Phase 1-2 trial of azacitidine, venetoclax, and gilteritinib for newly diagnosed and relapsed or refractory FLT3-mutated AML

Azacitidine plus venetoclax is a standard of care for patients with newly diagnosed AML who are unfit for intensive chemotherapy. However, FLT3 mutations are a common mechanism of resistance to this regimen. A phase 1-2 trial at MD Anderson Cancer Center (Houston, TX) evaluated the combination of the oral FLT3 inhibitor gilteritinib with azacitidine and venetoclax for FLT3-mutated AML. In the cohort with newly diagnosed disease the combination resulted in CR/CRi rate 96%, while 65% of the patients achieved FLT3-internal tandem duplication measurable residual disease <5 x 10^-5 within four cycles. With a median follow-up of 19.3 months, the median relapse-free and overall survival were not reached, with 18-months RFS and OS rates 71% and 72%, respectively. In the cohort with relapsed or refractory disease, the CR/CRi rate was 27%, with an additional 41% achieving a morphologic leukemia-free state. The most common grade 3 or higher nonhematologic adverse events were infection (62% of patients) and febrile neutropenia (38%). The authors conclude that the combination of azacitidine, venetoclax, and gilteritinib resulted in high rates of CR/CRi, deep FLT3 molecular responses, and encouraging survival in newly diagnosed FLT3-mutated AML. Myelosuppression was manageable with mitigative dosing strategies.