Abstract
Gilteritinib is a potent and selective FLT3 kinase inhibitor with single-agent clinical efficacy in relapsed/refractory FLT3-mutated acute myeloid leukemia (AML). In this context, however, gilteritinib is not curative, and response duration is limited by the development of secondary resistance. To evaluate resistance mechanisms, we analyzed baseline and progression samples from patients treated on clinical trials of gilteritinib. Targeted next-generation sequencing at the time of AML progression on gilteritinib identified treatment-emergent mutations that activate RAS/MAPK pathway signaling, most commonly in NRAS or KRAS. Less frequently, secondary FLT3-F691L gatekeeper mutations or BCR-ABL1 fusions were identified at progression. Single-cell targeted DNA sequencing revealed diverse patterns of clonal selection and evolution in response to FLT3 inhibition, including the emergence of RAS mutations in FLT3-mutated subclones, the expansion of alternative wild-type FLT3 subclones, or both patterns simultaneously. These data illustrate dynamic and complex changes in clonal architecture underlying response and resistance to mutation-selective tyrosine kinase inhibitor therapy in AML. SIGNIFICANCE: Comprehensive serial genotyping of AML specimens from patients treated with the selective FLT3 inhibitor gilteritinib demonstrates that complex, heterogeneous patterns of clonal selection and evolution mediate clinical resistance to tyrosine kinase inhibition in FLT3-mutated AML. Our data support the development of combinatorial targeted therapeutic approaches for advanced AML.See related commentary by Wei and Roberts, p. 998.This article is highlighted in the In This Issue feature, p. 983.
Highlights
Driver mutations in the class III receptor tyrosine kinase FLT3 occur in approximately one third of patients with acute myeloid leukemia (AML; ref. 1)
Fifty-nine patients with relapsed and/or refractory FLT3mutated AML who were enrolled on clinical trials of singleagent gilteritinib (NCT02014558, NCT02421939) at three institutions, received gilteritinib at FLT3-inhibitory doses (≥80 mg/day; ref. 14), and separately consented for institutional tissue banking protocols were considered for inclusion in our cohort
Until recently AML has been treated with nonspecific chemotherapy, but targeted therapies are being rapidly developed and approved
Summary
Driver mutations in the class III receptor tyrosine kinase FLT3 occur in approximately one third of patients with acute myeloid leukemia (AML; ref. 1). As responses to salvage chemotherapy in patients with relapsed and/or refractory FLT3-ITD–mutated AML are suboptimal [6], a number of small-molecule kinase inhibitors targeting FLT3 have been developed [7,8,9,10,11,12]. The addition of the multikinase inhibitor midostaurin to front-line chemotherapy has been shown to improve survival in FLT3-mutated AML [13]. In the relapsed/refractory setting, the potent and selective second-generation FLT3 inhibitors gilteritinib, quizartinib, and crenolanib have demonstrated promising activity as monotherapies [12, 14,15,16,17]. In the p ivotal phase III ADMIRAL trial (NCT02421939), which compared gilteritinib with salvage chemotherapy in patients with relapsed and/or refractory FLT3-mutant AML, gilteritinib was associated with a significant improvement in overall survival [12]. Based on response rates from ADMIRAL and prior single-agent trials, gilteritinib was recently approved by the FDA
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