Optimizing Reduced-Intensity Conditioning for Older Patients with AML and MDS: A Large-Scale Analysis from the CIBMTR

The optimal reduced-intensity conditioning (RIC) regimen for older patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) undergoing allogeneic hematopoietic stem cell transplantation (AHCT) remains undefined. We utilized CIBMTR registry data (2013-2022) to compare five common fludarabine-based regimens in 11,731 patients aged ≥50 years: fludarabine combined with 2 days of busulfan (FB2), melphalan 100 mg/m² (FM100), melphalan 140 mg/m² (FM140), or 2 Gy TBI with (FCT) or without (FT) cyclophosphamide. Using propensity score inverse probability weighting and Bayesian Additive Regression Trees (BART), we found that Fludarabine-melphalan (FM) regimens demonstrated superior long-term survival. Although FM140, FCT, and FT showed higher early mortality (≤6 months) than FB2 (P=.036), both FM100 (HR 0.79) and FM140 (HR 0.77) achieved significantly better late (> 6 months) overall survival (OS), outperforming all other regimens (P<.0001). In the 2019-2022 cohort, FM100, FM140, and FCT provided improved disease-free survival (DFS) relative to FB2. Specifically, FM100 yielded superior DFS compared to FCT (P=0.002) and FT (P=0.007). FM-based conditioning consistently resulted in lower relapse rates (P<.0001) and improved late GVHD-free/relapse-free survival. While FM regimens faced higher early non-relapse mortality (NRM), this impact did not persist beyond 6 months. BART analysis confirmed that these survival and relapse benefits remained robust across various patient comorbidities. In conclusion, FM100 and FM140 provide superior long-term survival and DFS for older patients with AML/MDS by providing potent anti-leukemic activity that offsets higher early toxicity. These findings support FM-based RIC as the preferred conditioning platform for this population, regardless of baseline comorbidities.