Comparative safety and efficacy of bendamustine versus fludarabine/cyclophosphamide prior to chimeric antigen receptor- T cell therapy: A systematic review and meta-analysis

Abstract Background: CAR T-cell therapy is a promising treatment for certain leukemias and lymphomas, particularly refractory non-Hodgkin lymphoma. Lymphodepletion prior to CAR T-cell therapy is a crucial step, as it can enhance the treatment's efficacy by facilitating CAR T-cell expansion, persistence, and activity. Traditionally, fludarabine/cyclophosphamide has been used for lymphodepletion. However, a global shortage of fludarabine evoked a search for alternatives such as bendamustine. In this review, we aim to compare the safety and efficacy of bendamustine with fludarabine/cyclophosphamide (Flu/Cy) for lymphodepletion prior to CAR T-cell therapy. Methods: A comprehensive search of electronic databases such as PubMed, Cochrane Library, and ClinicalTrials.gov was conducted using relevant keywords and MeSH terms from inception to July 2025, complemented by a targeted search of Google Scholar. The search elicited 17 studies, of which 7 were included in the meta-analysis based on predefined selection criteria. Data from included studies were extracted using a standardized data collection sheet for bendamustine and Flu/Cy groups. A meta-analysis was performed using the Cochrane Review Manager online version. Dichotomous outcomes were compared using risk ratios and odds ratios. Heterogeneity among studies was assessed using Chi2 test and quantified with the I2 statistic. Results A total of 634 patients were included in the analysis. Males comprised 63% of the bendamustine group and 66% of the Flu/Cy group. Most patients in both groups had an ECOG performance status of ≤1. The included studies encompassed a range of hematologic malignancies, including refractory non-Hodgkin lymphoma, relapsed/refractory large B-cell lymphoma, and mantle cell lymphoma. Patients in both groups group had received 2 to 7 prior lines of therapy. Prior stem cell transplantation was more common in the bendamustine group (43%) compared to the Flu/Cy group (28%), and approximately 66% of patients in both groups received bridging therapy. Regarding efficacy outcomes, there were no statistically significant differences between bendamustine and Flu/Cy. One-year overall survival was similar between groups (RR = 1.07, 95% CI: 0.99–1.16; p = 0.09; I² = 0%), as were progression-free survival (RR = 0.93, 95% CI: 0.60–1.45; p = 0.68; I² = 28%), complete response (RR = 0.93, 95% CI: 0.71–1.21; p = 0.50; I² = 0%), and overall response (RR = 1.01, 95% CI: 0.87–1.18; p = 0.86; I² = 0%). However, safety outcomes largely favored Flu/Cy. The Flu/Cy regimen was associated with significantly lower rates of neutropenic fever (RR = 0.15, 95% CI: 0.07–0.29; p < 0.00001; I² = 0%), any-grade infections (RR = 0.36, 95% CI: 0.24–0.55; p < 0.000001; I² = 0%), and grade ≥3 infections (RR = 0.33, 95% CI: 0.18–0.58; p = 0.0001; I² = 81%). Additionally, Flu/Cy was associated with a reduced risk of any-grade cytokine release syndrome (CRS) (OR = 0.42, 95% CI: 0.20–0.89; p = 0.03; I² = 0%) and both any-grade and grade ≥3 immune effector cell-associated neurotoxicity syndrome (ICANS) (RR = 0.55, 95% CI: 0.36–0.83; p = 0.004; I² = 53% and RR = 0.44, 95% CI: 0.20–0.96; p = 0.04; I² = 0%, respectively). Rates of grade ≥3 CRS were similar between the two groups. In terms of hematologic toxicity, bendamustine significantly reduced the risk of grade ≥3 anemia compared to Flu/Cy (RR = 0.36, 95% CI: 0.22–0.59; p < 0.0001; I² = 61%). However, Flu/Cy was superior in preserving platelet and neutrophil counts. Patients in the Flu/Cy group experienced lower rates of any-grade thrombocytopenia (RR = 0.22, 95% CI: 0.12–0.41; p < 0.00001; I² = 64%) and grade ≥3 thrombocytopenia (RR = 0.45, 95% CI: 0.31–0.64; p < 0.0001; I² = 71%). Similarly, the Flu/Cy group had reduced rates of any-grade neutropenia (RR = 0.81, 95% CI: 0.65–0.99; p = 0.04; I² = 0%) and grade ≥3 neutropenia (RR = 0.52, 95% CI: 0.44–0.63; p < 0.00001; I² = 77%). Conclusion This meta-analysis suggests that bendamustine is non-inferior to fludarabine/cyclophosphamide (Flu/Cy) in terms of efficacy for lymphodepletion prior to CAR T-cell therapy. Bendamustine offers some hematologic benefits, particularly in reducing severe anemia, fludarabine/cyclophosphamide) shows broader safety advantages, including lower rates of infections, CRS, ICANS, and cytopenias. However, further prospective randomized studies are essential to confirm these findings and optimize lymphodepletion strategies tailored to individual patient needs.