Research Article

Updated insights on cardiac risks of CD19-directed chimeric antigen receptor T-cell therapy: a pharmacovigilance study

Clinical Research Center, School of Medicine, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, 200011, China

‡Authors contributed equally

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Fangyuan Hu‡

Department of Medical Service, Naval Hospital of Eastern theater, Zhejiang Zhoushan, 316000, China

Department of Health Statistics, Second Military Medical University, Shanghai, 200433, China

‡Authors contributed equally

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Borui Zhu‡

Department of Medical Service, Naval Hospital of Eastern theater, Zhejiang Zhoushan, 316000, China

‡Authors contributed equally

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Jinfang Xu

Department of Health Statistics, Second Military Medical University, Shanghai, 200433, China

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Xiaojing Guo

Department of Health Statistics, Second Military Medical University, Shanghai, 200433, China

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Wentao Shi

Clinical Research Center, School of Medicine, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, 200011, China

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Xiang Zhou

Department of Medical Service, Naval Hospital of Eastern theater, Zhejiang Zhoushan, 316000, China

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Yi Zheng

Department of Health Statistics, Second Military Medical University, Shanghai, 200433, China

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Xiao Xu

Tongji University School of Medicine, 1239 Siping Road, Yangpu District, Shanghai, 200092, China

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Xiaofei Ye

**Author for correspondence:

E-mail Address: yexiaofei@smmu.edu.cn

Department of Health Statistics, Second Military Medical University, Shanghai, 200433, China

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Jia He

https://orcid.org/0000-0002-2338-9501

Tongji University School of Medicine, 1239 Siping Road, Yangpu District, Shanghai, 200092, China

Department of Health Statistics, Second Military Medical University, Shanghai, 200433, China

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Feng Xu

*Author for correspondence:

E-mail Address: xufenghhou@163.com

Clinical Research Center, School of Medicine, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, 200011, China

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Published Online:23 Mar 2023https://doi.org/10.2217/imt-2022-0145

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Abstract

Aim: Comprehensively characterize the cardiotoxicity of CD19-directed chimeric antigen receptor T-cell (CAR-T) products. Materials & methods: Data between 2017 and 2021 in the US FDA's Adverse Event Reporting System database were utilized. Disproportionality was measured using reporting odds ratio and information component. Hierarchical clustering analysis was performed to explore the relationships among cardiac events. Results: Tisagenlecleucel exhibited the highest percentage of death (53.24%) and life-threatening (13.39%) outcomes. Axicabtagene ciloleucel and tisagenlecleucel were equal in the number of positive signals (n = 15), while the former had excessive reporting of several cardiac events versus the latter, such as atrial fibrillation, cardiomyopathy, cardiorenal syndrome and sinus bradycardia. Conclusion: Several cardiac risks should be considered for CAR-T treatment and these events might vary in frequency and severity following different CAR-T agents.

Plain language summary

Chimeric antigen receptor T-cell (CAR-T) therapy is effective in a wide spectrum of malignancies. However, the complete cardiotoxicity profile associated with this new treatment has not been characterized. This study systematically analyzed the reported cardiac events of four approved CAR-T agents using the US FDA's Adverse Event Reporting System database. It indicated that the type of cardiac events was broad and overlapped a lot with cytokine release syndrome. Pre-therapy assessment, intensive monitoring and appropriate intervention were critical to reduce the level of cardiac damage or the rate of mortality in patients receiving CAR-T.

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Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

