Real-World Delivery, Dose Adaptation, and Molecular Monitoring of Gilteritinib, Venetoclax, and Azacitidine in...

Gilteritinib (GIL)-based venetoclax regimens are active in relapsed or refractory (R/R) fms-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML), but real-world delivery after prior targeted therapy remains challenging.

Adults with FLT3-mutated AML treated with GIL-based therapy from May 2021 to May 2025 were retrospectively reviewed. The analysis focused on patients with active R/R disease who received GIL, venetoclax (VEN), and azacitidine (AZA); patients who received single-agent GIL as post-allogeneic hematopoietic stem cell transplantation (allo-HSCT) maintenance without active leukemia were not the subject of this study and were excluded. The primary endpoint was modified composite remission (mCRc) within 2 cycles.

Thirty-eight patients received GIL/VEN/AZA for active R/R disease. Prior FLT3-inhibitor and VEN exposure were present in 63.2% and 28.9%. Early day 14-21 marrow clearance/aplasia occurred in 63.2%, and VEN shortening/interruption in 78.9%. mCRc occurred in 60.5% (95% confidence interval [CI], 43.4-76.0). Among evaluable responders, multiparameter flow-cytometry measurable residual disease (MRD) negativity and FLT3 molecular MRD negativity occurred in 66.7% and 72.2%. Median overall survival was 11.2 months. Prior FLT3-inhibitor exposure was not associated with inferior outcome, whereas RAS/mitogen-activated protein kinase (RAS/MAPK)-pathway co-mutation was associated with lower mCRc and shorter survival. Grade 3 or higher infection occurred in 47.4%, and 60-day mortality was 5.3%. Paired failure profiling showed FLT3-persistent and FLT3-loss patterns.

GIL/VEN/AZA was feasible in selected heavily pretreated R/R FLT3-mutated AML with early marrow-guided dose adaptation. Molecular context and repeat profiling may guide subsequent therapy.