Immune Checkpoint Inhibitor-Induced Myocarditis: A Review of Published Cases
DOI:
https://doi.org/10.5281/zenodo.22279295Keywords:
Immune checkpoint inhibitor, Myocarditis, Melanoma, Cardiotoxicity, Immune-related adverse eventAbstract
ackground: Immune checkpoint inhibitors (ICIs) targeting CTLA-4, PD-1 and PD-L1 have transformed treatment of metastatic
melanoma and other cancers, but the same mechanism that unleashes anti-tumour immunity can also attack the myocardium.
Objective: To review the published case reports, series, registries and mechanistic literature on ICI myocarditis, drawing on
melanoma-specific reports where the literature specifies them. Methods: Narrative review of case reports, case series, pharmacovigilance analyses, registry cohorts, mechanistic studies and guideline documents. Findings: Reported incidence ranges from roughly 0.06% to 1.3% of ICI-treated patients, rising toward 2% with combination therapy. Onset is typically early (median 34 days, one registry of 35 patients), and historical fatality has reached 25-50%. Published cases document fulminant presentations with conduction abnormalities, cardiogenic shock and myositis; refractory cases have been treated with anti-thymocyte globulin, abatacept and ruxolitinib, the latter combination linked in one cohort to a marked fatality reduction. Conclusions: The published record supports early biomarker-based suspicion, prompt ICI discontinuation, and stepwise escalation of immunosuppression in refractory disease, with still-limited evidence for targeted second-line agents.
References
Jiménez-Alejandre, R., Martín, P. (2022) Pathophysiology of Immune Checkpoint Inhibitor-Induced Myocarditis. Cancers, 14(18): 4494.
Johnson, D.B., Balko, J.M., Compton, M.L., Chalkias, S., Gorham, J., Xu, Y., et al. (2016) Fulminant Myocarditis with Combination Immune Checkpoint Blockade. New England Journal of Medicine, 375(18): 1749-1755.
Zimmer, L., Goldinger, S.M., Hofmann, L., Loquai, C., Ugurel, S., Thomas, I., et al. (2016) Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy. European Journal of Cancer, 60: 210-225.
Heinzerling, L., Ott, P.A., Hodi, F.S., Husain, A.N., Tajmir-Riahi, A., Tawbi, H., et al. (2016) Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy. Journal for ImmunoTherapy of Cancer, 4: 50.
Ganatra, S., Neilan, T.G. (2018) Immune Checkpoint Inhibitor-Associated Myocarditis. The Oncologist, 23(8): 879-886.
Moslehi, J.J., Salem, J.E., Sosman, J.A., Lebrun-Vignes, B., Johnson, D.B. (2018) Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. The Lancet, 391(10124): 933.
Wang, D.Y., Salem, J.E., Cohen, J.V., Chandra, S., Menzer, C., Ye, F., et al. (2018) Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis. JAMA Oncology, 4(12): 1721-1728.
Nielsen, D.L., Juhl, C.B., Nielsen, O.H., Chen, I.M., Herrmann, J. (2024) Immune Checkpoint Inhibitor-Induced Cardiotoxicity: A Systematic Review and Meta-Analysis. JAMA Oncology, 10(10): 1390-1399.
Mahmood, S.S., Fradley, M.G., Cohen, J.V., Nohria, A., Reynolds, K.L., Heinzerling, L.M., et al. (2018) Myocarditis in Patients Treated With Immune Checkpoint Inhibitors. Journal of the American College of Cardiology, 71(16): 1755-1764.
Wang, C., Zhao, G., Zhang, Z., Yang, L., Liu, S., Li, G., Wang, H., Huang, J., Wang, S., Li, N. (2023) Immune checkpoint inhibitor-associated myocarditis: a systematic analysis of case reports. Frontiers in Immunology, 14: 1275254.
Vasbinder, A., Chen, Y., Procureur, A., Catalan, T., Blakely, P., Nelapudi, N., et al. (2022) Biomarker Trends, Incidence, and Outcomes of Immune Checkpoint Inhibitor-Induced Myocarditis. JACC: CardioOncology, 4(5): 689-700.
Wei, S.C., Meijers, W.C., Axelrod, M.L., Anang, N.A.S., Screever, E.M., Wescott, E.C., et al. (2021) A Genetic Mouse Model Recapitulates Immune Checkpoint Inhibitor-Associated Myocarditis and Supports a Mechanism-Based Therapeutic Intervention. Cancer Discovery, 11(3): 614-625.