1. Barac A, Sharon E. From detecting signals to understanding cardiovascular toxicities of cancer therapies: all the light we could see. J. Am. Coll. Cardiol. 78, 1814–1816 (2021). • Brief overview of the cardiovascular toxicities of cancer therapies.
MedlineGoogle Scholar
2. Safarzadeh KP, Shabani S. Adverse events and side effects of chimeric antigen receptor (CAR) T cell therapy in patients with hematologic malignancies. Trends Mol. Med. 1(1), e116301 (2021).
Google Scholar
3. Lei W, Xie M, Jiang Q et al. Treatment-related adverse events of chimeric antigen receptor T-cell (CAR T) in clinical trials: a systematic review and meta-analysis. Cancers (Basel) 13(15), 3912 (2021). •• Meta-analysis demonstrating various chimeric antigen receptor T-cell (CAR-T)-related events in clinical trials.
Medline CASGoogle Scholar
4. Westin JR, Kersten MJ, Salles G et al. Efficacy and safety of CD19-directed CAR-T cell therapies in patients with relapsed/refractory aggressive B-cell lymphomas: observations from the JULIET, ZUMA-1, and TRANSCEND trials. Am. J. Hematol. 96(10), 1295–1312 (2021).
MedlineGoogle Scholar
5. Prasad V. Tisagenlecleucel – the first approved CAR-T-cell therapy: implications for payers and policy makers. Nat. Rev. Clin. Oncol. 15(1), 11–12 (2018).
MedlineGoogle Scholar
6. Hashem Boroojerdi M, Rahbarizadeh F, Safarzadeh Kozani P, Kamali E, Safarzadeh Kozani P. Strategies for having a more effective and less toxic CAR T-cell therapy for acute lymphoblastic leukemia. Med. Oncol. 37(11), 100 (2020).
MedlineGoogle Scholar
7. Mullard A. FDA approves first BCMA-targeted CAR-T cell therapy. Nat. Rev. Drug. Discov. 20(5), 332 (2021).
Google Scholar
8. American Association for Cancer research. FDA approves second CAR T-cell therapy. Cancer Discov. 8(1), 5–6 (2018).
MedlineGoogle Scholar
9. Voelker R. CAR-T therapy is approved for mantle cell lymphoma. JAMA 324(9), 832 (2020).
Google Scholar
10. Mian A, Hill BT. Brexucabtagene autoleucel for the treatment of relapsed/refractory mantle cell lymphoma. Expert Opin. Biol. Ther. 21(4), 435–441 (2021).
Medline CASGoogle Scholar
11. Stein-Merlob AF, Rothberg MV, Ribas A, Yang EH. Cardiotoxicities of novel cancer immunotherapies. Heart 107(21), 1694–1703 (2021).
Medline CASGoogle Scholar
12. Goldman A, Maor E, Bomze D et al. Adverse cardiovascular and pulmonary events associated with chimeric antigen receptor T-cell therapy. J. Am. Coll. Cardiol. 78(18), 1800–1813 (2021). •• Disproportionality analysis highlighting several cardiac toxicities associated with CAR-T treatment.
MedlineGoogle Scholar
13. Alvi RM, Frigault MJ, Fradley MG et al. Cardiovascular events among adults treated with chimeric antigen receptor T-cells (CAR-T). J. Am. Coll. Cardiol. 74(25), 3099–3108 (2019). • Retrospective cohort study evaluating the possible cardiac toxicities of CAR-T.
Medline CASGoogle Scholar
14. Ganatra S, Redd R, Hayek SS et al. Chimeric antigen receptor T-cell therapy-associated cardiomyopathy in patients with refractory or relapsed non-Hodgkin lymphoma. Circulation 142(17), 1687–1690 (2020).
Medline CASGoogle Scholar
15. Burstein DS, Maude S, Grupp S et al. Cardiac profile of chimeric antigen receptor T cell therapy in children: a single-institution experience. Biol. Blood Marrow Transplant. 24(8), 1590–1595 (2018).
MedlineGoogle Scholar
16. Lefebvre B, Kang Y, Smith AM, Frey NV, Carver JR, Scherrer-Crosbie M. Cardiovascular effects of CAR T cell therapy: a retrospective study. JACC CardioOncol. 2(2), 193–203 (2020).
MedlineGoogle Scholar
17. Kasliwal R. Spontaneous reporting in pharmacovigilance: strengths, weaknesses and recent methods of analysis. J. Clin. Prev. Cardiol. 1, 20–23 (2012).
Google Scholar
18. Guha A, Addison D, Jain P et al. Cardiovascular events associated with chimeric antigen receptor T cell therapy: cross-sectional FDA adverse events reporting system analysis. Biol. Blood Marrow Transplant. 26(12), 2211–2216 (2020).
Medline CASGoogle Scholar
19. Garcia CR, Jayswal R, Adams V, Anthony LB, Villano JL. Multiple sclerosis outcomes after cancer immunotherapy. Clin. Transl. Oncol. 21(10), 1336–1342 (2019).
MedlineGoogle Scholar
20. Fukazawa C, Hinomura Y, Kaneko M, Narukawa M. Significance of data mining in routine signal detection: analysis based on the safety signals identified by the FDA. Pharmacoepidemiol. Drug Saf. 27(12), 1402–1408 (2018).
MedlineGoogle Scholar
21. Harpaz R, DuMouchel W, LePendu P, Bauer-Mehren A, Ryan P, Shah NH. Performance of pharmacovigilance signal-detection algorithms for the FDA adverse event reporting system. Clin. Pharmacol. Ther. 93(6), 539–546 (2013).
Medline CASGoogle Scholar
22. Salem JE, Manouchehri A, Bretagne M et al. Cardiovascular toxicities associated with ibrutinib. J. Am. Coll. Cardiol. 74(13), 1667–1678 (2019).
Medline CASGoogle Scholar
23. Ang PS, Chen Z, Chan CL, Tai BC. Data mining spontaneous adverse drug event reports for safety signals in Singapore – a comparison of three different disproportionality measures. Expert Opin. Drug Saf. 15(5), 583–590 (2016).
Medline CASGoogle Scholar
24. Hou Y, Ye X, Wu G, Cheng G, Du X, He J. A comparison of disproportionality analysis methods in national adverse drug reaction databases of China. Expert Opin. Drug Saf. 3(7), 853–857 (2014). •• Introduction and comparison of several disproportionality analysis methods.
Google Scholar
25. Norén GN, Hopstadius J, Bate A. Shrinkage observed-to-expected ratios for robust and transparent large-scale pattern discovery. Stat. Methods Med. Res. 22(1), 57–69 (2013). • Explanation of the statistical shrinkage technique.
MedlineGoogle Scholar
26. Meng J, Wu X, Sun Z et al. Efficacy and safety of CAR-T cell products axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel for the treatment of hematologic malignancies: a systematic review and meta-analysis. Front. Oncol. 11, 698607 (2021).
MedlineGoogle Scholar
27. Ghosh AK, Chen DH, Guha A, Mackenzie S, Walker JM, Roddie C. CAR T cell therapy-related cardiovascular outcomes and management: systemic disease or direct cardiotoxicity? JACC CardioOncol. 2(1), 97–109 (2020).
MedlineGoogle Scholar
28. Grigor EJM, Fergusson D, Kekre N et al. Risks and benefits of chimeric antigen receptor T-cell (CAR-T) therapy in cancer: a systematic review and meta-analysis. Transfus. Med. Rev. 33(2), 98–110 (2019).
MedlineGoogle Scholar
29. Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood 127(26), 3321–3330 (2016).
Medline CASGoogle Scholar
30. Brudno JN, Kochenderfer JN. Recent advances in CAR T-cell toxicity: mechanisms, manifestations and management. Blood Rev. 34, 45–55 (2019). •• Latest research developments in CAR-T toxicity.
Medline CASGoogle Scholar
31. Bonaldo G, Montanaro N, Vaccheri A, Motola D. Safety profile of chimeric antigen receptor T-cell immunotherapies (CAR-T) in clinical practice. Eur. J. Clin. Pharmacol. 77(8), 1225–1234 (2021).
Medline CASGoogle Scholar
32. Maude SL, Laetsch TW, Buechner J et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 378(5), 439–448 (2018).
Medline CASGoogle Scholar
33. Salem JE, Ederhy S, Lebrun-Vignes B, Moslehi JJ. Cardiac events associated with chimeric antigen receptor T-cells (CAR-T): a VigiBase perspective. J. Am. Coll. Cardiol. 75(19), 2521–2523 (2020).
Medline CASGoogle Scholar
34. Yáñez L, Sánchez-Escamilla M, Perales MA. CAR T cell toxicity: current management and future directions. Hemasphere 3(2), e186 (2019). •• Highlighting strategies to diminish side effects of several most important toxicities associated with CAR-T.
MedlineGoogle Scholar
35. Totzeck M, Michel L, Lin Y, Herrmann J, Rassaf T. Cardiotoxicity from chimeric antigen receptor-T cell therapy for advanced malignancies. Eur. Heart J. 43(20), 1928–1940 (2022).
Medline CASGoogle Scholar
36. Bihan K, Lebrun-Vignes B, Funck-Brentano C, Salem JE. Uses of pharmacovigilance databases: an overview. Therapie 75(6), 591–598 (2020).
MedlineGoogle Scholar

