Comparative Efficacy of Bendamustine Versus Fludarabine/Cyclophosphamide for Lymphodepletion Before Chimeric Antigen Receptor T-Cell Therapy in Lymphoma

Abstract

Background: Chimeric antigen receptor T-cell (CAR-T) therapy represents a transformative advance in treating relapsed/refractory non-Hodgkin lymphomas (NHLs). Effective pre-infusion lymphodepleting chemotherapy (LDC) is essential for optimizing CAR-T outcomes. Traditionally, a combination of fludarabine and cyclophosphamide (Flu/Cy) has been used; however, a global fludarabine shortage warranted a search for alternative regimens. This study compares the efficacy and safety of bendamustine versus Flu/Cy as LDC in NHL patients.

Objectives: The purpose of this study was to compare the efficacy and safety of bendamustine versus Flu/Cy as LDC regimens in patients with relapsed/refractory NHL undergoing CAR-T therapy. We hypothesized that bendamustine would offer comparable outcomes to Flu/Cy while providing logistical advantages in outpatient settings.

Study design: This retrospective analysis evaluated 265 NHL patients treated with FDA-approved CAR-T products from January 2018 to October 2023. Outcomes included cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), hematologic recovery, progression-free survival (PFS), overall survival (OS), and healthcare resource utilization. Kaplan-Meier survival analysis and multivariable Cox proportional hazards models were employed to adjust for CAR-T product type, infusion year, disease subtype, and dexamethasone prophylaxis.

Results: Both LDC regimens effectively prepared patients for CAR-T therapy, with no significant differences in CRS, ICANS, OS, or PFS. At one year, OS was 71% for bendamustine versus 68% for Flu/Cy, and PFS was 68% versus 60% (P = .3 and P = .4, respectively). Bendamustine was associated with less severe hematologic toxicity; ANC levels did not fall below 0.5 K/µL in 71% of bendamustine recipients compared to 17% for Flu/Cy (P < .001). Multivariable analysis identified infusion year as a significant predictor of OS (HR 0.77, P = .008) and PFS (HR 2.6, P < .001), reflecting improvements in CAR-T practices over time.

Conclusion: Bendamustine is a viable alternative to Flu/Cy for LDC prior to CAR-T therapy in relapsed/refractory NHL, as it demonstrates comparable efficacy and safety. Its operational advantages, including reduced hospitalization rates and suitability for outpatient administration, underscore its potential in diverse clinical settings. Prospective studies are needed to confirm long-term outcomes and further optimize LDC strategies.

Keywords: Axicabtagene ciloleucel; Bendamustine; Brexucabtagene autoleucel; CAR T-cell therapy; Flu/Cy; LDC; Lisocabtagene maraleucel; Relapsed lymphoma; Tisagenlecleucel.