Are FLT3 inhibitors likely to improve FLT3-mutated acute myeloid leukemia in the foreseeable future?

Abstract

9 ISSN 2045-1393 10.2217/IJH.12.32 © 2013 Future Medicine Ltd Int. J. Hematol. Oncol. (2013) 2(1), 9–11 Approximately one-quarter of acute myeloid leukemia (AML) cases are characterized by an internal tandem duplication (ITD) mutation in the FLT3 gene. Patients with FLT3-ITD AML carry an especially poor prognosis, with few patients surviving 5 years or longer [1,2]. Point mutations at the D835 locus on the FLT3 gene occur in approximately 8% of adult AML cases, although the prognostic value of de novo FLT3 D835 mutations remains a topic of debate [3–5]. A growing number of smallmolecule tyrosine kinase inhibitors (TKIs) are being developed as FLT3 inhibitors and used in clinical trials, primarily for the treatment of FLT3-ITD AML. Early failures of FLT3 inhibitors in clinical trials prompted speculation that the ITD may be a passenger mutation. However, in a Phase II study of the FLT3 inhibitor quizartinib, there was a population of FLT3-ITD AML patients who initially exhibited blast reduction to <5% but later relapsed. In this group of patients, the resistance to quizartinib was conferred by consistent point mutations at two specific amino acid residues in the FLT3 kinase domain, including the D835 residue [6]. This discovery of a reproducible, adaptive resistance mechanism to TKI treatment suggests that the FLT3-ITD represents a driver mutation in AML. A randomized trial of FLT3-mutated patients in f irst relapse receiving chemotherapy with or without the TKI lestaurtinib showed no overall survival benefit in the lestaurtinib arm [7]. Only 27% of patients receiving lestaurtinib achieved sustained, adequate FLT3 inhibition, due, at least in part, to the complex pharmacokinetics of this drug. Nevertheless, the study was encouraging insofar as there was a high degree of correlation between FLT3 inhibition and remission [7,8]. The newer FLT3 inhibitor quizartinib is particularly potent and selective, and these characteristics will likely help this drug overcome some of the challenges posed by earlier FLT3 inhibitors [9]. In the quizartinib Phase II study, the composite complete remission rate among relapsed FLT3-ITD AML patients aged ≥60 years was 54%, with an additional 17% of patients achieving a partial response [10].