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Commentary | Open Access | Volume 3 | Issue 1 | 2022 | DOI No.:
10.46439/stemcell.3.015

POST-ALLOGENEIC STEM CELL TRANSPLANT FLT3- TARGETED MAINTENANCE THERAPY: UPDATES
AND CONSIDERATIONS FOR CLINICAL PRACTICE

Jonathan Cohen1,2,#*, Richard T. Maziarz1,3

1Knight Cancer Institute, Oregon Health & Science University, Portland, OR USA

2Department of Pharmacy, Oregon Health & Science University, Portland,OR USA

3Center for Hematologic Malignancies,Oregon Health & Science
University,Portland, OR USA

#New address: University of Washington Medical Center/Seattle Cancer Care
Alliance, Seattle, WA USA

*Corresponding Author:
Jonathan Cohen
Knight Cancer Institute, Oregon Health
& Science University, Portland, OR USA
E-mail:cohenjon@uw.edu

Received date: May 18, 2022; Accepted date: May 25, 2022

Citation: Cohen J, Maziarz RT. Post-allogeneic stem cell transplant
FLT3-targeted maintenance therapy: updates and considerations for clinical
practice.Arch Stem Cell Ther. 2022;3(1):23-27.

Copyright: © 2022 Cohen J, et al. This is an open-access article distributed
under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution,and reproduction in any medium,provided the
original author and source are credited.

 

ABSTRACT

Acute myeloid leukemia (AML) is characterized by multiple molecular and
cytogenetic abnormalities, with increasing data to support clinical and
prognostic implications to guide clinical decision making. One of the most well
described mutations involves fms-like tyrosine kinase 3 (FLT3) that results in a
constitutively active tyrosine kinase and is generally associated with poor
prognosis involving shorter overall survival and higher rates of relapse.
Advancements in targeted therapies have greatly influenced available treatment
options in a landscape that has remained largely unchanged for the past five
decades. Tyrosine kinase inhibitors (TKI), specifically FLT3-targeted therapies,
are now integral treatment options for patients with this targetable mutation.
As allogeneic hematopoietic cell transplant (alloHCT) remains the primary
curative therapy for most adult AML patients, the goal is for eligible patients
to proceed to transplant. However, post-alloHCT relapse remains exceedingly high
even in patients achieving deep responses to therapy. Limited evaluation of
FLT3-targeted TKIs as post-alloHCT maintenance therapy in FLT3-positive patients
suggest improved outcomes and tolerable safety profiles, with ongoing studies
further investigating second-generation agents. Thus, this commentary aims to
review the role of postalloHCT FLT3-targeted maintenance therapy and
considerations for clinical practice.

 

KEYWORDS

Allogeneic stem cell transplant, FLT3, Maintenance

 

INTRODUCTION

Acute myeloid leukemia (AML) is estimated to account for about one-third of new
leukemia cases in 2022 [1,2]. AML is characterized by multiple molecular and
cytogenetic abnormalities, with data to support that these well-defined genomic
mutations have prognostic importance [3]. As a consequence of these detailed
characterizations of the AML genomic landscape, there has been an emergence of
molecularly targeted therapies over the past decade. Innovative therapy options
for AML are now emerging, amidst standards of care that have otherwise, remained
largely unchanged over the past 50 years [4]. However, despite these recent
advancements, outcomes remain poor with an estimated 5-year relative survival of
~25-30% [2].

Allogeneic hematopoietic cell transplant (alloHCT) remains the primary curative
therapy for most adult AML patients, particularly in those individuals who
achieve complete remission (CR), due in part to the immunologic benefit of the
associated graft versus leukemia (GVL) effect. However, relapse remains
exceedingly high in certain patient populations, such as in individuals with
treatment related AML, monosomal karyotype or complex cytogenetics on
presentation or those with detectable minimal residual disease (MRD) after
induction/consolidation therapy. Currently, high relapse risk populations are
also increasingly being identified upfront with next generation sequencing,
targeting known myeloid gene panels. One well-defined mutation in AML involves
the fms-like tyrosine kinase 3 (FLT3), occurring in 30% of adult AML patients
[5]. Generally, FLT3 AML has been associated with poor prognosis involving
shorter overall survival and higher rates of relapse, due in part to its role as
a driver mutation and contribution to possible clonal evolution [5-7]. As a
result, subjects with FLT3+ AML are generally considered for alloHCT. Given the
associated risk with FLT3-positivity, development of second-generation
FLT3-targeted therapies, and understanding of the critical nature of MRD status,
there is growing interest in continuation of FLT3-targeted therapies following
alloHCT in an effort to deepen remission and prevent relapse.

