Comparison of Myeloablative Busulfan/Cyclophosphamide and Busulfan/Fludarabine for Allogeneic Hematopoietic Stem Cell...

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for many hematological malignancies. The busulfan plus cyclophosphamide (Bu/Cy) combination is a standard myeloablative conditioning (MAC) regimen, but it is associated with significant regimen-related toxicity and non-relapse mortality (NRM). To mitigate these issues, a regimen combining high-dose busulfan with fludarabine (Bu/Flu) was developed, aiming to reduce toxicity while preserving efficacy. While a previous meta-analysis suggested Bu/Flu may reduce early mortality, it included non-randomized studies, and several large-scale trials have been published since. Therefore, an updated, robust comparison of these two widely used MAC regimens is clinically essential. The primary objective of this study was to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) to comprehensively evaluate and compare the efficacy and safety profiles of Bu/Flu versus Bu/Cy as MAC regimens for adults undergoing allo-HSCT for hematological malignancies. This systematic review and meta-analysis was conducted following PRISMA guidelines, with a protocol registered on PROSPERO. We systematically searched PubMed, EMBASE, and CENTRAL databases for RCTs comparing Bu/Flu with Bu/Cy in adult patients with hematological malignancies receiving myeloablative busulfan doses. The primary outcome was NRM at 100 d and 1-yr. Secondary outcomes included all-cause mortality, relapse, and grade 3 to 5 adverse events. For statistical analysis, we calculated pooled risk ratios (RR) with 95% confidence intervals (CIs) using fixed- or random-effects models. The certainty of evidence was assessed using the Grades of Recommendations, Assessment, Development, and Evaluations methodology. Five RCTs met the inclusion criteria, encompassing a total of 975 patients. The meta-analysis demonstrated that the Bu/Flu regimen was associated with a significantly lower NRM at 1-yr compared to Bu/Cy (RR 0.49; 95% CI 0.31 to 0.79; I² = 0%; moderate certainty; 629 patients, 2 trials). Furthermore, Bu/Flu resulted in a significantly reduced incidence of grade 3 to 5 adverse events (RR 0.83, 95% CI 0.74 to 0.94; I² = 40%; high certainty; 385 patients, 2 trials). There were no statistically significant differences between the two regimens in terms of all-cause mortality at the end of the study (RR 0.99, 95% CI 0.83 to 1.19; I² = 48%; moderate certainty; 965 patients, 5 trials) or relapse rates (RR 1.11, 95% CI 0.86 to 1.44; I² = 20%; moderate certainty; 972 patients, 5 trials). Bu/Flu and Bu/Cy demonstrate comparable efficacy concerning long-term overall survival and relapse control in the setting of myeloablative allo-HSCT. However, the Bu/Flu regimen presents a superior safety profile, evidenced by a significant reduction in both NRM at 1-yr and severe adverse events. Bu/Flu should be considered a safer MAC alternative to Bu/Cy, particularly for patients at an increased risk of treatment-related toxicity.