Comparison of Bendamustine Versus Fludarabine/ Cyclophosphamide Lymphodepletion in Adult Patients Receiving CD19 CAR-T Cell Therapy
Authors: Landego Ivan , Nemirovsky David , Devlin Sean M. , Wills Beatriz , Parascondola Allison , Saldia Amethyst , Dahi Parastoo B. , Alarcon Tomas Ana , Ip Andrew , Suh Hyung C , Leslie Lori A. , Nath Karthik , Giralt Sergio A. , Lin Richard J. , Palomba Maria Lia , Salles Gilles , Shah Gunjan L. , Shouval Roni , Perales Miguel-Angel , Scordo Michael 
Published: December 2023

INTRODUCTION: Lymphodepleting chemotherapy (LDC) prior to CAR-T infusion is required for more effective expansion and persistence of infused T cells. Most commonly, fludarabine and cyclophosphamide (flu/cy) has been used. Given recent drug shortages, alternative chemotherapeutic agents such as bendamustine have been used, although limited data exists to evaluate its safety and efficacy. Our study aimed to investigate the outcomes and toxicity profile associated with the use of bendamustine compared to flu/cy LDC in patients receiving CD19 CAR T cells for B-cell non-Hodgkin lymphoma (B-NHL).

METHODS: In this retrospective analysis we included patients with relapse/ refractory B-NHL (follicular lymphoma (FL), mantle cell lymphoma (MCL), and large B cell lymphoma (LBCL)) treated with commercial CD19 CAR-T from Memorial Sloan Kettering Cancer Center (MSKCC) and Hackensack Meridian Health (HMH) between January 2020 to December 2022. We compared the outcomes and toxicity of those patients who received bendamustine LDC to historical controls treated with flu/cy. Response and toxicities including CRS and ICANS were assessed using the Lugano 2014 and ASTCT criteria, respectively.

RESULTS: Two hundred and forty-two B-NHL (21 FL, 25 MCL, 196 LBCL) patients underwent CAR-T infusion, with 179 receiving flu/cy and 63 receiving bendamustine LDC. Baseline characteristics were comparable in each group except for number of lines of prior therapy, with the bendamustine group having received a median of 2 lines of prior therapy compared to 3 lines in the flu/cy group (p = 0.005). Patients with LBCL receiving bendamustine LDC had overall lower rates of all grade CRS (58% vs. 83%, p &lt; 0.001), and all grade ICANS (6% vs. 31%, p &lt; 0.001), as well as grade 3+ CRS (0% vs. 28%, p = 0.6) and grade 3+ ICANS (0% vs. 12%, p = 0.004). Additionally, LBCL patients receiving bendamustine had lower rates of D+30 neutropenia (absolute neutrophil counts 2.05 versus 1.40, p = 0.02), and a lower cumulative incidence of febrile neutropenia at D+30 (6.2% (95% CI 1.6 - 16) versus 38% (95% CI 30-46%)). The median follow-up for patients with LBCL who received bendamustine LDC was 4.3 months (95% CI 3.8 - 6) and 13 months (95% CI 12-17) in those receiving flu/cy LDC. Analysis of the best overall response rate (ORR) by day 100 of the LBCL cohort did not reveal any significant difference based on the type of LDC received (70% versus 77%, respectively, p = 0.4). Within the LBCL group, there was no significant difference in the bendamustine versus flu/cy groups with the estimated 1-year progression free survival at 40% (95% CI 25-64) versus 42% (95% CI 33-52) (Figure 1), and 1-year overall survival of 76% (95% CI 61-93) versus 68% (95% CI 59-77), respectively.

CONCLUSIONS: Bendamustine LDC appears to be a satisfactory LDC agent with a more favorable toxicity profile compared to flu/cy in patients receiving CD19 CAR T cells for B-NHL. While we noted comparable outcomes between the two groups, the short follow-up time in the bendamustine group currently limits a clearer assessment of potential differences in survival between the two groups. Longer follow up is necessary to ensure responses are sustained in those receiving bendamustine.