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A.J. Ambinder and M. Levis
ic cells.6 FL is produced by a much broader array of cell types, including lymphocytes, HSC, and BM stromal cells, and functions as a growth factor that stimulates myelopoiesis. The ubiquity of FLT3 expression on MPP and its role as a stimulant of myelopoiesis identifies this receptor as an obvious candidate driver of leukemogene- sis.
Thirty percent of patients with AML harbor mutations in FLT3 (mFLT3) that result in constitutive activation of the receptor and its downstream pathways.7,8 The two canonical varieties of mutation are internal tandem dupli- cations (ITD), which typically occur in or near the jux- tamembrane domain (JMD), and point mutations in the tyrosine kinase domain 2 (TKD). ITD and TKD mutations occur in about 23% and 7% of AML patients, respectively. The potential for FLT3 as a driver of leukemogenesis goes beyond these two mutation types. Non-canonical activat- ing mutations are now being detected through next-gener- ation sequencing (NGS) at diagnosis or are emerging in the setting of FLT3 inhibition.9-11 Even in cases in which no FLT3 coding mutation is detectable, the receptor can be overexpressed on the cell surface of leukemic blasts and contributes to the survival and proliferation of the leukemic clone.12-17 Furthermore, chemotherapy-induced aplasia stimulates the BM stroma to produce FL, fueling the recovery, selection, and expansion of any AML clone that is positioned to take advantage of it.
The pervasiveness of aberrant FLT3 signaling across the spectrum of AML subtypes defies straightforward classifi- cation. FLT3 mutations are most common in AML with normal cytogenetics, but may also occur in the setting of other disease-defining genetic lesions such as inv(16), t(8;21) and t(15,17). They frequently co-occur with other driver mutations such as DNMT3A, NPM1, and IDH1/2.3 A FLT3 mutation is almost invariably the final mutation in a series of genetic and epigenetic ‘hits’, propelling the affected clone from a preleukemic state to full-blown leukemia. While FLT3 mutations may be detected in almost any AML subtype, they are rarely observed in other myeloid neoplasms or clonal states.18 FLT3 muta- tions are uniquely specific to the AML phenotype and their signature is one of hyper-proliferation and worsened outcomes.
Collectively, these features provide ample rationale for targeting the FLT3 receptor. It is also a particularly appeal- ing drug target because it appears to be non-essential. In mice, knock out of FL or FLT3 is non-lethal, but it does reduce the capacity to repopulate an aplastic marrow and results in the marked absence of NK and dendritic cells.6,19,20 This thinking has led to the incorporation of FLT3 mutation status into every aspect of AML manage- ment and to the investigation of nearly a dozen FLT3 inhibitors in clinical trials across the spectrum of the dis- ease’s trajectory. The resulting successes have confirmed the centrality of aberrant FLT3 signaling to the pathogen- esis of AML and highlight the importance of addressing unfettered FLT3 signaling throughout the disease’s trajec- tory.
Current standard of care for acute myeloid leukemia and for FLT3-mutated acute myeloid leukemia
With the exception of acute promyelocytic leukemia (APL), the first branching point in the decision tree for the management of de novo AML is determined by a patient’s fitness for intensive chemotherapy and their age. For
those who are fit, induction with conventional chemotherapy (most commonly 7+3 or CPX-351) is stan- dard, whereas those who are elderly or unfit are treated with an HMA or low-dose cytarabine and venetoclax, if the latter is available. At most centers, treating clinicians will not yet have the results of FLT3 mutation testing at the time that this decision is made. So how should a clini- cian respond when a patient who has already embarked on a therapeutic path is found to have mFLT3?
The fit patient
Historically, the standard of care for fit patients with mFLT3 AML was conventional chemotherapy alone. Patients with mFLT3-ITD AML respond to induction chemotherapy in a manner similar to their WT counter- parts, but their remissions are shorter and their rates of relapse are higher. The discrepancy between remission rates and outcomes is explained by the polyclonal nature of new-onset AML and the relatively low proportion of blasts that harbor mFLT3 at this stage. Chemotherapy induces aplasia and mFLT3 clones eventually expand, pos- sibly driven by increasing expression of FL during succes- sive rounds of aplasia.21 The relapsed leukemia that emerges after traditional chemotherapy is oligoclonal and more “addicted” to FLT3 signaling with a larger proportion of blasts harboring mFLT3.
The standard of care for fit patients with mFLT3 AML was re-defined by the phase III RATIFY trial, in which patients with mFLT3-ITD or mFLT3-TKD were random- ized to standard induction chemotherapy plus midostau- rin or chemotherapy alone. Midostaurin, a first generation FLT3 inhibitor, was administered on days 8 through 21 and was then included in subsequent cycles of consolida- tive chemotherapy and as maintenance. The addition of midostaurin resulted in higher rates of event-free survival (EFS) (8.2 vs. 3.0 months, P=0.002) and better overall sur- vival (OS) (HR 0.78, 95% confidence interval [CI], 0.63- 0.96) compared to chemotherapy alone.22 The addition of midostaurin appeared to benefit patients running the gamut of mFLT3 AML including those with ITD and TKD mutations, low or high allelic ratios, and in the presence or absence of other significant co-mutations.22,23 Midostaurin was approved in Europe for use in the induction, consoli- dation and maintenance phases, as administered in the RATIFY trial. In the US, however, it was only approved for use with induction and consolidation, reflecting the US Food and Drug Administration's uncertainty regarding the need for maintenance therapy. This question of whether midostaurin maintenance provides clinical bene- fit is complicated by the frequency with which these patients undergo allogeneic hematopoietic stem cell trans- plant (alloHSCT).
The unfit or elderly patient
For the unfit or elderly patient with de novo AML, vene- toclax-based regimens have become the new standard of care. The diminished role of traditional DNA-damaging chemotherapeutic agents as well as venetoclax’s novel mechanism of action led to some hope that these regi- mens might mitigate the negative prognostic significance of mFLT3. This does not seem to be the case. Recent evi- dence suggests that mFLT3 AML are less responsive to these regimens and that progression on these regimens is frequently driven by the acquisition or expansion of mFLT3 clones.24,25
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haematologica | 2021; 106(3)