Clinical and molecular response of AML harboring non-canonical FLT3 N676K driver mutations to contemporary FLT3 inhibitors

Abstract

The treatment of acute myeloid leukemia (AML) has been enhanced by the development and regulatory approval of a series of novel agents, including midostaurin and gilteritinib (FLT3 inhibitors), venetoclax (BCL2 inhibitor), ivosidenib (IDH1 inhibitor), and enasidenib (IDH2 inhibitor). A difficulty that has arisen in the era of molecular therapies, however, is determining the efficacy of these agents for patients with AML harboring atypical driver mutations. The non-canonical FLT3 p.N676K variant was initially described as an acquired resistance mechanism in patients with FLT3 internal tandem duplication (ITD) mutations who were treated with midostaurin. Clinical data from patients with the FLT3 N676K mutations are limited. Here, we detail our experience caring for nine different patients with AML harboring FLT3 N676K at the University of Chicago. Seven of nine (78%) individuals received intensive induction chemotherapy, with FLT3 inhibitors utilized in three patients upfront and five patients during subsequent lines of treatment. With the use of FLT3 inhibitors, we noted reduction, and in some instances, complete molecular suppression of detectable FLT3 N676K variant allele fraction (VAF) on NGS, underscoring the activity of FLT3 inhibitors in this population regardless of line of therapy. Individuals with FLT3 N676K-mutated AML who received FLT3 inhibitors had longer median survival (940 days) than those who did not (408 days), however, the difference was not significant likely due to small size of the study (p = 0.2). The presence of concurrent canonical FLT3 mutations was associated with loss of treatment response. In silico visualization models of the FLT3 tyrosine kinase domain in the presence of gilteritinib demonstrate that the mechanism of N676K-mediated resistance is not due to disruption of FLT3 inhibitor binding at the ATP-binding site but rather influenced by other allosteric forces on protein structure. In conclusion, this is the largest study to date demonstrating that the atypical FLT3 N676K driver mutation is sensitive to contemporary FLT3 inhibitors, such as midostaurin and gilteritinib. Our data suggest that FLT3 inhibitors should be included in both the upfront induction setting as well as in the relapsed/refractory setting for patients harboring the FLT3 N676K mutation.