Fulminant Myocarditis with Combination Immune Checkpoint Blockade

TLDR

Immune checkpoint inhibitors improve cancer outcomes but can cause severe immune‑related adverse events, especially when used in combination. This report describes two melanoma patients who developed fatal myocarditis after receiving ipilimumab and nivolumab. Both patients exhibited myositis with rhabdomyolysis, refractory cardiac electrical instability, and myocarditis infiltrated by T‑cells and macrophages, with clonal T‑cell populations matching those in tumor and skeletal muscle, and pharmacovigilance data indicate a 0.27 % incidence of such rare, potentially fatal T‑cell‑driven reactions. Funding was provided by the Vanderbilt‑Ingram Cancer Center Ambassadors and others.

Abstract

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.).