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

Adam Goldman; Elad Maor; David Bomze; Jennifer E. Liu; Joerg Herrmann; Joshua Fein; Richard M. Steingart; Syed S. Mahmood; Wendy L. Schaffer; Miguel Angel Perales; Roni Shouval

doi:10.1016/j.jacc.2021.08.044

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

Adam Goldman
, Elad Maor
, David Bomze
, Jennifer E. Liu
, Joerg Herrmann
, Joshua Fein
, Richard M. Steingart
, Syed S. Mahmood
, Wendy L. Schaffer
, Miguel Angel Perales
, Roni Shouval

Research output: Contribution to journal › Article › peer-review

126 Scopus citations

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.

Original language	English
Pages (from-to)	1800-1813
Number of pages	14
Journal	Journal of the American College of Cardiology
Volume	78
Issue number	18
DOIs	https://doi.org/10.1016/j.jacc.2021.08.044
State	Published - 2 Nov 2021
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2021 American College of Cardiology Foundation

Funding

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. 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.

Funders	Funder number
Center for International Blood and Marrow Transplant Research
National Institutes of Health
National Cancer Institute	P30 CA008748, R01CA233610

Keywords

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

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10.1016/j.jacc.2021.08.044

Cite this

@article{ade3e0c640404438a959f9e3c8a87d29,

title = "Adverse Cardiovascular and Pulmonary Events Associated With Chimeric Antigen Receptor T-Cell Therapy",

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",

author = "Adam Goldman and Elad Maor and David Bomze and Liu, \{Jennifer E.\} and Joerg Herrmann and Joshua Fein and Steingart, \{Richard M.\} and Mahmood, \{Syed S.\} and Schaffer, \{Wendy L.\} and Perales, \{Miguel Angel\} and Roni Shouval",

note = "Publisher Copyright: {\textcopyright} 2021 American College of Cardiology Foundation",

year = "2021",

month = nov,

day = "2",

doi = "10.1016/j.jacc.2021.08.044",

language = "אנגלית",

volume = "78",

pages = "1800--1813",

journal = "Journal of the American College of Cardiology",

issn = "0735-1097",

publisher = "Elsevier Inc.",

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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

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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DO - 10.1016/j.jacc.2021.08.044

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AN - SCOPUS:85117202191

SN - 0735-1097

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JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

IS - 18

ER -

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

Abstract

Bibliographical note

Funding

Keywords

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