Treatment with FLT3 inhibitor in patients withFLT3-mutated acute myeloid leukemia is associated with development of secondaryFLT3–tyrosine kinase domain mutations

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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. Cancer2014;120:2142–2149. © 2014 American Cancer Society.

Secondary FLT3-tyrosine kinase domain mutations can arise after treatment with FLT3 inhibitors in patients with FLT3-internal tandem duplication–mutated acute myeloid leukemia. D835/I836 mutations were observed in at least 20% of patients after treatment, and are associated with resistance and poor prognosis.

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