Highlights • Fludarabine, melphalan, and total body irradiation is an acceptable reduced-intensity conditioning regimen than can induce full donor chimerism. • Less robust patients with residual malignant disease may benefit most from fludarabine (160 mg/m2), melphalan (75 mg/m2), and total body irradiation. ABSTRACT Disease relapse and toxicity are the shortcomings of reduced-intensity conditioning (RIC) for allogeneic hematopoietic cell transplantation (alloHCT). We hypothesized that adding total body irradiation (TBI) to and decreasing melphalan (Mel) from a base RIC regimen of fludarabine (Flu) and Mel would increase cytoreduction and improve disease control while decreasing toxicity. We performed a phase II trial of Flu 160 mg/m2, Mel 50 mg/m2, and TBI 400 cGy (FluMelTBI-50, n = 61), followed by a second phase II trial of Flu 160 mg/m2, Mel 75 mg/m2, and TBI 400cGy (FluMelTBI-75, n = 94) as RIC for alloHCT. Outcomes were compared with a contemporaneous cohort of 162 patients who received Flu 125 mg/m2 and Mel 140 mg/m2. Eligibility criteria were equivalent for all 3 regimens. All patients were ineligible for myeloablative/intensive conditioning. The median (range) follow-up for all patients was 51 (15 to 103) months. Day 100 donor lymphoid chimerism and transplant-related mortality, neutrophil and platelet engraftment, acute and chronic graft versus host disease incidence, overall survival (OS), and progression-free survival (PFS) were equivalent between FluMel, FluMelTBI-50, and FluMelTBI-75. Stomatitis wasdecreased for FluMelTBI versus FluMel (P <.01). PFS for patients not in complete remission on alloHCT was improved for FluMelTBI-75 versus FluMel (P =.03). On multivariate analysis, OS (P =.05) and PFS (P =.05) were significantly improved for FluMelTBI-75 versus FluMel. FluMelTBI-75 is better tolerated than FluMel, with improved survival and disease control. [ABSTRACT FROM AUTHOR]