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Targeting of FLT3 AML
Even if a clinician has the results of FLT3 mutation test- ing prior to initiation of therapy, a superior alternative to a venetoclax-based regimen that makes use of FLT3 inhibitors has not yet been identified. The combination of azacitidine and sorafenib was studied in a phase II trial and has a 2A recommendation in the most recent National Comprehensive Cancer Network (NCCN) guidelines, but is unlikely to outperform a venetoclax-based regimen due to sorafenib’s limited activity against FLT3.26,27 More potent FLT3 inhibitors such as gilteritinib have not been approved for use in the upfront setting and are unlikely to succeed as monotherapy at this early stage due to the rel- atively low mFLT3 allelic burden.28 It is only with the selective pressure of other therapies that the hardier mFLT3 clones come to dominate the tumor bulk.29 Currently, the discovery of a FLT3 mutation in an unfit or elderly patient receiving a standard of care venetoclax- based regimen is a cause for concern, but one for which there is as yet no evidence-based response.
Consolidative strategies: chemotherapy or allogeneic transplant?
The next dilemma that the treating clinician faces in the management of mFLT3 AML is determining the most appropriate consolidative therapy. For the fit patient who received intensive induction with 7+3+midostaurin, should they proceed with consolidative high-dose cytara- bine and midostaurin or alloHSCT?
This question is one of risk and prognosis. There is gen- eral agreement that alloHSCT is most beneficial in patients with AML who are at the highest risk of relapse. FLT3 is a bad actor, but the degree to which it impacts prognosis (and therefore the decision to pursue alloHSCT) may depend upon the specific characteristics of the FLT3 mutation and the company it keeps. In the 2017 European LeukemiaNet (ELN) guidelines’ risk classification system, FLT3-ITD allelic ratio (mut/WT threshold of 0.5) is com- bined with NPM1 mutation status into a single risk vari- able with three levels.30 Patients with a low FLT3-ITD allelic ratio and mutated NPM1 are categorized as favor- able, whereas a high allelic ratio and WT NPM1 are cate- gorized as adverse risk. The other two combinations fall within the intermediate category.
This risk classification system was recently validated in a retrospective analysis of the RATIFY trial.23 This study found a clear benefit for alloHSCT in patients with adverse risk AML (i.e., high allelic ratio mFLT3-ITD and NPM1 WT) in first complete remission (CR), but no differ- ence in outcomes for favorable and intermediate risk mFLT3 AML. These findings stand in contrast to a sub- stantial body of evidence demonstrating a survival benefit for alloHSCT in patients with mFLT3 without regard for FLT3 characteristics or co-mutations.31-36 There are other considerations not included in the guidelines, however, that may account for these discrepant findings.
First, FLT3-ITD have other prognostic characteristics other than allelic ratio. ITD consist of in-frame duplica- tions in exons 14 and 15 and they vary significantly in length. Shorter ITD occupy the JMD (70%) alone while longer ITD extend beyond the JMD and encroach upon the TKD.37,38 The JMD has an autoinhibitory function that is disabled with the insertion of an ITD leading to consti- tutive activation.39 FLT3-ITD AML with longer ITD length and higher mutant allelic ratio at diagnosis are associated with worse clinical outcomes and may be less responsive to FLT3 inhibitors.28,34,40-43
Second, determining the mFLT3 allelic ratio is not straightforward. FLT3-ITD are detected and characterized using polymerase chain reaction (PCR). Shorter ITD are transcribed more efficiently than longer ones, so longer ITD lead to underestimation of the true mutant allelic ratio; this phenomenon is known as PCR bias.44,45 Therefore, a patient harboring a long ITD is more likely to have a low mutant allelic ratio and to be classified as low- risk, when in fact, they may be high-risk and would ben- efit from an aggressive consolidating strategy. To compli- cate matters further, mFLT3 is a polyclonal disease and some patients have more than one ITD variant.
Third, the ELN guidelines recognize that the prognosis of FLT3 AML may be modulated by co-mutations such as NPM1, but there are other pertinent mutations that are not incorporated into the guidelines. For example, muta- tions in FLT3, NPM1 and DNMT3A tend to cluster togeth- er more frequently than would be expected by chance alone.46 AML bearing mutations in all three genes (so called ‘triple-mutant AML’) are biologically distinct and have dismal prognoses.3,47,48 By ELN guidelines, these patients might be classified as favorable risk, when in fact, they may belong in the adverse-risk category. This phe- nomenon has recently been recognized and transplant outcomes have not been specifically reported, but follow- ing the principle that adverse-risk AML benefits most from alloHSCT, this subset should be considered for alloHSCT.
In our practice, we routinely pursue alloHSCT for patients with mFLT3 AML. Of course, other factors ulti- mately influence the decision to transplant, such as the patient’s medical co-morbidities or difficulties in finding a suitable donor. With a better understanding of the prog- nostic significance of specific FLT3 characteristics and co- mutations, a low risk population may be identified that does not need alloHSCT.
Post-transplant maintenance
Finally, is there a role for targeting FLT3 as maintenance? This is an area of intense interest, but for which equipoise remains. In the phase II SORMAIN study, post-transplant maintenance with sorafenib was compared to placebo and showed an overall survival (OS) benefit (HR=0.447, P=0.03), but a major limitation of this study was that patients had not received pre-transplant treatment with a FLT3 inhibitor.49 In the era of upfront FLT3 inhibition, this is likely to be a rare circumstance. Another phase II study of post-transplant midostaurin maintenance compared to placebo demonstrated relapse rates of 11% and 24%, respectively, but the study was not statistically powered to show a difference (P=0.34) and therefore was only able to conclude that maintenance therapy was safe.50 In a post- hoc analysis, patients with greater inhibition of FLT3 had improved survival outcomes compared to standard of care, suggesting that maintenance with a FLT3 inhibitor may have clinical benefit.
The relapsed/refractory setting
Relapsed or refractory (R/R) mFLT3 AML is overwhelm- ingly unresponsive to salvage chemotherapy. In the phase III ADMIRAL trial, patients with R/R mFLT3 AML were randomized to single agent gilteritinib or salvage chemotherapy. The percentages of patients with complete remission and full or partial hematologic recovery were 34% and 15.3% (risk difference 18.6%, 95% confidence
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