Immune Checkpoint Inhibitor-Associated Myocarditis

Abstract

Immune checkpoint inhibitors (ICIs) are approved for a wide range of malignancies. They work by priming the immune system response to cancer and have changed the landscape of available cancer treatments. As anticipated, modulation of the regulatory controls in the immune system with ICIs results in diverse immune-related adverse events, targeting any organ or gland. These toxicities are rarely fatal and generally regress after treatment discontinuation and/or prescription of corticosteroids. Recently, several cases of ICI-related cardiotoxicity have been reported with complications ranging from cardiogenic shock to sudden death. The true incidence of ICI-associated myocarditis is likely underestimated, due to a combination of factors including the lack of specificity in the clinical presentation, the potential of overlap with other cardiovascular and general medical illnesses, the challenges in the diagnosis, and a general lack of awareness of this condition. Currently, there are no clear guidelines for surveillance, diagnosis, or management of this entity. There are multiple unresolved issues including, but not limited to, identifying those at risk of this uncommon toxicity, elucidating the pathophysiology, determining if and what type of surveillance is appropriate, optimal work-up of suspected patients, and methods for resolution of myocarditis. Here we describe a clinical vignette and discuss the salient features and management strategies of ICI-associated myocarditis.

Key points: The incidence of immune checkpoint inhibitor (ICI)-associated myocarditis is unclear and has been reported to range from 0.06% to 1% of patients prescribed an ICI.Myocarditis may be difficult to diagnose.The risk factors for ICI-associated myocarditis are not well understood but may include underlying autoimmune disease and diabetes mellitus.The prevalence of myocarditis has been reported to be higher with combination immune therapies.Myocarditis with ICI's typically occurs early, with an elevated troponin, may present with an normal left ventricular ejection fraction and may have a fulminant course.The optimal management of myocarditis associated with ICI's is unclear but most cases are treated with high-dose steroids.

Figure 1.

Electrocardiogram (ECG), cardiac magnetic resonance imaging (MRI), and endomyocardial biopsy findings in a patient with immune checkpoint inhibitor‐associated myocarditis. (A): 12‐lead ECG showing sinus tachycardia. (B): Cardiac MRI: Arrow showing mid‐myocardial delayed enhancement of interventricular septum. (C): High‐power view of endomyocardial biopsy (EMB) sample shows an intense lymphocytic infiltrate and mild fibrosis. (D): CD‐3 immunostain of EMB sample shows that the majority of the inflammatory infiltrate consists of CD‐3‐positive T lymphocytes. (E): CD‐8 immunostain of EMB sample shows presence of cytotoxic (CD‐8 positive) T cells.

Figure 2.

Proposed algorithm for management of ICI‐associated myocarditis. The proposed management algorithm suggests a stepwise approach for a patient with suspected myocarditis.*, the data are very limited and are based on retrospective analysis. Abbreviations: ATG, antithymocyte globulin; CMR, cardiac magnetic resonance imaging; ECG, electrocardiogram; EMB, endomyocardial biopsy; HF, heart failure; ICI, immune checkpoint inhibitors; IVIg, intravenous immunoglobulin; PD‐1, programmed cell death 1; LVEF, left ventricular ejection fraction; NT‐proBNP, N‐terminal‐pro‐brain natriuretic peptide.