Adverse Cardiovascular and Pulmonary Events Associated With Chimeric Antigen Receptor T-Cell Therapy

J Am Coll Cardiol. 2021 Nov 2;78(18):1800-1813. doi: 10.1016/j.jacc.2021.08.044.

Abstract

Background: Pivotal trials of chimeric antigen receptor T-cell (CAR-T) have identified common toxicities but may have been underpowered to detect cardiovascular and pulmonary adverse events (CPAEs).

Objectives: This study sought to investigate CPAEs associated with commercial CD19-directed CAR-T therapy.

Methods: In this retrospective, pharmacovigilance study, the authors used the Food and Drug Administration adverse event reporting system to identify CPAEs associated with axicabtagene-ciloleucel and tisagenlecleucel. The authors evaluated disproportionate reporting by the reporting odds ratio (ROR) and the lower bound of the information component 95% credibility interval (IC025 >0 is deemed significant). Significant associations were further adjusted to age and sex (adj.ROR).

Results: The authors identified CAR-T reports of 2,657 patients, including 546 CPAEs (20.5%). CPAEs overlapped with cytokine release syndrome in 68.3% (373 of 546) of the reports. Compared with the full database, CAR-T was associated with overreporting of tachyarrhythmias (n = 74 [2.8%], adj.ROR = 2.78 [95% CI: 2.21-3.51]), cardiomyopathy (n = 69 [2.6%], adj.ROR = 3.51 [2.42-5.09]), pleural disorders (n = 46 [1.7%], adj.ROR = 3.91 [2.92-5.23]), and pericardial diseases (n = 11 [0.4%], adj.ROR = 2.26 [1.25-4.09], all IC025 >0). Venous thromboembolic events (VTEs) were associated only with axicabtagene-ciloleucel therapy (n = 28 [1.6%], adj.ROR = 1.80 [1.24-2.62], IC025 >0). Atrial fibrillation (n = 55) was the leading tachyarrhythmia, followed by ventricular arrhythmias (n = 14). Tachyarrhythmias and VTEs were reported more often following axicabtagene-ciloleucel than tisagenlecleucel in an age- and sex-adjusted model (adj.ROR = 1.82 [1.04-3.18] and adj.ROR = 2.86 [1.18-6.93], respectively). Finally, the fatality rate of CPAEs was 30.9%.

Conclusions: In this largest post-marketing study to date, the authors identified an association between CAR-T and various CPAEs, including tachyarrhythmias, cardiomyopathy, pericardial and pleural disorders, and VTEs. These findings should be considered in the multidisciplinary assessment for and monitoring of CAR-T therapy recipients.

Keywords: cardiac arrhythmias; cardio-oncology; cardiovascular adverse events; chimeric antigen receptor T cell; pharmacovigilance; venous thromboembolism.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adverse Drug Reaction Reporting Systems / statistics & numerical data
  • Antineoplastic Agents, Immunological / administration & dosage
  • Antineoplastic Agents, Immunological / adverse effects
  • Biological Products* / administration & dosage
  • Biological Products* / adverse effects
  • Cardiotoxicity* / diagnosis
  • Cardiotoxicity* / etiology
  • Cardiotoxicity* / prevention & control
  • Cardiovascular Diseases* / chemically induced
  • Cardiovascular Diseases* / classification
  • Cardiovascular Diseases* / diagnosis
  • Cardiovascular Diseases* / prevention & control
  • Drug Monitoring / methods
  • Humans
  • Immunotherapy, Adoptive* / adverse effects
  • Immunotherapy, Adoptive* / methods
  • Immunotherapy, Adoptive* / statistics & numerical data
  • Lung Diseases* / chemically induced
  • Lung Diseases* / classification
  • Lung Diseases* / diagnosis
  • Lung Diseases* / prevention & control
  • Needs Assessment
  • Pharmacovigilance
  • Receptors, Antigen, T-Cell / administration & dosage*
  • United States
  • United States Food and Drug Administration / statistics & numerical data

Substances

  • Antineoplastic Agents, Immunological
  • Biological Products
  • CD19-specific chimeric antigen receptor
  • Receptors, Antigen, T-Cell
  • tisagenlecleucel
  • axicabtagene ciloleucel