Vol. 15, No. 6

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History

Received 8 June 2022

Accepted 6 March 2023

Published online 23 March 2023

Published in print April 2023

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Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/imt-2022-0145

Author contributions

Conception and design: YH Zhai, FY Hu and BR Zhu. Administrative support: XF Ye, J He and F Xu. Acquisition or review of data: JF Xu, XJ Guo, WT Shi and X Zhou. Data analysis and interpretation: FY Hu and YH Zhai. Manuscript writing: YH Zhai. Manuscript reviewing and revising: YH Zhai, FY Hu, BR Zhu, Y Zheng, and X Xu. All authors contributed to the article and approved the submitted version.

Financial & competing interests disclosure

This study was supported by the National Nature Science Foundation of China (no. 82073671), the Leading Talents of Public Health in Shanghai (no. GWV-10.2-XD22), the Shanghai Municipal Commission of Health and Family Planning Fund for Excellent Young Scholars (no. 2018YQ47), the Excellent Young Scholars of public health in Shanghai (no. GWV-10.2- YQ33), Three-Year Action Program of Shanghai Municipality for Strengthening the Construction of Public Health System (GWV-10.1-XK05) Big Data and Artificial Intelligence Application, and Military Key Discipline Construction Project (Health Service – Naval Health Service Organization and Command) (no. 03). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Data sharing statement

The authors certify that this manuscript reports the secondary analysis of clinical trial data that have been shared with them, and that the use of this shared data is in accordance with the terms (if any) agreed upon their receipt. The source of this data is: https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html

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