Comparative efficacy of TBI-based vs. non-TBI reduced toxicity conditioning regimens in adult ALL undergoing allogeneic HCT in CR1: Improved outcomes with TBI-based RTC and ATG/ptcy combination

Abstract

Abstract Background: The optimal conditioning regimen for adult patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic cell transplantation (allo-HCT) remains controversial, particularly regarding the role of total body irradiation (TBI) in reduced-toxicity conditioning (RTC). While TBI has shown efficacy in pediatric settings, its benefit and tolerability in adults, especially with modern GVHD prophylaxis, are less well defined. Aim: We aimed to evaluate a novel low-dose TBI-based RTC regimen combined with anti-thymocyte globulin and post-transplant cyclophosphamide (ATG/PTCy) for GVHD prophylaxis in adult ALL patients undergoing allo-HCT in first complete remission (CR1). This study compared its survival outcomes, relapse rates, and toxicity profiles to those of conventional non-TBI-based RTC regimens. Methods: We retrospectively analyzed 96 adult patients with ALL in first complete remission (CR1) who underwent allo-HCT using a TBI-based RTC regimen consisting of fludarabine (150 mg/m²), melphalan (100 mg/m²), and low-dose TBI (400–800 cGy), in combination with ATG/PTCy – ATG 4.5mg/kg for haploidentical donor (HID) and 2.5mg/kg for other than HID, and Cyclophosphamide 30mg on D+3 and D+4. Outcomes were compared to 256 historical controls who received non-TBI RTC (fludarabine + busulfan [9.6 mg/kg] or melphalan [140 mg/m²]) with ATG alone. Key endpoints included disease-free survival (DFS), overall survival (OS), cumulative incidence of relapse (CIR), non-relapse mortality (NRM), and incidence of GVHD. Results: At 1-year post-transplant, the TBI-based group demonstrated superior DFS (76.2% vs. 67.8%, p=0.046) and lower CIR rates (12.0% vs. 22.0%, p=0.023) compared to the non-TBI group. OS (83.5% vs. 82.3%, p=0.180) and NRM (11.8% vs. 10.2%, p=0.859) were comparable. Incidence of grade II-IV acute GVHD trended higher in the TBI group (45.8% vs. 36.7%, p=0.065), with significantly higher grade III-IV acute GVHD (21.9% vs. 10.9%, p=0.019). Moderate to severe chronic GVHD rates were similar (20.4% vs. 18.4%, p=0.805), but all-grade chronic GVHD was lower in the TBI group (25.7% vs. 45.1%, p<0.001). Multivariate analysis identified age ≥40 years (HR 1.5, p<0.001) and HCT-CI ≥3 (HR 1.2, p<0.001) as predictors of inferior DFS. The TBI-based regimen independently predicted improved DFS (HR 0.5, p<0.001) and lower relapse (HR 0.3, p=0.002). Occurrence of chronic GVHD was associated with better DFS (HR 0.3, p<0.001). Non-hematologic toxicities were similar between groups, though diarrhea and vomiting were more frequent with the TBI regimen. Conclusions: Our data suggested that a low-dose TBI-based RTC regimen with dual GVHD prophylaxis (ATG/PTCy) offered superior disease control without compromising OS or increasing GVHD in adult patients with ALL undergoing allo-HCT in CR1. This regimen may serve as a promising platform for improved long-term outcomes in this population.