Bendamustine Lymphodepletion Before Axicabtagene Ciloleucel Is Safe and Associates with Reduced Inflammatory Cytokines.

Lymphodepletion (LD) is an integral component of chimeric antigen receptor T cell immunotherapies (CART). In this study, we compared the safety and efficacy of bendamustine (Benda) with standard fludarabine/cyclophosphamide (Flu/Cy) LD before CD19-directed, CD28-costimulated CART axicabtagene ciloleucel (axi-cel) in patients with large B-cell lymphomas (LBCL) and follicular lymphoma (FL). We analyzed 59 patients diagnosed with LBCL (48) and FL (11) consecutively treated with axi-cel at the University of Pennsylvania.. We also analyzed serum samples for cytokine levels and metabolomic changes pre- and post-LD. Flu/Cy and Benda demonstrated similar efficacy, with complete remission rates of 51.4% and 50.0% (p=0.981), respectively, and similar progression-free and overall survivals. Any-grade cytokine-release syndrome occurred in 91.9% of Flu/Cy-receiving patients versus 72.7% of patients receiving Benda (p=0.048); any-grade neurotoxicity after Flu/Cy occurred in 45.9% and after Benda in 18.2% of patients (p=0.031). Additionally, Flu/Cy was associated with a higher incidence of grade ≥3 neutropenia (100% vs. 54.5%; p<0.001), infections (78.4% vs. 27.3%; p<0.001), and neutropenic fever (78.4% vs. 13.6%; p<0.001). These results were confirmed in both LBCL and FL patients. Mechanistically, Flu/Cy patients had a greater increase in inflammatory cytokines associated with neurotoxicity and reduced levels of metabolites critical for redox balance and biosynthesis. This study suggests that Benda LD may be a safe alternative to Flu/Cy for CD28-based CART19 immunotherapy with similar efficacy and reduced toxicities. Benda is associated with reduced levels of inflammatory cytokines and increased anabolic metabolites.