FLT3 inhibitors across the allogeneic transplant continuum in <i>FLT3</i> -mutated acute myeloid leukemia: A systematic review and meta-analysis.

Abstract

e18523 Background: FLT3-mutated AML (30% of cases) carries a high relapse risk despite allogeneic hematopoietic stem cell transplantation (allo-HSCT). Currently, FLT3 inhibitor use is typically limited to the post-transplant maintenance phase. However, there may be substantial benefit to coordinated FLT3 inhibition throughout distinct treatment phases: from salvage therapy, which prepares patients for transplantation, to post-transplant consolidation after allo-HSCT. The integrated role in both the pre-transplant (bridge-to-transplant salvage therapy) and post-transplant (maintenance) phases has not been systematically evaluated. This study assesses the efficacy of FLT3 inhibitors in both phases. Methods: We conducted a systematic review of phase II–III trials and observational studies evaluating FLT3 inhibitors in adults with FLT3-mutated AML used as (1) salvage/bridge to allo-HSCT and/or (2) post-transplant maintenance. Primary outcomes were composite complete remission (CR/CRi) and proportion proceeding to allo-HSCT in the salvage setting, and relapse-free survival (RFS) in the maintenance setting. Random-effects meta-analysis was performed for randomized maintenance trials with comparator arms and extractable hazard ratios. Salvage and bridge outcomes were summarized descriptively due to heterogeneity. Results: Across included studies, FLT3 inhibitors used as salvage therapy in relapsed/refractory AML consistently achieved clinically meaningful remission and facilitated subsequent transplantation. In the phase III ADMIRAL trial, gilteritinib achieved a composite remission rate of 54% and enabled 26% of patients to proceed to allo-HSCT, compared with 22% remission and 15% transplant rates with salvage chemotherapy. For post-transplant maintenance, quantitative meta-analysis of randomized sorafenib-based trials demonstrated a significant reduction in relapse or death compared with control (pooled HR 0.45, 95% CI 0.31–0.66; I²=0%). In sensitivity analyses incorporating midostaurin maintenance, results were consistent, though underpowered. Exploratory pooled analysis of overall survival across maintenance studies showed improved survival (HR 0.55, 95% CI 0.36–0.86). Rates of acute and chronic graft-versus-host disease were generally comparable between maintenance and control arms, while treatment discontinuation varied by agent. Conclusions: FLT3 inhibitors establish standard-of-care benefit across the allo-HSCT continuum. Pre-transplant salvage FLT3 inhibition improves remission and enables transplantation. Post-transplant maintenance with sorafenib (all patients) and gilteritinib (MRD-positive) significantly reduces relapse and improves survival. These findings support integrated FLT3 inhibition across the transplant continuum as standard of care for FLT3-mutated AML.