TY - JOUR
T1 - Adverse Cardiovascular and Pulmonary Events Associated With Chimeric Antigen Receptor T-Cell Therapy
AU - Goldman, Adam
AU - Maor, Elad
AU - Bomze, David
AU - Liu, Jennifer E.
AU - Herrmann, Joerg
AU - Fein, Joshua
AU - Steingart, Richard M.
AU - Mahmood, Syed S.
AU - Schaffer, Wendy L.
AU - Perales, Miguel Angel
AU - Shouval, Roni
N1 - Funding Information:
This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748. This study was supported in part by NIH/NCI grant RO1-CA 233610 (Dr Herrmann). Dr Perales has received personal fees from Abbvie, Bellicum, Bristol Myers Squibb, Celgene, Cidara Theraputics, Incyte, Kite/Gilead, Medigene, Miltenyi, MolMed, Nektar Therapeutics, NexImmune, Novartis, Omeros, Merck, Servier, and Tekeda; has served on data safety and monitoring boards for Cidara Therapeutics, Medigene, and Servier; and has received clinical trial support from Incyte, Kite/Gilead, and Miltenyi. Data presented in this study do not represent the opinion of the United States Food and Drug Administration (FDA). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Funding Information:
The authors thank Dr. Marcelo Pasquini and the Cellular Immunotherapy Data Resource (CIDR) from the Center for International Blood and Marrow Transplant Research (CIBMTR) for providing registry data on patients treated with chimeric antigen receptor T-cells.
Publisher Copyright:
© 2021 American College of Cardiology Foundation
PY - 2021/11/2
Y1 - 2021/11/2
N2 - 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.
AB - 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.
KW - cardiac arrhythmias
KW - cardio-oncology
KW - cardiovascular adverse events
KW - chimeric antigen receptor T cell
KW - pharmacovigilance
KW - venous thromboembolism
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U2 - 10.1016/j.jacc.2021.08.044
DO - 10.1016/j.jacc.2021.08.044
M3 - Article
C2 - 34711339
AN - SCOPUS:85117202191
VL - 78
SP - 1800
EP - 1813
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
SN - 0735-1097
IS - 18
ER -