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

Uttam K Rao; Navneet S Majhail; Betsy Blunk; Karin Abernathy; Carlos Bachier; Vikas Bhushan; Jose Carlos Cruz; Mohammed Elayan; Tara Gregory; Charles F LeMaistre; Shahbaz A Malik; Casey Martin; Meredith Mattlin; Gabrielle Blade; Michael B Maris; John Mathews; Luke Mountjoy; Jeremy M Pantin; Aravind Ramakrishnan; Paul Shaughnessy; Michael T Tees; Estil A Vance; Behyar Zoghi; Minoo Battiwalla

doi:10.1016/j.jtct.2025.03.012

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

Transplant Cell Ther. 2025 Mar 22:S2666-6367(25)01101-7. doi: 10.1016/j.jtct.2025.03.012. Online ahead of print.

Authors

Uttam K Rao¹, Navneet S Majhail², Betsy Blunk², Karin Abernathy², Carlos Bachier³, Vikas Bhushan⁴, Jose Carlos Cruz³, Mohammed Elayan², Tara Gregory⁵, Charles F LeMaistre², Shahbaz A Malik⁶, Casey Martin⁷, Meredith Mattlin⁷, Gabrielle Blade⁷, Michael B Maris⁵, John Mathews⁴, Luke Mountjoy⁵, Jeremy M Pantin², Aravind Ramakrishnan⁶, Paul Shaughnessy³, Michael T Tees⁵, Estil A Vance⁴, Behyar Zoghi⁴, Minoo Battiwalla²

Affiliations

¹ Sarah Cannon Transplant and Cellular Therapy Network, St. David's South Austin Medical Center, Austin, Texas. Electronic address: uttam.rao@hcahealthcare.com.
² Sarah Cannon Transplant and Cellular Therapy Network, TriStar Centennial Medical Center, Nashville, Tennessee.
³ Sarah Cannon Transplant and Cellular Therapy Network, Methodist Hospital, San Antonio, Texas.
⁴ Sarah Cannon and Texas Oncology Transplant and Cellular Therapy Network, Medical City Dallas, Dallas, Texas.
⁵ Sarah Cannon Transplant and Cellular Therapy Network, Presbyterian/St Luke's Medical Center, Denver, Colorado; Colorado Blood Cancer Institute, Denver, Colorado.
⁶ Sarah Cannon Transplant and Cellular Therapy Network, St. David's South Austin Medical Center, Austin, Texas.
⁷ Genospace, Boston, Massachusetts.

PMID: 40122282
DOI: 10.1016/j.jtct.2025.03.012

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.