Impact of antibiotic timing on survival outcomes in CD19 and BCMA CAR-T cell therapy

Abstract

Abstract Introduction: Patients undergoing chimeric antigen receptor T-cell (CAR-T)therapy are often treated with antibiotics in the post CAR-T period due to fevers in the setting of cytokine release syndrome. Prior work has suggested that broad spectrum antibiotics both in the post and pre CAR-T period may be deleterious to CAR-T cell efficacy and overall survival (OS) in patients with B-cell malignancies. In particular, the PIM (piperacillin-tazobactam, imipenem, and meropenem) have been implicated with poor outcomes.This is possibly related to dysregulation of the gut microbiome and/or impairment of hematopoietic recovery. Here, we aimed to investigate the effect of pre and post CAR-T antibiotics in patients receiving both CD19 and BCMA CAR-T cell therapy. Methods: This is a single-center retrospective study of adult patients with multiple myeloma, B-cell lymphoma, and acute lymphoblastic leukemia treated with autologous CD19 and BCMA targeting CAR-T cell therapy at our center between April 2017 and August 2024. CD19 CAR-T cell products included lisocabtagene maraleucel, tisagenlecleucel, brexucabtagene autoleucel, and axicabtagene ciloleucel. BCMA CAR-T cell products included idecabtagene vicleucel and ciltacabtagene autoleucel. We also included patients on clinical trials receiving experimental CAR-T products (labelled “other”). We collected data on pre CAR-T cell therapy antibiotic exposure (defined as antibiotics received 30 days prior up to day of CAR T-cell infusion), post CAR-T cell therapy exposure (defined as antibiotics received on day of CAR T-cell infusion up to 30 days after). Primary outcomes were progression free survival (PFS) and overall survival (OS). Secondary outcome was progression at first PET-CT scan. We constructed Cox regression models to model survival outcomes adjusted for age, prior lines of therapy, and infection rate. Results: Of the 329 total patients, 96 received CD19 CAR-T cell therapy, 198 received BCMA CAR-T cell therapy and 35 were enrolled in clinical trials for experimental products. The median age for the entire population was 61, and 60% were male. Patients receiving CD19 therapy were more likely to receive pre CAR-T antibiotics than patients receiving BCMA therapy (17.7% vs 7.5%, p-value 0.016). Median duration of pre CAR-T antibiotic was 7 days for CD19 CAR-T patients and 8 days for BCMA CAR-T patients. The majority of patients received antibiotics post CAR-T, with 83% of CD19 patients, 57% of BCMA patients, and 66% of other patients receiving antibiotics post CAR-T. Patients receiving CD19 therapy were more likely to receive longer durations of post CAR-T antibiotics (defined as >5 days versus 5 or less days) than BCMA patients (62.5% vs 42.4%, p-value 0.0026). Median duration of post CAR-T antibiotics was 7 days for CD19 CAR-T patients and 6 days for BCMA CAR-T patients. Post CAR-T antibiotics were largely fourth generation cephalosporins such as cefepime in combination with vancomycin. Few patients received PIM antibiotics. Median OS for patients who received no pre CAR-T antibiotics was 559 days [IQR 212,973] compared to 216 days [IQR 91,727] for patients who did receive pre CAR-T antibiotics. After multivariable adjustment, pre CAR-T antibiotic exposure was still associated with worse OS (HR 2.52 [1.03,6.16]). This remained true when done for subset analyses: BCMA therapy patients who received pre CAR-T antibiotics had worse OS (HR 2.6 [1.1, 6.3]) as did CD19 therapy patients who received pre CAR-T antibiotics (HR 2.45 [1.01,5.9]) than patients who did not receive any pre CAR-T antibiotics. Post CAR-T antibiotics did not have an effect on overall survival. Neither pre nor post CAR-T antibiotics had a statistically significant effect on PFS nor on progression at first PET-CT scan. Conclusions: Exposure to antibiotics in the 30 days prior to CAR-T cell therapy was associated with worse OS, even when adjusted for age, prior lines of therapy, and infection rate. Post CAR-T antibiotics did not have an effect on PFS or OS, nor on progression at first PET-CT scan. Clinicians should be judicious with antibiotic exposure in the 30 days prior to CAR-T cell therapy.