Efficacy and safety of Busulfan–Fludarabine versus Busulfan–Cyclophosphamide as a conditioning regimen prior to hematopoietic stem cell transplant in hematologic malignancy patients: a meta-analysis of randomized controlled trials and observational studies

Background: Conditioning regimen selection significantly impacts the outcomes of allogeneic hematopoietic stem cell transplantation (HSCT) in patients with hematologic malignancies. However, comparative evidence between Busulfan-Fludarabine and Busulfan-Cyclophosphamide remains inconclusive. Objectives: To compare the efficacy and safety of Busulfan-Fludarabine versus Busulfan-Cyclophosphamide as conditioning regimens prior to HSCT. Design: Systematic review and meta-analysis conducted in accordance with PRISMA 2020 guidelines. Data sources and methods: MEDLINE, CENTRAL, and Embase were searched through October 2024. Eligible studies included randomized controlled trials and cohort studies comparing Busulfan-Fludarabine and Busulfan-Cyclophosphamide in HSCT recipients. Primary outcomes included overall survival and acute graft-versus-host disease (GVHD). Risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using random-effects models. Risk of bias was assessed using RoB 2.0 and the Newcastle-Ottawa Scale. Results: Eighteen studies (6 randomized controlled trials, 12 cohorts) comprising 2888 patients (1539 received Busulfan-Fludarabine, 1349 received Busulfan-Cyclophosphamide) were included. Busulfan-Fludarabine showed higher 1-year overall survival (RR 1.13, 95% CI: 1.01-1.26), but no significant difference at 2 or 5 years. Grade III-IV acute GVHD was significantly lower with Busulfan-Cyclophosphamide (RR 0.45, 95% CI: 0.21-0.98). Busulfan-Fludarabine resulted in lower 5-year non-relapse mortality (RR 0.63, 95% CI: 0.48-0.83), and significantly reduced pulmonary and gastrointestinal toxicities. Event-free survival favored Busulfan-Fludarabine at 2 and 5 years. No significant differences were found for relapse-related mortality, chronic GVHD, cytomegalovirus infection, or total mortality. Meta-regression identified conditioning regimen and graft source as contributors to 1-year survival variability. Conclusion: Busulfan-Fludarabine offers early survival and toxicity advantages, while Busulfan-Cyclophosphamide may reduce severe acute GVHD. Conditioning regimen selection should consider patient-specific factors. Further prospective trials are needed to guide clinical decisions. Trial registration: PROSPERO ID: CRD42025630836.