Patient-tailored azacitidine, venetoclax and gilteritinib triplet therapy appear to improve tolerability while preserving encouraging clinical outcomes in FLT3-mutated relapsed/refractory AML.

FLT3-mutated acute myeloid leukemia (AML) is associated with high relapse rates and treatment resistance. Triplet therapy with azacitidine (AZA), venetoclax (VEN), and the FLT3 inhibitor gilteritinib (GILT) yields high response rates but is limited by myelosuppression and infections. We conducted a multicenter retrospective study of 29 FLT3-mutated AML patients treated with GILT-triplets. The primary endpoint was overall survival (OS); secondary endpoints event-free survival (EFS) and time to neutrophil and platelet recovery. Patients received one of three regimens: concomitant triplet therapy (Group 1); concomitant AZA + VEN followed by concomitant VEN+GILT (Group 2); or overlapping AZA + VEN followed by GILT monotherapy (Group 3). For the entire cohort median OS was not reached after more than five years of follow-up. High response rates were observed across all schedules. Limiting concomitant exposure reduced myelosuppression and decreased infectious complications compared with full triplet therapy. Median OS was not reached in Groups 1 and 2 after three years, whereas Group 3 had a median OS of 18 months. Median EFS was 40.5 months in Group 1 and was not reached at five years in Group 2, compared with 11.5 months in Group 3. Our data suggest that reducing the duration of triple-drug overlap may improve tolerability without compromising clinical outcomes.