 

FLT3 MUTATIONS IN AML

 

Whole genome sequencing of multiple AML patient samples has revealed increasing
numbers of genetic mutations. However, the FLT3 gene remains one of the most
frequently identified mutated genes [8-10]. FLT3 mutations generally present
with either (1) inframe internal tandem duplication (ITD) or (2) point mutations
within the tyrosine kinase domain (TKD) [5]. Either phenotype results in
constitutive activity of the transmembrane tyrosine kinase, promoting aberrant
cell growth and survival. Internal tandem duplication is more prevalent (25% of
AML cases) and generally confers a more unfavorable prognosis compared to the
less well defined FLT3-TKD (5-10% of cases) [5]. Furthermore, higher degree of
FLT3-ITD allelic ratio confers increased risk with concomitant expression of
other mutations, namely NPM1 [4,5].

Comparative studies evaluating clonal evolution of patients with relapsed AML
suggest that FLT3-ITD mutations may likely confer a selective survival advantage
within the tumor microenvironment. One study reported persistent FLT3- ITD
clones in 75% of patients at the time of relapse [5,11]. These clinical findings
have supported the development of FLT3-targeted therapy with high specificity
and binding affinity (discussed below).

 

FLT3-TARGETED THERAPY

 

There are now several FLT3-targeted therapies available. Initial studies
evaluated use of first generation multi-targeted kinases including sunitinib and
sorafenib [5]. Both agents were evaluated in phase 1 or phase 2 studies with
mixed results given limited antileukemic activity and poorer tolerability as
single-agent therapy. Combination therapy with high-intensity chemotherapy also
had limited application to older patient populations after one study found no
improvement in survival and increased mortality due to infection [5]. However,
current guideline recommendations support use of sorafenib in combination with a
hypomethylating agent in patients who are FLT3-ITD positive and not candidates
for transplant nor able to receive high-intensity therapy [12].

The major breakthrough involving FLT3-targeted therapy was the phase 3
RATIFY/CALGB 10603 trial of midostaurin, another tyrosine kinase inhibitor (TKI)
that targets FLT3, in combination with conventional induction (7+3) chemotherapy
for the treatment of newly diagnosed FLT3-mutated AML. Improved event-free
survival (EFS; Hazard Ratio (HR) 0.78; P = 0.002) and overall survival (OS; HR
0.78; P = 0.009) was shown compared to conventional chemotherapy alone [5,13].
Many patients proceeded to alloHCT but in that study, patients in the RATIFY
trial did not continue midostaurin. However, despite the relative success of
midostaurin, relapse remained significant. Thus, more potent, second-generation
agents gilteritinib, crenolanib, and quizartinib have been developed and have
shown promise in relapsed/refractory FLT3+ AML and appear to remain effective as
single-agent therapy [5].

 

FLT3-TARGETED MAINTENANCE THERAPY POST-ALLOHCT

 

