Long-term outcomes of azacitidine, venetoclax, and gilteritinib in newly diagnosed FLT3-mutated AML.

Among patients with FLT3-mutated acute myeloid leukemia (AML) who receive frontline azacitidine plus venetoclax, relapses are commonly driven by the expansion of the FLT3-mutated clone, supporting FLT3 inhibitor-based triplet lower-intensity regimens. We report long-term outcomes of a phase 2 study of azacitidine, venetoclax, and gilteritinib for adults with newly diagnosed FLT3-mutated AML who were unfit for intensive chemotherapy. Thirty patients were treated; median age was 71 years, and 22 (73%) had an FLT3 internal tandem duplication (FLT3-ITD) mutation. The complete remission (CR)/CR with incomplete hematologic recovery rate was 96%, and 14 patients (47%) underwent allogeneic hematopoietic stem cell transplantation (HSCT) in first remission. With a median follow-up of 41.5 months, 11 patients (37%) relapsed; in 67% of evaluable relapses, the FLT3 mutation was not detectable. The median relapse-free survival (RFS) and overall survival (OS) were 23.4 and 29.7 months, respectively, and the 3-year RFS and OS rates were 43% and 46%, respectively. Among patients with FLT3-ITD-mutated AML, the median RFS and OS were 17.0 and 21.8 months, respectively, and the 3-year RFS and OS rates were 32% and 36%, respectively. The presence of a baseline RAS pathway mutation was associated with worse outcomes. Survival rates were similar regardless of HSCT in first remission. Among patients who received ≥1 consolidation cycle, 68% had a reduction in the dose or duration of at least one of the study drugs. The triplet regimen of azacitidine, venetoclax, and gilteritinib is associated with durable remissions and encouraging long-term survival. Randomized studies comparing this regimen to standard of care approaches are warranted. This trial was registered at www.clinicaltrials.gov as #NCT04140487.