Optimizing the Use of FLT3 Inhibitors in AML

FLT3 mutations occur in approximately one-third of patients with newly diagnosed AML. These consist of the more common FLT3-ITD in approximately 20-25% of cases, and point mutations in the tyrosine kinase domain in approximately 5-10%. FLT3 mutations, particularly FLT3-ITD, are associated with increased risk of relapse and inferior overall survival when treated with chemotherapy alone. However, the recent development of active FLT3 inhibitors has significantly improved the outcomes of this aggressive subtype of AML. In 2017, midostaurin was approved for the frontline treatment of patients with FLT3-mutated AML in combination with induction chemotherapy. In 2018, the second-generation FLT3 inhibitor gilteritinib was approved as a single agent for patients with relapsed/refractory FLT3-mutated AML. Promising phase I/II efficacy data for quizartinib is likely to lead to a third regulatory approval for relapsed/refractory AML in the near future. Studies are ongoing combining these and other FLT3 inhibitors with standard therapies (e.g. chemotherapy or hypomethylating agents) and also with novel agents that may help to prevent or overcome FLT3 inhibitor resistance.