Biomarkers and cardiovascular outcomes in chimeric antigen receptor T-cell therapy recipients

Abstract

Aims Chimeric antigen receptor T-cell therapy (CAR-T) harnesses a patient’s immune system to target cancer. There are sparse existing data characterizing death outcomes after CAR-T-related cardiotoxicity. This study examines the association between CAR-T-related severe cardiovascular events (SCE) and mortality. Methods and results From a multi-centre registry of 202 patients receiving anti-CD19 CAR-T, covariates including standard baseline cardiovascular and cancer parameters and biomarkers were collected. Severe cardiovascular events were defined as a composite of heart failure, cardiogenic shock, or myocardial infarction. Thirty-three patients experienced SCE, and 108 patients died during a median follow-up of 297 (interquartile range 104–647) days. Those that did and did not die after CAR-T were similar in age, sex, and prior anthracycline use. Those who died had higher peak interleukin (IL)-6 and ferritin levels after CAR-T infusion, and those who experienced SCE had higher peak IL-6, C-reactive protein (CRP), ferritin, and troponin levels. The day-100 and 1-year Kaplan–Meier overall mortality estimates were 18% and 43%, respectively, while the non-relapse mortality (NRM) cumulative incidence rates were 3.5% and 6.7%, respectively. In a Cox model, SCE occurrence following CAR-T was independently associated with increased overall mortality risk [hazard ratio (HR) 2.8, 95% confidence interval (CI) 1.6–4.7] after adjusting for age, cancer type and burden, anthracycline use, cytokine release syndrome grade ≥ 2, pre-existing heart failure, hypertension, and African American ancestry; SCEs were independently associated with increased NRM (HR 3.5, 95% CI 1.4–8.8) after adjusting for cancer burden. Conclusion Chimeric antigen receptor T-cell therapy recipients who experience SCE have higher overall mortality and NRM and higher peak levels of IL-6, CRP, ferritin, and troponin.

Cardiovascular toxicities associated with bispecific T-cell engager therapy

“…The observation of substantial cardiovascular risks with BTEs adds to a growing body of evidence linking T-cell modulatory therapies with prognostic CVAEs. 17 27 In an analysis of patients treated with CAR-T therapy, CVAE development was the second-leading cause of death following therapy initiation. 17 Combined with our analysis, these observations suggest CVAEs following anticancer T-cell therapy are poorly tolerated and lead to reduced survival after treatment.…”

Inflammation and acute cardiotoxicity in adult hematological patients treated with CAR-T cells: results from a pilot proof-of-concept study

“…Having said that the high incidence of CTRCD observed in our study originates from the updated definition of CTRCD released by ESC [ 13 ], largely based on subclinical indexes like GLS and serum biomarkers, we believe that detecting such early manifestations might be important for improving CV outcomes in the cancer patient. A multicenter registry of 202 CART-cell patients receiving anti-CD19 therapies aimed at assessing a composite endpoint of heart failure, cardiogenic shock, or myocardial infarction [ 25 ]. Sixteen percent of subjects experienced severe cardiac events, which were independently associated with overall mortality (hazard ratio 2.8).…”

“…Sixteen percent of subjects experienced severe cardiac events, which were independently associated with overall mortality (hazard ratio 2.8). In analyzing determinants of event occurrence the authors identified a role for CV risk factors, in particular hypertension and history of atrial fibrillation or heart failure; interestingly, however, there was no information on clinical usage of anti-IL6 medications to mitigate CRS in these patients [ 25 ]. Post-marketing analyses similarly showed a fatality rate of CV and pulmonary adverse events, including late-occurring cardiomyopathy, tachyarrhythmias, pleural and pericardial effusions, as high as 30.9% [ 26 ].…”

Toxicities, intensive care management, and outcome of chimeric antigen receptor T cells in adults: an update

“…The mechanisms involved in cardiovascular dysfunction are thought to be primarily mediated by the systemic inflammation of CRS, particularly IL-6. In a recent trial, CAR-T-related severe cardiovascular events were independently associated with increased non-relapse mortality and overall mortality risk [ 52 ]. ICU management is not specific, but cardiac MRI has emerged as an interesting tool for the diagnosis of CAR-T cell-related cardiotoxicity and differential diagnoses [ 53 , 54 ].…”

“…ICU management is not specific, but cardiac MRI has emerged as an interesting tool for the diagnosis of CAR-T cell-related cardiotoxicity and differential diagnoses [ 53 , 54 ]. Because of the close interaction between CRS and CAR-T cell-related cardiotoxicity, cardiovascular complications must be managed with intravenous tocilizumab and are associated with rapid improvement [ 52 ] .…”