received imatinib (pre-emptive, n=4; prophylactic,
n=3) after allo-HSCT when compared to no TKI (n=27). The OS at 1 year with TKI vs without

was 100% vs 33.3%, and at 2 years was 66.7% vs 29.6% (p=0.03) [21]. The EFS was not

significantly different between the two groups at 1 and 2 years (55.6% vs 55.6% and 33.3% vs

29.6%, p=0.29) [21]. Kebriaei et al. (2012) [22](n=102) conducted a study between 1990 and

2009 of imatinib given as maintenance regimen at transplant. 62 patients in this study received

imatinib pre-transplant and 16 received it pre and post transplant (duration-10.5 months)[22].

The 2 and 5-year OS was 44% and 33% respectively and EFS was 36% and 31% respectively

[22]. Zhang el al. (2013)[23] contrary to other studies reported 3- year OS of 62.3% for patients

that did not receive imatinib post transplant (n=33) in comparison to 41.7% for those who

received it as prophylactic maintenance treatment (duration-6 months) after allo-HSCT (n=11).

The corresponding DFS at 3 years was 53.6% and 33.3% for former and later groups[23]. The

univariate and multivariate analysis in this study showed that patients who were not in CR before

allo-HSCT had significantly worse outcomes in terms of OS, DFS and relapse rate compared to

patients transplanted in CR [23]. Thirty six percent of patients included in this study were not in

CR at the time of allo-HSCT, which could have biased the outcomes unfavourably for imatinib

given prophylactically after allo-HSCT [23]. Brissot et al. (2015) [28] studied a cohort in which

157 out of 473 patients with Ph+ ALL received TKI post allo-HSCT. 124 patients in this group

received imatinib prophylactically. TKI use post transplant significantly improved LFS (Hazard

Ratio[HR]=0.44; P=0.002), OS (HR=0.42; P=0.004) and patients had a lower relapse incidence

(HR=0.40; P=0.01) [24].

To summarize, the cumulative OS for these retrospective studies of imatinib at 1-2 and 3-5 years

was 42-100% and 33-40% respectively. The EFS at 1-2 and 3-5 years was 33.3-67% and 20-31%

respectively.
Overview of prospective trials with nilotinib:

Three prospective trials studied nilotinib in a heterogeneous population of patients with CML

and Ph+ ALL (n=45) [11, 19, 20]. 16 patients in these three studies had Ph + ALL and received

nilotinib prophylactically, in doses ranging 200-300mg twice a day depending on the tolerance of

medication.

Varda-Bloom et al. (2016) (n=12) studied the effects of post allo-HSCT nilotinib in patients with

CML (n=7) and Ph+ ALL (n=5). Nilotinib was administered in dose range of 200-300mg twice

daily. 3 of the 5 patients with Ph+ ALL remained alive and in complete remission after follow-up

of 5-8 years. OS in the remaining 2 patients was 10.2 months and 32.5 months. The DFS for

these two patients was 10.2 and 23.3 months [25]. The phase I/II study conducted by Shimoni et

al. (2015) showed that nilotinib (median duration of treatment 20 months) was safe and effective

to prevent relapse after allo-HSCT in patients with CML (n=15) and Ph+ ALL (n=7). This study

did not report of outcomes separately for the Ph+ ALL group [26]. The 2-year OS and PFS of 16

of the 22 patients who received nilotinib was higher (69% and 56%) as compared to the entire

transplant population (55% and 45%).

Nagler et al. (2009) reported interim results of an ongoing prospective study on patients with

ALL (n=4) and advanced CML (n=7). 7 patients received 200 mg of nilotinib twice a day post-

transplant for a median duration of 7.5 months, 6 of these patients were still alive and in

complete molecular remission. This study did not report outcomes of patients with ALL

separately [27].

To summarize, two prospective studies of nilotinib reported combined outcomes of patients with

Ph+ ALL and advanced CML [11, 20]. The OS and EFS/DFS at 7.5 months- 2 years ranged 69-
84% and 56-84% respectively. The third trial reported EFS and OS at 5 years of 60% each in

patients with Ph+ALL [19].

Overview of retrospective trials with dasatinib:

Dasatinib was studied as maintenance regimen after allo-HSCT in Ph+ ALL in three

retrospective studies (n=34) [28-30].

