Long-term outcomes in FLT3-mutated acute myeloid leukemia after frontline hypomethylating agent, venetoclax and a FLT3 inhibitor.

Triplet regimens with a hypomethylating agent, venetoclax and a FLT3 inhibitor yield high rates of response in newly diagnosed FLT3-mutated acute myeloid leukemia (AML). However, the long-term outcomes and patterns of relapse with these triplet regimens are not well-established. In this retrospective analysis, 73 patients with newly diagnosed FLT3-mutated AML received a frontline FLT3 inhibitor-containing triplet regimen. The composite complete remission and complete remission with incomplete hematologic recovery rate was 93%. According to next-generation sequencing (sensitivity: 0.005%), FLT3-ITD minimal residual disease negativity was achieved in 60% of patients after cycle 2 and 90% after cycle 4. The estimated 3-year relapse-free survival for FLT3-ITD-mutated and FLT3 TKD-mutated AML was 38% and 76%, respectively, and the 3-year overall survival (OS) was 45% and 76%, respectively. Neither age, NPM1 co-mutation, European LeukemiaNet 2022 risk category, nor allogeneic stem cell transplantation in first remission significantly impacted OS. Baseline RAS pathway mutations were associated with poor long-term survival (3-year OS 22% vs. 63% in those without a RAS pathway mutation). FLT3 wild-type relapses accounted for 65% of relapses, and new RAS pathway mutations were observed in 24% of relapses. Outcomes were poor after relapse (median OS of 6.1 months), particularly for those with persistently detectable FLT3 mutations. Triplet combinations of a hypomethylating agent, venetoclax and a FLT3 inhibitor result in durable remission and encouraging long-term OS in older adults with newly diagnosed FLT3-mutated AML. However, better strategies to prevent FLT3 wild-type relapses and to overcome RAS pathway-mediated resistance are still needed.