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

• Published in: Journal of the American College of Cardiology 2021-11, Vol.78 (18), p.1800-1813
• Main Authors: Goldman, Adam, Maor, Elad, Bomze, David, Liu, Jennifer E., Herrmann, Joerg, Fein, Joshua, Steingart, Richard M., Mahmood, Syed S., Schaffer, Wendy L., Perales, Miguel-Angel, Shouval, Roni
• Format: Article
• Language: English
• Subjects: 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; cardiac arrhythmias; cardio-oncology; Cardiotoxicity - diagnosis; Cardiotoxicity - etiology; Cardiotoxicity - prevention & control; cardiovascular adverse events; Cardiovascular Diseases - chemically induced; Cardiovascular Diseases - classification; Cardiovascular Diseases - diagnosis; Cardiovascular Diseases - prevention & control; chimeric antigen receptor T cell; 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; venous thromboembolism
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2021.08.044

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). This study sought to investigate CPAEs associated with commercial CD19-directed CAR-T therapy. 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). 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%. 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. [Display omitted]