Characterizing risk factors for the development of cardiovascular events in CAR-T Patients
Authors: Song J J , Vuong J T , Gornbein J , Rothberg M , Pan C , Dhaliwal J , Gaut D , Mead M D , Larson S M , Eradat H A , Schiller G J , De Vos S , Timmerman J M , Young P A , Yang E H 
Published: November 2023

Abstract

Introduction
Chimeric antigen receptor (CAR) T-cell therapy, which involves ex-vivo engineering of autologous T-cells against cancer cells, has transformed the management of B and plasma cell malignancies, leading to further efforts in identifying new targets and indications. As the use of CAR T therapy expands, understanding its effects on the cardiovascular (CV) system becomes increasingly relevant. The systemic inflammatory response elicited by CAR T therapy can result in cytokine release syndrome (CRS) with manifestations including sinus tachycardia, hypotension, arrhythmias, and in severe cases, left ventricular dysfunction and cardiogenic shock. Risk factors for CAR T related CV events are not well-described. We evaluated risk factors for a primary composite endpoint of adverse CV events in a real-world cohort of patients with B and plasma cell malignancies receiving standard of care (SOC) CAR T therapy.

Methods
Medical records from all consecutive patients treated with SOC CAR T cell therapy at a U.S. health system from March 2018 to December 2021 were retrospectively reviewed under an IRB approved protocol. Our outcome was a single composite endpoint of clinically significant CV events including arrhythmia, acute coronary syndrome, stroke, CV death, ejection fraction decrease under 52.5%, heart failure exacerbation, and acute pericardial disease. All events resulted in an inpatient cardiology consult, upgrade to an ICU, or outpatient cardiology appointment. A multivariable Fine-Gray model was used to model CV risk and account for the competing risk of non-CV death.

Results
123 patients were evaluated with a median follow-up of 16 months. 32 (26.0%) patients experienced the composite endpoint, with 1 CV death and 18 subsequent non-CV deaths, primarily from progressive disease (PD). Of the 91 patients that did not experience an adverse CV event, 35 (28.5%) died of non-CV causes, most commonly PD. In bivariate analysis, history of Coronary Artery Disease, Atrial Fibrillation (AF), Mantle Cell lymphoma, Tyrosine Kinase Inhibitor (TKI) exposure, Eastern Cooperative Oncology Group (ECOG) score ≥ 1, and CRS grade ≥ 2 were associated with the composite outcome (Table 1). A multivariable Fine-Gray regression model developed with stepwise selection showed a history of AF, ECOG score ≥ 1, Hispanic ethnicity, or CRS grade ≥ 2 were simultaneously associated with the composite outcome (Figure 1).

Conclusions
Risk factors associated with adverse CV events in CAR T include a history of AF, ECOG score ≥1, CRS grade ≥ 2, and Hispanic ethnicity. These findings are limited by sample size and number of events. These predictors, if validated in larger cohorts, have the potential to identify patients at high risk for CV complications who may benefit from multidisciplinary care pre- and post-CAR T infusion. Enhanced collaboration between oncologists and cardiologists to optimize CV function for this high-risk cohort may lead to improved outcomes.