Comparative 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

Abstract Introduction: Chimeric antigen receptor T-cell (CAR-T) therapy has become an established treatment for acute lymphoblastic leukemia, B-cell non-Hodgkin lymphomas, and multiple myeloma. Lymphodepleting (LD) chemotherapy is a critical preparatory step that facilitates CAR-T cell expansion and persistence. The choice of LD regimen may influence overall efficacy and CAR-T-associated adverse events such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and infections. While the combination of fludarabine and cyclophosphamide (FluCy) is a standard LD regimen, bendamustine has emerged as a potential alternative. Ultimately, the optimal LD regimen remains uncertain. To address this gap, we conducted a systematic review and meta-analysis to compare the efficacy and safety of these LD regimens in patients with hematological malignancies treated with CAR-T therapy. Methods: We performed a systematic review and meta-analysis of retrospective and randomized controlled trials comparing the efficacy and safety of bendamustine versus fludarabine and cyclophosphamide as LD regimens in patients with hematological malignancies undergoing CAR-T therapy. A comprehensive search of PubMed, Scopus, and Cochrane CENTRAL databases was conducted up to July 2025. This review adheres to the recommendations from the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement guidelines. R software version 4.5.1 was used for statistical analyses. Results: A total of 687 patients from seven retrospective studies were included in the systematic review and meta-analysis. Axicabtagene ciloleucel was used in four studies, brexucabtagene autoleucel and tisagenlecleucel in two studies, and lisocabtagene maraleucel, idecabtagene vicleucel, and ciltacabtagene autoleucel in one study each. The patient population included individuals with B-cell lymphomas and multiple myeloma. Bendamustine cohort was associated with a significantly lower incidence of all grade CRS (OR 0.51; 95% CI 0.28-0.95; p = 0.034; I2 = 46.5%) and infections (OR 0.19; 95% CI 0.09-0.41; p <0.001; I2 = 25.1%) compared to FluCy cohort. There were no significant differences between these two cohorts in the incidence of grade ≥3 CRS (OR 0.99; 95% CI 0.51-1.92; p = 0.966; I2 = 0.0%), any-grade ICANS (OR 0.59; 95% CI 0.32-1.08; p = 0.085; I2 = 54.0%), or grade ≥3 ICANS (OR 0.62; 95% CI 0.33-1.18; p = 0.149; I2 = 13.4%). Regarding efficacy outcomes, no significant differences were found between two groups in overall survival (HR 0.89; 95% CI 0.60-1.33; p = 0.585; I2 = 21.5%), progression free survival (HR 0.96; 95% CI 0.71-1.29; p = 0.7905; I2 = 19.7%), and overall response rate (OR 1.00; 95% CI 0.62-1.62; p = 0.988; I2 = 0.0%). Conclusions: Compared to FluCy, benadmustaine appears to have a significantly reduced incidence of CRS and infections without compromising CAR-T efficacy. These findings suggest that bendamustine may serve as a viable alternative LD regimen, especially for patients at high risk of infections. Further prospective studies are warranted to confirm the safety and efficacy of bendamustine compared to standard FluCy regimen.