Feasibility of TBI-Augmented Reduced Toxicity Conditioning Regimen with ATG/Ptcy Combination for Haploidentical Donor Transplantation in Adult Acute Lymphoblastic Leukemia

Background : Reduced-toxicity conditioning (RTC) regimens and haploidentical donor transplantation (HIDT) have expanded the availability of allogeneic hematopoietic cell transplantation (allo-HCT) by facilitating the use of less compatible donors and applications for comorbid or elderly recipients. Despite the critical need for effective conditioning regimens and graft-versus-host disease (GVHD) prophylaxis, the optimal conditioning regimen especially for HIDT in acute lymphoblastic leukemia (ALL) remains uncertain. Previously, we demonstrated a lower relapse rate and superior disease-free survival (DFS) with RTC using fludarabine/melphalan (FM) compared to fludarabine/busulfan (FB), and several favorable results of total body irradiation (TBI) have been reported in ALL. Consequently, we further optimized the FM regimen, with TBI and refined GVHD prophylaxis to prevent relapse and improve survival outcomes. Methods: Our study includes 26 adult ALL patients undergoing HIDT since 2023 following an RTC regimen of FMTBI (fludarabine 150 mg/m² + melphalan 100 mg/m² + TBI 400 or 800 cGy). As historical control to FMTBI group, 52 consecutive patients treated with FB (fludarabine 150 mg/m² + busulfan 9.6 mg/kg) from 2017 to 2022 were analyzed. GVHD prophylaxis included anti-thymocyte globulin (ATG) 6 mg/kg for FB regimen and a further optimized combination of ATG 4.5 mg/kg with 2 days of post-transplantation cyclophosphamide (PTCy) 30mg/kg for FMTBI regimen. Results : The FMTBI regimen exhibited significantly lower relapse rates (7.7% vs. 32.7%, p=0.034) with superior 1-year GVHD-free, relapse-free survival (GRFS) (84.0% vs. 51.9%, p=0.034), DFS (84.0% vs. 51.9%, p=0.016), and overall survival (87.9% vs. 78.8%, p=0.276). The incidence of acute GVHD grades II-IV (50.0% vs. 46.3%, p=0.433), III-IV (15.4% vs. 15.4%, p=0.937), and non-relapse mortality rates (8.2% vs. 15.4%, p=0.354) were similar between the two regimens. However, FMTBI showed a lower incidence of all grades (13.3% vs. 32.9%, p=0.058) and moderate-to-severe (0.0% vs. 11.5%, p=0.074) chronic GVHD compared to historical FB. Slightly delayed neutrophil (12 vs. 13 days, p=0.025) and platelet (13 vs. 14 days, p=0.515) recovery were observed in the FMTBI group, though comparable. The final multivariate analysis indicated poorer 1-year DFS in patients with HCT-CI score ≥3 (HR 2.81; 95%CI 1.39-5.72, p=0.004) and superior DFS in the FMTBI group (HR 0.27; 95%CI 0.09-0.78, p=0.015). Conclusions : The newly implemented FMTBI regimen demonstrated lower relapse rates with longer 1-year DFS and GRFS compared to historical FB in HIDT of adult ALL. Reduced chronic GVHD and comparable acute GVHD incidences suggest the effectiveness of ATG/PTCy for GVHD prevention. These findings underscore the necessity of refining conditioning regimens and GVHD prophylaxis to improve transplantation outcomes within tolerable adverse events for HIDT in ALL, holding significant implications for enhancing HCT strategies in this challenging patient population.