Background Over the past six years, chimeric antigen receptor (CAR) T cell therapy has shown great efficacy and promise for the treatment of hematologic malignancies and research is ongoing in a variety of other disease areas.¹ Cardiovascular events are serious potential side effects of many oncological therapies, but have only been evaluated retrospectively in the context of CAR T cells and thus mainly in symptomatic patients in the respective study cohorts.² In a patient population that is already heavily pretreated and therefore at increased risk, our aim was to prospectively evaluate the incidence of cardiotoxicity. Additionally, we analyzed the importance of cardiac biomarkers and cardiac risk factors in relation to cardiac events and all-cause mortality (ACM).

Methods This observational study included patients who received CAR T cells at the University Hospital of Heidelberg between October 2018 and October 2022. ACM was defined as the primary endpoint of the study, while cardiotoxicity, determined by clinical syndromes such as a decrease in the ejection fraction, served as the secondary endpoint. Monitoring included 2D echocardiography, 12-lead electrocardiogram, as well as cardiac biomarkers (highly sensitive troponin T (hs-cTnT); brain N-terminal natriuretic peptide (NT-proBNP)) at multiple timepoints, starting before lymphodepleting chemotherapy and continuing through 180 days after CAR T-cell infusion.

Results A total of 137 patients with a median age of 60 years (range 20–83, 72% male) were included in the study. During the follow-up, 46 patients deceased (34%), while the secondary endpoint was met by 93 patients (68%). No major adverse cardiac events (MACE) were reported in the study cohort and no baseline parameter predicted an increased cardiac risk. However, a 35%-cutoff for hs-cTnT change from lymphodepletion to within the first 14 days after CAR T cell infusion was identified, which was predictive not only for patients with an increased ACM (35%: OR 2.26, 95%-CI 1.00–5.17; p=0.050) but also for patients at risk of cardiac events. A continuous increase in significance for predicting survival was observed with increasing hs-cTnT change (e.g., 60%: OR 6.18, 95%-CI 2.28–18.19; p<0.001).

Conclusions In this first prospective observational study, CAR T cell application shows a relatively low incidence of cardiotoxic events in general and no MACE was detected. However, with an increase in cardiac biomarkers within 14 days after CAR T cell infusion, extended cardio-oncologic monitoring is recommended.

Acknowledgements All authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

1. Wang V, Gauthier M, Decot V, Reppel L, Bensoussan D. Systematic Review on CAR-T Cell Clinical Trials Up to 2022: Academic Center Input. Cancers (Basel). 2023 Feb 4;15(4):1003.

2. Ghosh AK, Chen DH, Guha A, Mackenzie S, Walker JM, Roddie C. CAR T Cell Therapy-Related Cardiovascular Outcomes and Management: Systemic Disease or Direct Cardiotoxicity? JACC CardioOncol. 2020 Mar 17;2(1):97–109.

Ethics Approval Ethical approval as well as approval from the local and federal competent authorities were granted (Ethics Committee of the Medical Faculty, University Heidelberg; October 2017, AFmu-405/2017).

Consent Written informed consent for all patients was obtained according to the Declaration of Helsinki.