Caocci et al. (2012) [30]studied 10 patients who received imatinib or dasatinib as induction

treatment and subsequently received dasatinib as maintenance regimen(median duration 15

months) after allo-HSCT. 2 of 3 (66%) patients who were MRD positive after transplant

successfully converted to molecular negativity with dasatinib [30]. The study is ongoing and the

median OS was 21 months at the time of publication of article [30]. In Czyz et al. (2016) [29], 19

patients received dasatinib (duration 11 months) either prophylactically or pre-emptively. After

median follow up of 3 years after allo-HSCT, the OS and LFS were 87% and 88% respectively.

14 of 15 patients (93%) who were MRD positive after transplant successfully converted to MRD

negativity and continued to be MRD negative at last follow up [29]. In another study by Maher et

al. (2016) [28], 9 patients with Ph+ ALL (n=7) and acute leukemia of ambiguous lineage (n=2)

underwent allo-HSCT after induction treatment. Subsequently, 6 patients received maintenance

treatment with dasatinib, out of which one patient was switched to imatinib due to dasatinib

intolerance [28]. In the five patients with Ph+ ALL who received dasatinib, LFS at 1.4 years was

100% [28].

To summarize, in these retrospective trials of dasatinib, the OS for patients with Ph+ ALL at 1.4-

3 years was 87-100% and DFS at 1.4-3 years was 89-100%.

Discussion:

The Philadelphia chromosome is a characteristic cytogenetic abnormality present in up to 30% of

adult patients with ALL [31, 32]. High relapse rate after allo-HSCT remains a significant

challenge in Ph+ ALL. Relapse rate without use of post-transplant TKI ranges from 15-37% and

EFS (1-3 years) ranges from 50-78% in various studies[5, 7, 33, 34]. In our review, usage of

imatinib given after allo-HSCT showed survival benefit in 4 of 6 studies (1 prospective, 3

retrospective), these studies performed direct comparison between patients who received TKI to

those that did not and showed improvement in OS.In a prospective study, patients who did not

receive imatinib did suffer from cytopenic or were symptomatic and suffering from allo-HSCT

related complications, which could have contributed to their lower OS compared to better

performing cohort who received TKI. [18]. In two studies, the use of imatinib after allo-HSCT

did not seem to improve survival [22, 23]. Kebriaei et al. (2012) study with its limitations of

being retrospective in nature and TKI use for maintenance in a small number of patients, TKI did

not improve outcomes. Only subgroup of patients who were younger, and achieved CR1 at the

time of allo-HSCT, and underwent transplant after 2000 demonstrated better outcomes and

improved prognosis [22]. In contrast, patients in the trial by Zheng et al. (2013) did not show

favorable survival outcomes despite maintenance imatinib, which may in part be explained by

the high percentage (36%) of patients in this small cohort (n=11) who were not in CR at time of

allo-HSCT [23].

In preclinical studies, on comparison to imatinib potency, newer generation TKI’s like dasatinib

(325 times) and nilotinib (50-100 times) have shown to be more potent. [35, 36]. Whether or not

this higher potency will translate into superior clinical outcomes remains to be proven. In our
review, dasatinib use has shown to have similar or better EFS and OS compared to imatinib[28-

30]. Available threestudies which reported data on dasatinib use after Allo-HSCT were

retrospective in nature and long-term outcomes are not available. Nilotinib also had similar

clinical outcomes when compared to imatinib use.. Two of the three studies using post-transplant

nilotinib had mix of CML and Ph+ALL patients [25-27]. The number of patients in studies using

newer TKI agents are small and appropriately powered prospective clinical trials are needed to

establish their true clinical efficacy potency compared to imatinib.

The direct comparison between prophylactic and pre-emptive administration of imatinib was

evaluated in one study. It appeared that there is a trend towards improved EFS and OS with

prophylactic administration, though statistical significance of this finding was not achieved[19].

