Salvage allogeneic hematopoietic stem cell transplantation conditioning regimens for relapsed/refractory acute leukemia: Efficacy of radiotherapy combined with CLAG vs FLAG

Abstract Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative option for relapsed/refractory acute leukemia (R/R AL), but outcomes remain suboptimal due to lack of standardized conditioning regimens. Intensive conditioning with chemotherapy (CLAG/FLAG) combined with radiotherapy (total body irradiation [TBI]/total marrow lymphoid irradiation [TMLI]) may improve efficacy, but comparative data are limited.We retrospectively analyzed 233 R/R AL patients (2015–2023) who underwent allo-HSCT with conditioning regimens of radiotherapy (TBI/TMLI) combined with CLAG or FLAG. Patients were grouped as: TBI/CLAG (n=139), TMLI/CLAG (n=21), TBI/FLAG (n=59), TMLI/FLAG (n=4). Disease subtypes included AML (n=180, 80.7%) and ALL (n=43, 19.3%). Most patients were not in remission at transplant (n=184, 82.5%); remitted patients (n=39, 17.5%) all had extramedullary disease. The last follow-up date was May 1, 2025. Primary endpoints: overall survival (OS), disease-free survival (DFS), cumulative incidence of relapse (CIR), and non-relapse mortality (NRM).For the entire cohort, 10-year outcomes were: OS 32.9% (95%CI 27.0–40.0%), DFS 29.6% (95%CI 23.9–36.6%), CIR 34.5% (95%CI 28.2–40.8%), and NRM 35.3% (95%CI 29.0–41.6%). No statistically significant differences in OS, DFS, CIR, or NRM were observed between radiotherapy+CLAG vs. radiotherapy+FLAG (all P>0.05). Subgroup analyses in AML and ALL (stratified by TBI-based regimens) also showed no significant differences in these endpoints. However, in ALL patients, TBI/CLAG trended toward better 5-year OS (56.6% vs. 36.7%, P=0.081) and lower 5-year NRM (18.2% vs. 44.4%, P=0.097) compared to TBI/FLAG. Conclusion: Intensive conditioning with CLAG/FLAG combined with radiotherapy is effective and well-tolerated in R/R AL patients undergoing allo-HSCT. TBI/CLAG may confer superior survival outcomes in ALL, warranting further validation in larger cohorts.