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

Syed S Mahmood; Peter A Riedell; Stephanie Feldman; Gina George; Stephen A Sansoterra; Thomas Althaus; Mahin Rehman; Elena Mead; Jennifer E Liu; Richard B Devereux; Jonathan W Weinsaft; Jiwon Kim; Lauren Balkan; Tarek Barbar; Katherine Lee Chuy; Bhisham Harchandani; Miguel-Angel Perales; Mark B Geyer; Jae H Park; M Lia Palomba; Roni Shouval; Ana A Tomas; Gunjan L Shah; Eric H Yang; Daria L Gaut; Michael V Rothberg; Evelyn M Horn; John P Leonard; Koen Van Besien; Matthew J Frigault; Zhengming Chen; Bhoomi Mehrotra; Tomas G Neilan; Richard M Steingart

doi:10.1093/eurheartj/ehad117

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

Eur Heart J. 2023 Jun 9;44(22):2029-2042. doi: 10.1093/eurheartj/ehad117.

Authors

Syed S Mahmood^{1

2}, Peter A Riedell³, Stephanie Feldman², Gina George⁴, Stephen A Sansoterra⁴, Thomas Althaus³, Mahin Rehman², Elena Mead⁵, Jennifer E Liu², Richard B Devereux¹, Jonathan W Weinsaft¹, Jiwon Kim¹, Lauren Balkan⁶, Tarek Barbar⁶, Katherine Lee Chuy², Bhisham Harchandani², Miguel-Angel Perales^{7

6}, Mark B Geyer^{8

6}, Jae H Park^{8

6}, M Lia Palomba^{9

6}, Roni Shouval^{7

6}, Ana A Tomas⁷, Gunjan L Shah^{7

6}, Eric H Yang¹⁰, Daria L Gaut¹¹, Michael V Rothberg¹², Evelyn M Horn¹, John P Leonard¹³, Koen Van Besien¹³, Matthew J Frigault^{14

15}, Zhengming Chen¹⁶, Bhoomi Mehrotra¹⁷, Tomas G Neilan¹⁸, Richard M Steingart²

Affiliations

¹ Cardio-Oncology Program, Division of Cardiology, Department of Medicine, Weill Cornell Medicine, 520 East 70th Street. ST 443, New York, NY 10021, USA.
² Cardiology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
³ The David and Etta Jonas Center for Cellular Therapy, University of Chicago, Chicago, IL 60637, USA.
⁴ Cornell MPH Program, Cornell University, Ithaca, NY 14853, USA.
⁵ Anesthesiology and Critical Care Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
⁶ Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA.
⁷ Adult BMT Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
⁸ Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
⁹ Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
¹⁰ UCLA Cardio-Oncology Program, Division of Cardiology, Department of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA.
¹¹ Division of Hematology/Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
¹² David Geffen School of Medicine, University of California at Los Angeles, CA 90095, USA.
¹³ Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA.
¹⁴ Cellular Immunotherapy Program, Division of Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
¹⁵ Division of Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
¹⁶ Division of Biostatistics, Department of Population Health Sciences, Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY 10021, USA.
¹⁷ The Cancer Center, St Francis Hospital, Roslyn, NY 11576, USA.
¹⁸ Cardio-Oncology Program, Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.

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.

Keywords: CAR-T cells; Cancer; Cardio-oncology; Cardiovascular events; Chimeric antigen receptor; Mortality.

MeSH terms

Biomarkers
C-Reactive Protein
Cell- and Tissue-Based Therapy
Heart Failure*
Humans
Interleukin-6
Neoplasms*
Receptors, Chimeric Antigen* / therapeutic use
Troponin

Substances

Receptors, Chimeric Antigen
Interleukin-6
Biomarkers
C-Reactive Protein
Troponin

Abstract

MeSH terms

Substances

Grants and funding