Patients who became MRD positive within 100 days of allo-HSCT in either arm had a 47%

chance of frank relapse despite use of imatinib[19]. Imatinib administered pre-emptively resulted

in 46-57% conversion of MRD positive patients to a negative status[18, 19]. Dasatinib appeared

to be more effective (70-90%) than imatinib in converting MRD positive patients to negative

state, though the cohort of patients was smaller in number, this is a historical comparison, no

direct comparison exists in the literature, selection bias and other compounding factors could

have affected this outcome. Larger studies are needed to determine if dasatinib would be better

suited to be given as a pre-emptive regimen.

The dose of imatinib as maintenance therapy in these studies ranged between 300-600 mg/day,

with a usual starting dose of 400 mg and target dose of 600 mg on daily basis. Dasatinib was

given at a dose range of 50-100 mg and nilotinib at dose range of 200-300 mg daily. In many

published studies and commonly in clinical practice, these recommended doses are chosen
arbitrarily based on the impression that after allo-HSCT, due to regimen related toxicity and

common gastrointestinal symptoms with GVHD, patient have difficulty tolerating full doses

recommended for CML indication. In most studies treatment with imatinib was planned for one

year after allo-HSCT, or for one year after negative PCR testing for BCR-ABL. Chen et al.

(2012) showed that superior long term outcomes were maintained even if imatinib was stopped

after 3 consecutive negative monthly BCR-ABL tests (5 year OS 86.7%) [18]. In study by Zhang

et al., imatinib was given for only 6 months after allo-HSCT, study showed inferior outcomes (3

year- OS 40%), however the patient population included a significant number of patients who

were not in CR at the time of allo-HSCT (36%) and most patients relapsed by the one year mark

[32]. Only limited studies reported duration for whichdasatinib (11-15 months) and nilotinib

(7.5-20 months) were administered.The timings of initiation of TKI was also arbitrary and

variable across included studies. In most studies, TKI was started once bone marrow showed

recovery with stable blood counts after allo-HSCT and if GVHD symptoms were manageable.

Imatinib used as maintenance regimen has not shown to decrease relapse or improve survival in

patients who were in >CR1 at time of allo-HSCT in multiple studies. The relapse rate in such

patietns is very high in the range of 40-60%, and OS is dismal (at 5 years: 5%). There is paucity

of data about the impact of newer generation TKI in patients who are in >CR1 at time of allo-

HSCT and needs to be studied prospectively. MRD positivity before allo-HSCT has traditionally

been considered to be a poor prognostic factor for relapse and survival [37]. Newer generation

TKI’s appears to improve prognosis for high-risk patients but this need to be proven in

appropriately powerd prospective trials [22, 24] [15, 18, 21]. [29, 30].
This review has certain limitations. First, due to a lack of prospective, randomized data, we

included many retrospective studies, most of which had a small sample size and limited follow-

up period especially for newer generation TKI. Second, the dose, initiation timing and duration

of TKI administration were variable amongst studies leading to a lack of standardization. Lastly,

decade in which patient underwent allo-HSCT, patient’s personal choice and physician’s

preferences served as an important confounding factors in numerous studies.

In conclusion, imatinib maintenance after allo-HSCT contributed to improvement in long term

survival of Ph+ ALL compared to historical studies. Imatinib though failed to improve survival

in patients who were >CR1 at the time of drug administration. Imatinib given prophylactically

resulted in 30% lower incidence of molecular recurrence compared to pre-emptive use but the

long-term outcomes were not statistically different in both groups. Patients who became MRD

positive within 100 days of allo-HSCT had 46% chance of disease recurrence despite using

imatinib either through a prophylactic or pre-emptive approach. Through historical comparison

and lacking any direct comparison, dasatinib appears to have better survival outcomes especially

in MRD positive patients. Larger, appropriately designed, prospective, randomised studies are

needed to study unsettled questions such as direct comparison of various TKI to explore most

effective agent, strategy of patient selection, dose and optimal duration for prophylaxis.
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Figure 1 - PRISMA Flow chart

 Figure 2: Recommendation for TKI Clinical use:

Ph +ve ALL (adults)

Pre-transplant risk Allo-HSCT

assessment
Post-transplant risk

MRDS Status TKI Resistance / MRD +ve or MRD -ve and Low
Mutation Positive High relapse risk relapse risk

