Survival After Fulminant Myocarditis Induced by Immune-Checkpoint Inhibitors.

Survival After Fulminant Myocarditis Induced by Immune-Checkpoint Inhibitors Background: Some patients with metastatic melanoma live longer when they are treated with combinations of immune-checkpoint inhibitors (1, 2). However, up to 55% of these patients experience high-grade, immune-related adverse events (3–5). In phase 3 trials of these drugs, immunerelated adverse events involving the heart affected only 0.19% of patients; fulminant myocarditis was the most serious of these (5). Objective: To report what we believe to be the first patient to survive fulminant myocarditis induced by immunecheckpoint inhibitors. Case Report: We admitted a 35-year-old woman with unresectable stage IIIc melanoma of the neck who developed progressive dyspnea 15 days after the first infusion of ipilimumab, 3 mg/kg of body weight, and nivolumab, 1 mg/kg. Physical examination was unremarkable. Electrocardiography revealed sinus tachycardia with a right bundle branch block and ST-segment elevation in the anteroseptal and inferolateral leads. Troponin I levels were 210 μg/L (normal, < 0.045 μg/L), and total creatine kinase levels were 187.6 μkat/L (normal, 0.4 to 3.2 μkat/L). Transthoracic echocardiography revealed a left ventricular ejection fraction of 50%. We discontinued the immunotherapy and began treatment with intravenous methylprednisolone, 1 g/d, and intravenous immunoglobulin therapy (Figure 1). Cardiac magnetic resonance imaging performed the next day showed severely impaired left and right ventricular ejection fractions and diffuse subepicardial late gadolinium enhancement, which confirmed the diagnosis of myocarditis (Figure 2). Four days after admission, the patient developed refractory ventricular tachycardia that led to emergency circulatory support using extracorporeal membrane oxygenation. Left ventricular ejection fraction measured by echocardiography decreased to 10%. We discontinued immunoglobulin therapy and performed plasma exchanges for 3 days. The patient developed hyperthyroidism with an undetectable thyroid-stimulating hormone level, and we diagnosed immune-related hyperthyroidism. This condition progressed to hypothyroidism within 3 days and required levothyroxine therapy. After 8 days of circulatory support, we began tacrolimus therapy with a target whole blood level of 10 to 15 ng/mL. The patient began to improve 2 days later and left the intensive care unit with a left ventricular ejection fraction of 35% on day 18 of admission. At 3-month follow-up, the patient had completely recovered with a left ventricular ejection fraction of 60%. Discussion: To reduce the likelihood of autoimmune disease, 2 cell pathways help keep T-cell immune function in check: cytotoxic T-lymphocyte–associated antigen 4 and programmed death 1. They are known as immune checkpoints, and inhibiting them increases immune system activity. This patient received 1 drug that inhibited the former pathway (ipilimumab) and another drug that inhibited the latter (nivolumab). Recent reports suggest that blocking both pathways may increase the incidence of fulminant myocarditis, and to our knowledge, all published cases of this condition induced by immune-checkpoint inhibitors have been fatal (3, 4). This case report shows that this adverse effect may be reversed, which may justify more aggressive attempts to save future patients. Moreover, 64% of patients who receive drugs that block both pathways survive at least 2 years even when treatment must be discontinued prematurely (1). The magnetic resonance imaging finding of extensive subepicardial late gadolinium enhancement of both ventricles has not been reported previously in patients with fulminant myocarditis induced by immune-checkpoint inhibitors. We advise clinicians to look for it when considering the possibility of this condition. Most immune-related adverse events from checkpoint inhibitors are manageable with corticosteroids and immunoFigure 1. Timeline of LVEF and treatment of fulminant myocarditis during hospitalization in the intensive care unit.