Title: Association of CAR-T product type with incidence of cancer Therapy–Related cardiac dysfunction (CTRCD)

Abstract Background: Chimeric antigen receptor T-cell (CAR-T) therapy has transformed the treatment landscape for hematologic malignancies, offering significant survival benefits in relapsed or refractory disease. However, emerging evidence suggests that CAR-T therapy may be associated with cardiovascular toxicities, including cancer therapy-related cardiac dysfunction (CTRCD). These effects are hypothesized to be mediated, at least in part, by the systemic inflammatory response triggered during cytokine release syndrome (CRS), particularly through cytokines such as interleukin-6 . Given the increasing number of FDA-approved CAR-T products, it is critical to evaluate whether specific therapies carry differential cardiac risks. This study aims to characterize the incidence of CTRCD across various CAR-T products using echocardiographic parameters and assess whether any product-specific variation in cardiac dysfunction exists. Methods: We retrospectively analyzed 79 CAR-T recipients with available pre- and post-treatment echocardiograms (TTE). Of these patients, 59 had available TTE metrics with which to assess CTRCD, thus defining our final analysis cohort. CTRCD was defined by the following left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) parameters: either a decrease in left ventricular ejection fraction (LVEF) to an absolute value less than 50%, a ≥10% reduction in LVEF from baseline TTE, or a ≥15% reduction in GLS from baseline TTE. Descriptive statistics were used to characterize the incidence of CTRCD by CAR-T product subtype. Chi-squared and Fisher's exact tests were applied to evaluate differences in CTRCD incidence across subtypes. Results: Five CAR-T products were evaluated for their association with CTRCD: axicabtagene ciloleucel, idecabtagene vicleucel, brexucabtagene autoleucel, lisocabtagene maraleucel, and ciltacabtagene autoleucel. The overall incidence of CTRCD was 39.0% (23/59), with variation observed across product subtypes. Axicabtagene ciloleucel was associated with the highest incidence at 52.1% (12/23), followed by lisocabtagene maraleucel at 40.0% (2/5) and idecabtagene vicleucel at 37.5% (9/24). No CTRCD events occurred in patients receiving brexucabtagene autoleucel (0/4) or ciltacabtagene autoleucel (0/3). There was no statistically significant association between CAR-T product subtype and CTRCD incidence (Chi-square = 6.18, df = 8, p = 0.627). Due to the presence of expected cell counts <5, Fisher's exact test was also performed, which similarly showed no significant association (p = 0.692). Conclusion: In this retrospective study of CAR-T recipients, the overall incidence of cancer therapy-related cardiac dysfunction (CTRCD) was notable at 39%, with variability observed across CAR-T products. Axicabtagene ciloleucel demonstrated the highest rate of CTRCD, while no events were seen with brexucabtagene autoleucel or ciltacabtagene autoleucel. Despite these trends, statistical analyses did not reveal a significant association between CAR-T product type and CTRCD incidence. These findings highlight the need for prospective studies with larger cohorts to better understand the cardiotoxic risk profiles of individual CAR-T therapies and to guide risk stratification and monitoring strategies.