Negative Positive Negative

High relapse Risk: Low Relapse risk

Strongly recommend Pre-emptive use
Low Risk High Risk Low Risk prophylactic TKI preferred
Prefer 2nd Gen TKI
Q4 week monitoring for
MRD monitoring
MRD status/relapse
(High Risk but +ive GVHD (peripheral blood
Significant GI symptoms Quantitative
Consider Pre-emptive TKI) BCR/ABL PCR)
monthly

Use 6 months to 1 year after MRD -ve

MRD negative

Use 6 months
to 1 year
Table No. 1: Prospective studies using Imatinib after AlloHSCT in Ph +ve ALL.
No of Duration
Author, Start Dose Donor Type of
No N Conditioning Regimen Pts on Strategy (median) OS DFS AE
Year (mo) (mg/day) Source Transplant
TKI Range

DFS 5 yrs -
83.9%
26 S-1 YR,R- 5 Yr OS
Prophylactic 1.6mo 400-600 CR=81% at
>CR1=3 6.7m 80%
30.3m GI intolrence n=6
Relapse= 2%, Hematotoxicity n=5
Pfeifer, MAR-TBI, BM MRD
1 54 >CR1=40% GVHD n=2;
2013 CY;TBI,VP16:TBI,FLU PB MUD
DFS 5 yrs - Imatinib dc = 67-
60.4% 71%
29 Pre- S-1 YR,R- 5 Yr OS CR=78% at
2.3mo 400-600
>CR1=2 emptively 4.2mo 74.5% 32.4m
relapse 17%
>CR1=40%
Neutropenia = 43%
Thrombocytopenia
=43%
62 Pre-emptive BCR-ABL 5 Yr DFS= 81.5%
5 Yr OS = Edema= 23%;
MAR-BUCY >CR1 & 2.3mo 300-400 Negtive -3 5 Yr
PBSCT 86.7% Nausea=35%
=12 Prophylactic mo relapse=10.2%
Chen, (n= 9) MRD Possibly unrelated
2 82 >CR1 OS HR=2.7
2012 BMT+PBSCT MUD major sideaffects-11
(n=73) pts

5 Yr OS = 5 Yr DFS= 33.5%
MAr-TBI/CY 20 NR NR non-TKI NR NR
34.3% 5 Yr relapse=
33.1%

Decreased
3 Yr OSS = mortality MRD
Grade II GVHD 53%;
Ram, 18 12mo BMT 62%;For HR=0.3 P value (n=17)
3 51 NMAR-Fludarabine,TBI Prophylactic 1/2mo 200-600 GI-2,Pleural effusion
2011 >CR1=4 (3-50m) PBSC MRD - 0.03,Relapse-MUD
-1
ve=73% 21% (n=3)
>CR1=1.5yr
os=25%
relapse (n=3), severe
1 year chronic GVHD (n=2),
<50(MAR) -
scheduled.9 MRD grade 3-4 toxicity
Ribera, TBI,Cyclophosphamide;>50 BM 1.7 yr
4 30 13 Prophylactic 3.9mo 200-400 MOs MUD 1.5 yr DFS=30% (n=2, hematologic in
2010 (NMAR)- PB OS=30%
average Autologous one patient and
Fludarabine,Melphalan
received gastrointestinal in
the other)
Prophylactic EFS 1.5 yrs -
Ottmann, 1.5- 1.5 yrs GI toxicity (n=5)
5 40 NR 27 & Pre- 400-600 NR NR NR 92% Relapse -
2009 3mo OS=92% GvHD (n=3)
emptive 0%
Emesis, N,
Increased AST/ALT
level
Anemia, Edema,
PB (n=10)
Carpenter, 22 MRD 1.3 yrs at Diarrhea; Grade 3/4-
6 27 MR-TBI BASED Prophylactic 1mo 260-400 12mo BM (n=4) Relapse rate
2007 >CR1=1 MUD OS =80% 17%;Tx terminated-
CB (n=1) 13%
16%
Thrombocytopenia
Neutropenia,
Anorexia