Given the significant findings related to peri-transplant MRD positive or
negative status and significant rates of relapse with FLT3+ AML, there has been
significant interest in ongoing FLT-directed maintenance therapy after alloHCT
while waiting to establish the donor GVL effect. Sorafenib was first evaluated
in a phase I doseescalation study by the Mass General Hospital group, in which
patients received sorafenib 45-120 days post alloHCT for up to 12 28-day cycles
[14]. Overall, 22 patients were enrolled, of which 3 relapsed (2 with primary
refractory AML prior to alloHCT; 1 in complete remission (CR) prior to alloHCT).
The majority of patients (n=19) were in CR1/CR2 prior to alloHCT with a 1-year
progression-free survival (PFS) and OS of 95% (90% CI, 76% to 99%) and 100%,
respectively [14]. A follow-up study conducted by Brunner and colleagues sought
to affirm the results of the phase I study. Overall, 26 patients received
sorafenib (n=16 included from the phase I study) compared to 55 controls [15].
Of note, a landmark analysis was conducted to include only control patients
alive at the median time of sorafenib initiation (n=43) to account for patients
with early relapse. In the entire cohort with sorafenib exposure as a
time-varying covariate, sorafenib patients experienced improved OS (HR 0.264;
P=0.021) and PFS (HR 0.25; P=0.016). In the landmark analysis, sorafenib
patients similarly had improved 2-year OS (81% vs. 62%; P=0.029), 2-year PFS
(82% vs 53%; P=0.0081) and decreased 2-year incidence of relapse (8.2% vs 37.7%;
P=0.0077). Although 42% of sorafenib patients discontinued therapy prior to 12
months, there was no difference in 2-year non-treatment related mortality (NRM;
9.8% vs 9.3%; P=0.82) or chronic graft-versus host disease (cGvHD rates; 55.5%
vs 37.2%; P=0.28). Since this time, other retrospective studies have similarly
suggested survival benefit and lower incidence of relapse with use of
maintenance sorafenib post-alloHCT [16-18].

Based on these initial observations, two randomized controlled trials of
maintenance sorafenib have been performed. The positive results have led to NCCN
and EBMT endorsement of sorafenib use post-alloHCT in AML patients with history
of FLT3-ITD in remission [12,19,20]. Specifically, the phase II SORMAIN trial
was a randomized, double-blind, placebo controlled study of postalloHCT
sorafenib maintenance starting D+60 to D+100 in patients with a history of
FLT3-ITD with complete hematologic remission (bone marrow blasts <5%) [21].
Patients were randomized to receive 24-month course of either sorafenib (400 mg
twice daily, reflecting maximum tolerated dose from prior retrospective studies)
or placebo. Overall, 83 patients were randomized (sorafenib n=43, placebo n=40).
The study was closed early due to slow accrual; however, results remained
encouraging with an estimated probability of 24-month RFS and 24-month OS of 85%
versus 53% and 90.5% (95% CI, 77% to 96%) versus 66.2% (95% CI, 49% to 79%) for
sorafenib versus placebo, respectively (HR of death 0.241; 95% CI 8% to 74%;
log-rank P=0.007). A larger open label phase III trial was conducted randomizing
patients to either sorafenib or no maintenance therapy 30-60 days post-alloHCT
in patients with hematopoietic recovery by D+60. Overall, 202 patients were
randomized (sorafenib n=100, placebo n=102).22 Patients who received sorafenib
had lower incidence of relapse compared to the control group 1-year post-alloHCT
(7% (95% CI 3.1% to 13.1%) versus 24.5% (95% CI 16.6% to 33.2%); HR 0.25 (95% CI
0.11 to 0.57; P = 0.0010). Sorafenib appeared to be better tolerated than
previously reported in the phase II study, with similar rates of aGvHD and cGvHD
between sorafenib and control groups (23% versus 21% and 18% versus 17%,
respectively).

