Efficacy and Safety of Bendamustine Versus Fludarabine and Cyclophosphamide as Lymphodepleting Regimens for CAR-T Therapy in Hematological Malignancies: A Systematic Review and Meta-Analysis.

OBJECTIVES: Chimeric antigen receptor T-cell (CAR-T) therapy has become an established treatment for hematological malignancies. Lymphodepleting (LD) chemotherapy is a preparatory step that facilitates CAR-T cell expansion and persistence. While fludarabine and cyclophosphamide (Flu/Cy) are a standard LD regimen, bendamustine has emerged as a potential alternative. METHODS: We performed a systematic review and meta-analysis comparing the efficacy and safety of bendamustine versus Flu/Cy as LD regimens. We systematically searched PubMed, Scopus, and the Cochrane Central Register of Controlled Trials from inception to July 2025. RESULTS: Nine retrospective studies comprising 768 patients were included. The bendamustine cohort demonstrated a lower incidence of all-grade cytokine release syndrome (CRS) compared with Flu/Cy (60.2% vs. 71.7%; p = 0.011), whereas no difference was observed in grade ≥ 3 CRS. Overall infections were less frequent with bendamustine (18.3% vs. 53.7%; p < 0.001). There were no significant differences between groups in the incidence of immune effector cell-associated neurotoxicity syndrome, overall response rate, overall survival, and progression-free survival. CONCLUSION: Bendamustine LD therapy significantly reduced the incidence of all-grade CRS and overall infections without compromising CAR-T efficacy. These findings suggest that bendamustine may serve as a viable alternative LD regimen.