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N Engl J Med. 2016 Nov 3;375(18):1749-1755.

Fulminant Myocarditis with Combination Immune Checkpoint Blockade.

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From the Departments of Medicine (D.B.J., J.M.B., M.H., I.P., M.R.A., T.L.B., J.R.B., D.A.S., E.J.P., M.A.P., D.M.R., J.A.S., J.J.M.), Cancer Biology (J.M.B., J.J.M.), Pathology, Microbiology, and Immunology (M.L.C., L.C.-O., R.D.H.), Biostatistics (Y.X.), Pharmacology (D.M.R.), and Biomedical Informatics (Y.X., D.M.R.), the Cardio-oncology Program (D.A.S., J.J.M.), the Breast Cancer Research Program (J.M.B.), and the Center for Quantitative Sciences (Y.X.), Vanderbilt University Medical Center, Nashville; the Department of Medicine (S.C.) and the Division of Neuroimmunology (S.C., I.J.K.), Beth Israel Deaconess Medical Center, the Departments of Medicine (B.A.O., C.E.S., J.G.S.) and Pathology (A.H.L.), Brigham and Women's Hospital, the Department of Genetics, Harvard Medical School (J.G., C.E.S., J.G.S.) - all in Boston; Howard Hughes Medical Institute, Chevy Chase, MD (C.E.S.); Bristol-Myers Squibb, New York (N.K., G.P., D.S.R., J.S.D.); Neon Therapeutics, Cambridge, MA (R.P.D.); and the Departments of Pathology (J.M.T., R.A.A.), Dermatology (J.M.T.), and Oncology (L.A.D.), Johns Hopkins University, Baltimore.


Immune checkpoint inhibitors have improved clinical outcomes associated with numerous cancers, but high-grade, immune-related adverse events can occur, particularly with combination immunotherapy. We report the cases of two patients with melanoma in whom fatal myocarditis developed after treatment with ipilimumab and nivolumab. In both patients, there was development of myositis with rhabdomyolysis, early progressive and refractory cardiac electrical instability, and myocarditis with a robust presence of T-cell and macrophage infiltrates. Selective clonal T-cell populations infiltrating the myocardium were identical to those present in tumors and skeletal muscle. Pharmacovigilance studies show that myocarditis occurred in 0.27% of patients treated with a combination of ipilimumab and nivolumab, which suggests that our patients were having a rare, potentially fatal, T-cell-driven drug reaction. (Funded by Vanderbilt-Ingram Cancer Center Ambassadors and others.).

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No other authors reported conflicts of interest.

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