Byer, S.H., Stewart, C., Mansour, S., Grewal, U.S. (2024) Novel use of abatacept and ruxolitinib as salvage therapy in steroid-refractory immune checkpoint blockade-induced myocarditis with myasthenia and myositis overlap syndrome. European Journal of Cancer, 202: 114027.
Saibil, S.D., Bonilla, L., Majeed, H., Sotov, V., Hogg, D., Chappell, M.A., et al. (2019) Fatal myocarditis and rhabdomyositis in a patient with stage IV melanoma treated with combined ipilimumab and nivolumab. Current Oncology, 26(3): e418-e421.
Läubli, H., Balmelli, C., Bossard, M., Pfister, O., Glatz, K., Zippelius, A. (2015) Acute heart failure due to autoimmune myocarditis under pembrolizumab treatment for metastatic uveal melanoma. Journal for ImmunoTherapy of Cancer, 3: 11.
Arangalage, D., Delyon, J., Lermuzeaux, M., Ekpe, K., Ederhy, S., Pinna, B., et al. (2017) Survival After Fulminant Myocarditis Induced by Immune-Checkpoint Inhibitors. Annals of Internal Medicine, 167(9): 683-684.
Salem, J.E., Bretagne, M., Abbar, B., Leonard-Louis, S., Ederhy, S., Redheuil, A., et al. (2023) Abatacept/Ruxolitinib and Screening for Concomitant Respiratory Muscle Failure to Mitigate Fatality of Immune-Checkpoint Inhibitor Myocarditis. Cancer Discovery, 13(5): 1100-1115.
Bonaca, M.P., Olenchock, B.A., Salem, J.E., Wiviott, S.D., Ederhy, S., Cohen, A., et al. (2019) Myocarditis in the Setting of Cancer Therapeutics: Proposed Case Definitions for Emerging Clinical Syndromes in Cardio-Oncology. Circulation, 140(2): 80-91.
Brahmer, J.R., Abu-Sbeih, H., Ascierto, P.A., Brufsky, J., Cappelli, L.C., Cortazar, F.B., et al. (2021) Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events. Journal for ImmunoTherapy of Cancer, 9(6): e002435.
Schneider, B.J., Naidoo, J., Santomasso, B.D., Lacchetti, C., Adkins, S., Anadkat, M., et al. (2021) Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update. Journal of Clinical Oncology, 39(36): 4073-4126.
Haanen, J., Obeid, M., Spain, L., Carbonnel, F., Wang, Y., Robert, C., et al. (2022) Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Annals of Oncology, 33(12): 1217-1238.
Lyon, A.R., Lopez-Fernandez, T., Couch, L.S., Asteggiano, R., Aznar, M.C., Bergler-Klein, J., et al. (2022) 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). European Heart Journal, 43(41): 4229-4361.
Escudier, M., Cautela, J., Malissen, N., Ancedy, Y., Orabona, M., Pinto, J., et al. (2017) Clinical Features, Management, and Outcomes of Immune Checkpoint Inhibitor-Related Cardiotoxicity. Circulation, 136(21): 2085-2087.
Tay, R.Y., Blackley, E., McLean, C., Moore, M., Bergin, P., Gill, S., Haydon, A. (2017) Successful use of equine anti-thymocyte globulin (ATGAM) for fulminant myocarditis secondary to nivolumab therapy. British Journal of Cancer, 117(7): 921-924.
Salem, J.E., Allenbach, Y., Vozy, A., Brechot, N., Johnson, D.B., Moslehi, J.J., et al. (2019) Abatacept for Severe Immune Checkpoint Inhibitor-Associated Myocarditis. New England Journal of Medicine, 380(24): 2377-2379.
Wadden, E., Lai, C., Grivas, P., Bhatia, S., Portuguese, A.J., Salem, J.E., Moslehi, J.J., Cheng, R.K. (2025) Successful treatment of immune checkpoint inhibitor-associated fulminant myocarditis with abatacept and ruxolitinib: a case report. European Heart Journal - Case Reports, 9(2): ytaf019.
Vockenhuber, T., Baldinger, L., et al. (2025) Successful Use of Ruxolitinib for Steroid-Refractory Immune Checkpoint Inhibitor-Associated Myocarditis. JACC: Case Reports, 30(35): 105543.