Although the majority of post-alloHCT FLT3-targeted maintenance therapy
describes sorafenib, there are emerging data that support use of midostaurin.
The phase II AMLSG 16-10 trial evaluated use of midostaurin in combination with
intensive chemotherapy similar to the RATIFY trial, but permitted continuation
of single-agent midostaurin as maintenance therapy starting as soon as 30 days
post-alloHCT [23]. Of the 284 patients who received induction therapy, 75
received post-alloHCT maintenance therapy. Compared to non-transplant patients
(patients in CR who received high dose cytaribine) receiving maintenance
therapy, alloHCT recipients experienced less relapse at 2 years (13.3% versus
43.5%, respectively). Additionally, alloHCT patients who started maintenance
therapy prior to D+100, were event-free at D+100, and in CR1/Cri prior to
alloHCT had significantly better EFS (P=0.01, univariable; P=0.004,
multivariable) and OS (P=0.02, univariable; P=0.01, multivariable) compared to
patients who started maintenance therapy after D+100. Findings from AMLSG 16-10
affirmed the importance of MRD status peri-alloHCT and suggested that early
initiation (prior to D+100) of maintenance therapy should be implemented, if
possible. More recently, the phase II RADIUS trial was the first randomized
control trial conducted to assess postalloHCT maintenance midostaurin [24].
RADIUS was an openlabel trial that randomized patients to either no maintenance
or midostaurin starting D+28 to D+60 for 12 4-week cycles. The results
demonstrated a trend to improved RFS at 18 months (HR 0.46 (95% CI 0.12- to
1.86), P =0.27) and OS at 24 months (HR 0.58 (95% CI 0.19 to 1.79), P=0.3418),
with estimated RFS and OS of 89% (95% CI 69% to 96%) versus 76% (95% CI 54% to
88%) and 85% versus 76% for midostaurin and the control group, respectively. The
authors note that a statistically significant improved RFS was observed in the
50% of patients who received midostaurin that achieved inhibition of FLT3
phosphorylation to <70% of baseline. The inability to achieve adequate
inhibition through the entire patient cohort may have been impacted from adverse
effects related to midostaurin, with 63% of patients requiring dose adjustments
and 8 patients requiring discontinuation of therapy. Also, it was noted that the
control group (76% OS) had better outcomes than otherwise seen historically or
in other FLT3 post-alloHCT studies, potentially influencing the outcomes seen.

A recent systematic review and meta-analysis assessing postalloHCT FLT3-targeted
therapies supported improved outcomes with generally well-tolerated adverse
effects and no overt safety concerns related to post-transplant complications
[25]. The analysis included 680 patients from 7 studies (5 sorafenib and 2
midostaurin). Relapse was significantly improved with use of FLT3 maintenance
therapy compared to placebo (pooled risk ratio (RR) = 0.35 (95% CI 0.23 to
0.51), P<0.001). Pooled RR for RFS (RR=0.48 (95% CI 0.37 to 0.61), P<0.001) and
OS (RR=0.48 (95% CI 0.36 to 0.64), P<0.001) were also significantly improved.
There was no difference in NRM or GvHD. Similarly, a large-scale retrospective
review across 8 countries involving 1208 patients identified 219 patients who
received FLT3-targeted maintenance therapy [26]. Maintenance therapy observed
improved RFS (adjusted HR 0.57 (95% CI 0.34 to 0.94), P<0.05) and OS (adjusted
HR 0.50 (95% CI 0.28 to 0.89), P<0.05).

Second generation FLT3 inhibitors with greater specificity may be ideal for
post-alloHCT maintenance therapy. Currently, only gilteritinib is approved in
the United States for use in relapsed/ refractory disease and is currently under
investigation for use as maintenance therapy in the phase III BMT CTN 1506 trial
(NCT02997202), with analysis pending [27]. There are significant differences in
coordination of this research trial as opposed to the prior studies (e.g.
Sormain, Radius). With the FDA label for midostaurin as part of induction and
consolidation therapy for FLT3- ITD+AML patients, most subjects will have
already been exposed to a TKI. This specific post-alloHCT trial randomizes
patients, after engraftment, to placebo vs gilteritinib. Maintenance continues
for two years after alloHCT. The primary objective is to compare RFS between the
gilteritinib and the placebo arms with secondary objectives of tolerability, OS,
aGVHD and exploratory objectives of quality of life analysis, healthcare
resource utilization, study drug pharmacokinetics, and determination of FLT3
status at relapse.

