Maintenance treatment with gilteritinib suppresses post-transplant relapse in relapsed/refractory FLT3-mutated acute myeloid leukemia: A Japanese nationwide registry study

Abstract Background: Gilteritinib, a FLT3 inhibitor, is widely used for relapse or refractory (R/R) FLT3-mutated acute myeloid leukemia (AML). However, its safety and effectiveness as maintenance therapy following allogeneic hematopoietic stem cell transplantation (allo-HSCT) in real-world settings remain underexplored. This nationwide Japanese registry-based study aimed to address this gap. Methods: We analyzed data from the Japanese national transplant registry, supplemented by a secondary survey for FLT3 mutation status and treatment details. The study included R/R FLT3-mutated AML patients who received gilteritinib before and/or after allo-HSCT. We evaluated post-HSCT gilteritinib dosing, safety, and outcomes including relapse-free survival (RFS), overall survival (OS), relapse incidence, and non-relapse mortality (NRM). Additionally, analyses for group comparisons between with/without gilteritinib maintenance and some subgroup analyses by graft were performed as post-hoc nature. Results: Of 120 FLT3-mutated AML patients who received gilteritinib, 55 received it as post-HSCT maintenance. Gilteritinib was initiated at a median of day 47 post-transplant (range, 23–379) at a median dose of 80 mg (range, 40–120 mg). Dose reductions or temporary discontinuations due to adverse events (infections, cytopenias, liver dysfunction) occurred in 52.7% of patients. The 3-year RFS for the entire cohort was 46.8%. Patients receiving post-HSCT gilteritinib maintenance showed significantly improved RFS as compared those who did not (58.8% vs. 36.4%, p < 0.001). The subgroup analysis suggested its effects particularly in cord blood transplant (CBT) recipients (79.4% vs. 26.1%, p < 0.001) as compared to bone marrow or peripheral blood stem cell transplant (BMT/PBSCT) recipients. Multivariate analyses indicated that gilteritinib maintenance significantly improved RFS in CBT (HR 0.13, 95%CI 0.05-0.40, p < 0.001) but not in BMT/PBSCT (HR 0.80, 95%CI 0.42-1.55, p = 0.511). At 3 years, OS was also higher in the maintenance group (64.4% vs. 41.4%), with CBT recipients suggesting particularly favorable outcomes (HR 0.09, 95%CI 0.03-0.28, p<0.001) as compared to BMT/PBSCT (HR 0.82, 95%CI 0.39-1.72, p = 0.593). The 3-year relapse rate for the entire cohort was 36.8%, lower in the maintenance group (27.6% vs. 44.8%), with significant reduction in CBT recipients (HR 0.10, 95%CI 0.02-0.45, p= 0.003), as compared to BMT/PBSCT patients (HR 0.94, 95%CI 0.43-2.07, p = 0.880). NRM was lower in the maintenance group overall (13.6% vs. 18.8%) and notably in CBT (10.3% vs. 22.4%). The cumulative incidence of grade 2–4 and grade 3–4 acute GVHD at Day 150 post-HSCT was 33.4% and 15.9%, respectively, with lower rates observed in the gilteritinib maintenance group. The 3-year cumulative incidence of chronic GVHD was 31.3% (≥mild), 21.2% (moderate to severe), and 8.5% (severe). Compared to the non-maintenance group, the gilteritinib group showed slightly higher rates of chronic GVHD: 36.7% vs. 26.7% (≥mild), 23.8% vs. 18.9% (moderate to severe), and 9.1% vs. 7.8% (severe). The most frequent adverse events leading to dose reduction or temporary suspension were infection (25.5%), cytopenia (21.8%), and liver enzyme elevation (16.4%). Conclusion: Post-transplant gilteritinib maintenance in FLT3-mutated AML is feasible, though often requires dose adjustment. This maintenance therapy significantly reduces relapse and improves survival, suggesting particular benefit in patients undergoing CBT. These real-world findings support the efficacy and tolerability of post-HSCT gilteritinib.