Bendamustine-based lymphodepletion prior to CAR T-cell therapy: a systematic review

Lymphodepletion (LD) is a critical prerequisite for successful chimeric antigen receptor T-cell (CAR-T) therapy. While fludarabine and cyclophosphamide (Flu/Cy) remain the standard LD regimen, bendamustine has emerged as a potential alternative due to its distinct immunomodulatory properties and more favorable toxicity profile. This systematic review evaluates the safety, efficacy, and feasibility of bendamustine-based LD in patients undergoing CAR-T therapy for hematologic malignancies. A comprehensive literature search was conducted through January 2026 across PubMed, Embase, Web of Science, and clinical trial registries. Studies were eligible if they reported clinical outcomes following bendamustine-based lymphodepletion prior to CD19-, CD30-, or BCMA-directed CAR-T therapy. Extracted endpoints included overall response rate (ORR), complete response rate (CRR), progression-free survival (PFS), overall survival (OS), and treatment-related toxicities. Eighteen studies comprising over 1400 patients were included. Across disease indications-including B- and T-cell non-Hodgkin lymphoma, Hodgkin lymphoma (HL), and multiple myeloma (MM)-ORRs ranged from 50% to 88%, with CRRs up to 74%. Compared with Flu/Cy, bendamustine-based LD demonstrated comparable efficacy while being associated with significantly lower rates of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and grade ≥3 cytopenias. Additionally, bendamustine facilitated outpatient CAR-T delivery, with reduced hospitalization and intensive care unit (ICU) utilization. However, prior exposure to bendamustine before leukapheresis was associated with inferior CAR-T outcomes. Bendamustine-based LD represents a safe and effective alternative to Flu/Cy, particularly in outpatient settings and in patients at higher risk of treatment-related toxicity. However, the current evidence is largely derived from retrospective and non-randomized studies. Prospective, comparative trials are warranted to validate these findings and to better define the optimal LD strategy across disease types and CAR-T platforms.