Treatment of older adults with FLT3-mutated AML: Emerging paradigms and the role of frontline FLT3 inhibitors

Abstract

FLT3 is the most frequently mutated gene in acute myeloid leukemia (AML), with FLT3 internal tandem duplication (ITD) mutations being associated with a more aggressive clinical course. While two large, randomized clinical trials have shown a survival benefit with the frontline use of an oral FLT3 inhibitor (midostaurin or quizartinib) in patients with FLT3-mutated AML, the role of FLT3 inhibitors in older adults with newly diagnosed FLT3-mutated AML remains unclear. A definitive improvement in survival has not been observed in intensively treated patients over 60 years of age receiving frontline FLT3 inhibitors. Furthermore, many patients with FLT3-mutated AML are unsuitable for intensive chemotherapy due to age and/or comorbidities, and this population represents a particular unmet need. For these older patients who are unfit for intensive approaches, azacitidine + venetoclax is a new standard of care and is used by many clinicians irrespective of FLT3 mutation status. However, FLT3-ITD mutations confer resistance to venetoclax and are a well-established mechanism of relapse to lower-intensity venetoclax-based regimens, leading to short durations of remission and poor survival. Preclinical and clinical data suggest synergy between FLT3 inhibitors and venetoclax, providing rationale for their combination. Novel strategies to safely incorporate FLT3 inhibitors into the standard hypomethylating agent + venetoclax backbone are now being explored in this older, less fit population with newly diagnosed FLT3-mutated AML, with encouraging early results. Herein, we discuss the frontline use of FLT3 inhibitors in older adults with FLT3-mutated AML, including the potential role of FLT3 inhibitors in combination with intensive chemotherapy and as part of novel, lower-intensity doublet and triplet regimens in this older population.

Fig. 1. Incidence of FLT3-ITD-mutated AML by age.

While the proportion of AML cases harboring a FLT3-ITD mutation decreases with age, the absolute incidence of FLT3-ITD-mutated AML increases with age, driven by overall higher incidences of new AML cases in older patients. Data adapted from Nagel et al. 2017, Schneider et al. 2012, and SEER database [–25].

Fig. 2. Theoretical disease trajectories of FLT3-mutated AML with different treatment approaches.

When treated with a doublet regimen of HMA plus venetoclax (top panel), a population of the FLT3-mutated subclone persists and contributes to relapse. Sequential therapy with gilteritinib is non-curative even in responding patients, and eventually resistance mechanisms contribute to relapse. A triplet regimen of HMA plus venetoclax plus a FLT3 inhibitor (bottom panel) has added synergy that may lead to longer, more durable responses, and possibly cure. The addition of a FLT3 inhibitor not only targets the FLT3-mutated clone, but some FLT3 inhibitors have been shown to increase the sensitivity of leukemia cells to gilteritinib by promoting a more pro-apoptotic phenotype.