Impact of Broad-Spectrum Antibiotic Exposure on CAR-T Therapy Outcomes in B-Cell Lymphoma: A Multicenter International Study

Background: Previous studies by us and others have shown that broad-spectrum antibiotic exposure, particularly with PIM (piperacillin-tazobactam, imipenem, and meropenem), before CD19-chimeric antigen receptor T-cell (CAR-T) therapy is associated with poor outcomes in B-cell malignancies. Larger studies are needed to clarify the impact of antibiotics administered after CAR-T infusion, especially in the context of cytokine release syndrome (CRS), where fevers and subsequent antibiotic use are common. Additionally, a more detailed understanding of the effects of specific antibiotics given before and after CAR-T therapy is necessary. This study aims to elucidate the influence of commonly used broad-spectrum antibiotics, including 4th generation cephalosporins (CS, e.g., Cefepime) and PIM, on the efficacy of CAR-T therapy.

Methods: This multicenter international observational study included adult patients treated with autologous CD19 CAR-T cells for large B-cell lymphoma (LBCL). We documented all antibiotic exposures from lymphodepletion initiation to 30 days post-infusion. Exposure between the start of lymphodepletion and the day preceding infusion was defined as pre-CAR-T, while exposure from the day of infusion to 30 days post-infusion was defined as post-CAR-T. Patients exposed to CS or PIM pre-CAR-T were excluded from the post-CAR-T analysis. We constructed multivariable logistic regression and Cox regression models to evaluate response and survival-related outcomes, respectively. All antibiotic exposure models were adjusted for age, pre-lymphodepletion LDH levels, bridging therapy, CAR-T product, and center. Post-CAR-T models were landmarked at day 30 post-infusion and adjusted for the occurrence of CRS.

Results: Among the 956 patients, the median age was 63 (IQR 52-70). Most patients (60%) were treated in US centers, with the remainder in European centers. Bridging therapy was administered to 69% of patients. Axi-cel was the most common CAR-T product (40%), followed by tisa-cel (35%), liso-cel (12%), and a CD19-point-of-care academic product (13%).

In the pre-CAR-T period, 12% of patients were exposed to broad-spectrum antibiotics (PIM and/or CS); 10% to PIM and 2.5% to CS, with 7 patients exposed to both. Post-CAR-T, 75% of patients experienced CRS. Additionally, 67% of patients were exposed to broad-spectrum antibiotics, with significant variation across centers. PIM was used in 56% of patients, with center-specific rates ranging from 10% to 90%. CS were used in 16% of patients, with rates ranging from 0% to 41%. The median duration of post-CAR-T broad-spectrum antibiotic exposure was 9 days (IQR 6-12). Post-CAR-T bloodstream infections were rarely identified, and antibiotic treatment was predominantly empiric.

In multivariable regression models, pre-CAR-T exposure to either PIM and/or CS was associated with a decreased likelihood of complete response (CR) (OR 0.50 [95% CI 0.30-0.82]), shorter overall survival (OS) (HR 2.12 [1.57-2.85]), and progression-free survival (PFS) (HR 1.66 [1.24-2.22]). When considered independently, both PIM and CS maintained a detrimental association with OS.

After multivariable adjustment, post-CAR-T exposure to either PIM and/or CS was not associated with CR, OS, or PFS. However, when PIM was considered independently, it was associated with shorter OS compared to non-exposed patients (HR 1.49 [1.00-2.11]). In multivariable Cox regression models, patients with post-CAR-T exposure to either PIM and/or CS for 10 days or more had shorter OS (HR 1.55 [1.01-2.37]), but not inferior PFS or CR, compared to those with no exposure. Notably, patients with exposure >10 days had higher pre-CAR-T LDH and more severe CRS and ICANS. Shorter exposure (<10 days) was not associated with lower OS or PFS or lower CR rates compared to no exposure.

Conclusions and Perspectives: In this large international multicenter study, two-thirds of patients were exposed to broad-spectrum antibiotics after CAR-T cell infusion, often for durations exceeding a week. Importantly, initiation of broad-spectrum antibiotics after CAR-T infusion with an exposure of less than 10 days did not appear to compromise anti-lymphoma treatment efficacy. These findings may help guide antibiotic use in patients undergoing CAR-T therapy.

Ghilardi:Vittoria Biotherapeutics: Honoraria. Peled:MaaT Pharma: Consultancy; Canaccord Genuity, Inc: Consultancy; Postbiotics Plus Research: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Prodigy Biosciences: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Seres Therapeutics: Patents & Royalties, Research Funding; DaVolterra: Consultancy; CSL Behring: Consultancy; Crestone Inc: Consultancy. Nasta:MERCK: Other: DSMB; Acrotech: Membership on an entity's Board of Directors or advisory committees; ADCT: Membership on an entity's Board of Directors or advisory committees; GenMab: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Takeda: Research Funding; Pharmacyclics: Research Funding; Loxo/Lilly: Research Funding; FortySeven/Gilead: Research Funding; ATAEA: Research Funding; ASTEX: Research Funding; ONO therapeutics: Research Funding; Caribou Biosciences: Research Funding. Rejeski:BMS/celgene: Consultancy, Honoraria; Pierre-Fabre: Other: Travel support; novartis: Honoraria; kite/gilead: Consultancy, Honoraria, Other: Travel support, Research Funding. Boardman:Bristol Myers Squibb: Consultancy; OncLive: Honoraria; Cancer Study Group, LLC: Consultancy. Scordo:Miltenyi Biotec: Consultancy; Sanofi: Research Funding; Kite - A Gilead Company: Consultancy; Angiocrine Biosciences, Inc.: Research Funding; MJH Life Sciences (Cancer Network): Honoraria; IDEOlogy: Honoraria; Medscape: Honoraria; Amgen: Research Funding; Omeros Corporation: Consultancy, Research Funding. 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Shah:Janssen, Amgen, Beyond Spring, BMS, GPCR, DSMB with ArcellX.: Research Funding. Palomba:Bristo Meyer Squibb: Consultancy; Synthekine: Consultancy; Novartis: Consultancy; Cellectar: Consultancy. Salles:BMS/Celgene: Consultancy; Genentech/Roche: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Kite/Gilead: Consultancy; Incyte: Consultancy; Genmab: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Merck: Consultancy; Ipsen: Consultancy, Research Funding; BeiGene: Consultancy; Molecular Partners: Consultancy; Nurix: Research Funding. 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Ruella:Vittoria Biotherapeutics: Current equity holder in private company, Patents & Royalties; AbClon Inc.: Other: Consultancy, Research Funding.