1-2 Yr DFS for

Autologous
1-2 Yr OS MRD -VE= 54.5-
Allogeneic GI discomfort n=1
Wassmann, MA-20;NMA-7;TBI-17;Non Pre- 12mo from BM for MRD - 91%
7 27 27 4.4mo 400-600 MRD edema and wt gain
2005 TBI-3 emptively negative pcr PB ve(n=14)= 1 yr DFS and OS
MUD n=1
80-100% for MRD
MisMUD
positive(n=13) =
8% and 23%
Abbreviations: AE, adverse effects, BM, bone marrow, BMT, bone marrow transplant, CB, cord blood, CR, complete remission, DFS, diease-free survival, GVHD, graft-versus-host disease, GI,
gastrointestinal, HCT, hematopoietic cell transplantation, HR, hazard ratio, IMI, imatinib, LFS, leukemia-free survival; MO, month, MRD, matched related donor, MUD, matched unrelated donor, N, total
number of patients, NR, not reported, OS, overall survival; PB, peripheral blood, PBSC, peripheral blood stem cell, TKI, tyrosine kinase inhibitor, Yr, year.
Table No. 2: Retrospective studies using Imatinib after AlloHSCT in Ph +ve ALL.
No of Dose
Author, Type of Start Donor Type of
No N Conditioning Regimen Pts on Strategy (mg/da Duration OS DFS AE
Year TKI (mo) Source Transplant
TKI y)
5 yrs LFS:
IMI
HR=0.44
(n=124) 5 yrs OS:
(0.26-0.74)
Brissot, DAS BM MRD HR=0.42
1 473 MA-375,NMA-98 157 Prophylactic 2.7mo NR NR P=0.002 NR
2015 (n=26) PBSC MUD (0.23-0.76)
5 yrs RI
NIL P=0.004
HR=0.4
(n=1)
p=0.01
3 Yr DFS=
Zhang, MA-TBI,CY-CR;TBI,CY,VP-16- 11 BM MRD 20%
2 44 IMI Prophylactic 2-3mo 400-600 6 mo 3 Yr OS= 40% NR
2013 Non CR >CR1=4 CB MUD 3 Yr relapse=
63.6%
fluid
MRD
S-1;r- retention
IMI 300 BM MUD OS-2 yrs - 44%, PFS-2 yrs-
Kebriaei, MA,Radiation based for 32 10.6 mo n=2
3 82 DAS Prophylactic 2mo (IMA) PB HID 5 yrs-33% 36%, 5 yrs-
2012 <50;MA only chemo>50 >CR1=11 (0.6–64 nausea n=2
(n=1) 70 (DAS) CB Mismatched >CR1=9% 31%>CR1=9%
MOs) cytopenia
cord
n=4
1 yr OS= 100% LFS was
2 yr OS= 66.7% 55.6% and
compared to 55.6% at 1
Pre-emptive
BM 33.3% and year and
Nishiwaki, 7 (n=4) & MRD (n=20)
4 34 MA-TBI-29; Non TBI-5 IMI NR 400-600 NR PB 29.6%, 33.3% and NR
2010 >CR1=3 Prophylactic MUD (n=14)
CB respectively, in 29.6% at 2
(n=3)
the non- years,
administration respectively
group (p=0.03) (p=0.29)
MRD 2 yrs
UCB
Burke, MA- MUD 2 yrs OS= RFS=100% anemia/
5 32 15 IMI Prophylactic 4mo 240-800 12 mo BM
2009 CY/TBI;CY,TBI,FLU;CY,VP16,TBI Partially 100% (P=0.28) (P=0.34) neutropenia
PBSC
MUD Relapse - 0%
Abbreviations: AE, adverse effects, BM, bone marrow, BMT, bone marrow transplant, CB, cord blood, CR, complete remission, DFS, diease-free survival, GVHD, graft-versus-host disease, GI,
gastrointestinal, HCT, hematopoietic cell transplantation, HR, hazard ratio, IMI, imatinib, LFS, leukemia-free survival; MO, month, MRD, matched related donor, MUD, matched unrelated donor, N, total
number of patients, NR, not reported, OS, overall survival; PB, peripheral blood, PBSC, peripheral blood stem cell, TKI, tyrosine kinase inhibitor, Yr, year.
Table No. 3: Use of Dastinib and Nilotinib after AlloHSCT in Acute Lymphoblastic Leukemia (Ph +ve)
