Treatment with FLT3 inhibitor in patients with FLT3-mutated acute myeloid leukemia is associated with development of secondary FLT3-tyrosine kinase domain mutations

Abstract

Background: FLT3-internal tandem duplication (ITD) mutations are found in approximately 30% of patients with acute myeloid leukemia (AML). FLT3 inhibitors have shown clinical activity in AML with FLT3-ITD, but responses are usually short-lived.

Methods: This study examined 69 FLT3-mutated patients with AML, who were treated with different FLT3 inhibitors to analyze emergence of new mutations.

Results: At baseline, 87% of patients had an ITD mutation, 7% had a D835/I836 mutation, and 6% had combined ITD and D835/I836 mutations. Responses occurred in 32% of patients, all with FLT3-ITD; none of the patients with D835/I836 or ITD+D835/I836 responded. Mutational assessment at the time of FLT3 inhibitor discontinuation showed that 68% of patients were unchanged, 10% had become undetectable, and 22% of patients progressed from a single ITD to have combined ITD+D835/I836 mutations. In those patients with unchanged FLT3 mutation at progression, the median survival was 5 months, whereas in those with undetectable and with combined ITD+D835/I836 mutations, the median survival was 7 months, respectively.

Conclusions: These data confirm in vitro observations that a secondary tyrosine kinase domain mutation may arise after the use of FLT3 inhibitors in patients with single FLT3-ITD mutated AML, a phenomenon that is associated with resistance and a poor prognosis.

Keywords: FLT3 inhibitors; FLT3-ITD; FLT3-TKD; acute myeloid leukemia; secondary FLT3 mutations.

Figure 1. Survival Curves

A: Overall Survival from beginning of treatment (Median 6 months), B: Overall Survival from FLT3 Inhibitor treatment discontinuation (Median 3 months), C: Survival Patients Transplanted (Median 7 Months), D: Survival Patients with Undetectable Mutation After Treatment (Median 7 months), E: Survival Patients with Unchanged Mutation Status (Median 5 months), F: Survival Patients Developing Both Mutations (Median 7 months).