Other studies examining second generation FLT3 inhibitors are smaller in scope.
A phase I dose escalation study of quizartinib included 13 post-alloHCT patients
with planned maintenance therapy of up to 24 months [28]. One patient relapsed,
with 5 patients completing the full 24 months of therapy and 4 patients
discontinuing therapy due to adverse effects. Subset analysis of the phase III
QuaANTUM-R study of quizartinib in relapse/refractory AML suggests that patients
who receive quizartinib may be more likely to proceed to alloHCT. Patients who
received alloHCT had improved median OS compared to those who did not (12.2
months versus 4.4 months, respectively; HR 0.315 (95% CI 0.233 to 0.427)) [29].
Patients with composite CR prior to alloHCT also had improved survival (20.1
months versus 8.8 months; HR 0.5066 (95% CI 0.296 to 0.864)). A proportion of
patients continued postalloHCT quizartinib and did not appear to have any overt
safety or tolerability concerns. Finally, there is limited experience with
crenolanib, with ongoing trials assessing use as maintenance therapy
(NCT02400255, NCT03258931).

 

FUTURE CONSIDERATIONS

 

There remain several ongoing clinical trials seeking to further investigate use
of FLT3-targeted therapy as post-alloHCT maintenance therapy. Encouraging
results thus far suggest improved survival and lower incidence of relapse with
targeted maintenance therapy after alloHCT. The data obtained consistently
demonstrate that patients with CR prior to alloHCT with MRD- status appear to
have better outcomes. Early use of alloHCT maintenance therapy is supported,
recognizing that relapse often occurs early (<100 days) [24]. With the observed
apparent benefits of maintenance therapy and high risk of relapse in FLT3-ITD
patients, some ethical concerns may exist related to continued investigation
involving placebo, as carefully outlined by Levis et al [30]. Yet, with better
tolerability of the second generation TKIs used as maintenance therapy, less
patients may discontinue therapy or require dose reductions due to adverse
effects. Thus, it is important to weigh the risks and benefits of continued
maintenance therapy.

Finally, we must recognize that there are cost considerations which justify the
needs for ongoing clinical trials. AlloHCT is an expensive procedure. One recent
analysis of a payor claims data base revealed a median of ~$417,000 adjudicated
claims payments for the first year of coverage [31]. The Milliman group reported
charges of ~ $930,000 from 30 days prior to alloHCT through day 180 [32]. Thus,
it will be important to acknowledge the additional cost of TKI administration,
recognizing that in the trials that were discussed herein, that the maintenance
treatment extended for up to 2 years. These costs will be balanced against the
cost of relapse care (reinduction therapy, donor leukocyte infusion vs second
transplant) [33]. Specifically, recent available data re: Average Wholesale
Price (AWP) of the TKIs are worthy of examination: [34].

Drug Formulation/Unit Cost per Unit (AWP) Estimated Annual Cost† Midostaurin 25
mg capsule $213.90 $287,481.60 Sorafenib 200 mg tablet $221.93 $298,273.92
Gilteritinib 40 mg tablet $343.59 $346,338.72

†Annual cost estimated with full dose of specified drug (e.g. midostaurin 50 mg
twice daily, sorafenib 400 mg twice daily, or gilteritinib 120 mg daily) over 12
28-day cycles.

Health resource utilization analysis re: the cost of care is needed to best
understand what are the true optimal outcomes, analyses often extending beyond
RFS to quality-adjusted life years (QALY) gained by an intervention (focusing on
length of survival and healthrelated quality of life) and the increasingly
recognized, critical need for patient reported outcome (PRO) measures.

 

CONCLUSION

 

Routine use of FLT3-targeted post-alloHCT maintenance therapy continues to be an
area of interest and ongoing investigations. Guideline recommendations support
use of sorafenib as maintenance therapy in patients with a history of FLT3-
positive disease. Encouraging results suggest similar application of
midostaurin, with analysis of second-generation therapies expected to mature in
the near future. Patients in CR prior to alloHCT may be ideal candidates to
start early maintenance therapy in an effort to maintain MRD negativity, but it
is important to note that use of maintenance therapy is not benign given
potentially significant adverse effects and costs to the health care system.

 

AUTHOR CONTRIBUTIONS STATEMENT

 

The material included within the review has not been published elsewhere, by the
authors.

 

CONFLICT OF INTEREST

 

No current conflict of interest exists related to the content of this review, by
the authors.

 

FUNDING

 

This work was partially supported by the National Institutes of Health grant UG1
HL138658 to Dr. Richard T. Maziarz.

 



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