No of
Duration
Author, Study Pts Type of Start Dose Type of Donor
No N Strategy (median) OS DFS AE
Year Design on TKI (mo) (mg/dl) Transplant Source
Range
TKI
Diarrhea
(grade 1)
Autologous: Pleural
Median OS:
Caocci, 3.78mo 15mo 2 MRD effusion
1 Retrospective 10 10 DAS Maintenance 50-100 22mo NR
2012 (1.63-9) (3-75mo) Allogenic: 8 MUD (grade 2)
(8-87mo)
Hematologic
toxicity (grade
2)
7mo Heme
15 DAS Pre-emptive 100 toxicities n=2
(1-22) 3 Yr LFS:
19/18 Pleural
Czyz, 11mo MRD 3 Yr OS: 88%
2 Retrospective (REP) AlloSCT effusion n=1,
2012 (2-39mo) MUD 87% Relapse
>CR1=5 5mo Infection n=2
4 DAS Prophylactic 100 rate: 10%
(2-6) Liver toxicities
n=1
Maher,
3 Retrospective 7 5 DAS Prophylactic 1.5mo 20-100 nl nl nl 1.4 yr OS PFS:100% nl
2016
Haplo sepsis = 1
OS: 10.2- DFS: 10.2-
Varda- 1.8mo CB nocardiasis =
200- 97.1mo 97.1mo
4 Bloom, Prospective 16 5 NILO Prophylactic (1.1- > or = 3mo AlloSCT SIB 1
300 (median (median
2016 6.67) MRD brain bleeding
35.5mo) 34.1mo)
MUD =1
2 Yr OS: 2 Yr Hemato-
69%, 4 Yr: PFS:56%, 4 toxicity = 2
46% Yr:42% LFT
MRD compared to compared to abnormalities
PB
Shimoni, 1.26mo 200- 12mo MUD entire entire =5
5 Prospective 22 16 NILO Prophylactic BM
2015 (1-5.26) 300 (0.3-65mo) Alternative transplant transplant Abd pain and
UCB
donors pt with pt with vomiting = 4
2 Yr OS: 2 Yr QTc
55%, 4 Yr: PFS:45%, 4 prolongation =
36% Yr:34% 1, CVA = 1
Heme
toxicities n=2
MRD = 5 Rash, pruritis,
Nagler, 1.26mo 7.5mo OS-77% at
6 Prospective 11 7 NILO Prophylactic 200mg AlloSCT Alternative Relapse: 0% vomiting,
2009 (1-1.63) (4-12 mo) 7.5 months
donor = 4 diarrhea=1
Increased
amylase n=1
Abbreviations: BM, bone marrow, CB, cord blood, DAS, dasatinib, DFS, disease-free survival, AlloHCT, allogeneic hematopoietic cell transplantation, MO, month, MRD, matched related donor, MUD,
matched unrelated donor, N, total number of patients, NILO, nilotinib, NR, not reported, OS, overall survival; PB, peripheral blood, PFS, progression-free survival, SIB, sibling, TKI, tyrosine kinase
inhibitor, UCB, umbilical cord blood, Yr, year.
Table No. 4 – Ongoing studies for relapse prevention in Ph+ve ALL
Agent Study Phase Inclusion Criteria Clinical Trial Number
Ph +ve ALL resistant to
Ponatinib II dasatinib/nilotinib or NCT01207440
has T3151 mutation

Hyper CVAD + Previously untreated

II NCT00390793
dasatinib Ph +ve ALL

Hyper CVAD + Previously untreated

II NCT01424982
ponatinib Ph +ve ALL

Dasatinib & Previously untreated

II NCT02744768
blinatumomab Ph +ve ALL

Ph + ve ALL –
Bosutinib +
Relapsed/Refractory.
inotuzumab I and II NCT02311998
New diagnosis of
ozogamicin
ALL>60 yrs
Ibrutinib +
Ph+ve ALL- New
dasatinib + I NCT02815059
diagnosis>60 yrs
prednisone
Relapsed or refractory
Abl 001 I NCT02081378
Ph+ve ALL
Ruxolitinib +
Previously untreated
dasatinib + I NCT02494882
Ph+ve ALL
dexamethasone

Nivolumab + Relapsed/Refractory
Ib NCT02819804
dasatinib ALL