Biomarkers Associated With Immune Checkpoint Inhibitor Myocarditis Revealed

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of various malignancies. The development and widespread use of ICIs have led to improved outcomes with a generally better tolerated side-effect profile compared with other therapies.

Immune-related adverse events (irAEs), while infrequent, are a direct result of the mechanism of action of ICIs, with disinhibition of T cells leading to a complex cascade of dysregulation of immune self-tolerance that can occur in almost any organ system. Myocarditis is the most severe cardiovascular manifestation of irAEs, with an estimated incidence of 1% to 2%.

A large team of international medical scientists led by those at the University of Michigan (Ann Arbor, MI, USA) conducted an observational cohort study of all adult (≥18 years of age) patients who had received treatment with single or dual ICI at Michigan Medicine between June 2014 and December 2021. Serial testing for aspartate aminotransferase (AST) and alanine aminotransferase (ALT), creatine phosphokinase (CPK), and lactate dehydrogenase during ICI therapy was carried out on a weekly basis in all patients receiving ICI at Michigan Medicine for the duration of ICI therapy.

A total of 2,606 adult patients (mean age 64 ± 13 years; 60.7% men) received at least one dose of ICI between June 2014 and December 2021. Of these patients, 27 (1.0%) or 0.14 (95% CI: 0.09-0.21) cases per 10,000 person-years had a diagnosis of myocarditis attributed to ICI therapy, of which five cases were classified as definite, four as probable, and 18 as possible. The overall number of patients who received ICI therapy and the incidence of ICI myocarditis increased steadily each year from 2014 to 2021.

The team reported that at diagnosis, patients with myocarditis had an elevated high-sensitivity troponin T (100%), ALT (88.9%), AST (85.2%), CPK (88.9%), and lactate dehydrogenase (92.6%). Findings were confirmed in an independent cohort of 30 patients with biopsy-confirmed ICI myocarditis. A total of 95% of patients with ICI myocarditis had elevations in at least three biomarkers compared with 5% of patients without myocarditis. Among the non-cardiac biomarkers, only CPK was associated (per 100% increase) with the development of myocarditis (HR: 1.83) and all-cause mortality (HR: 1.10) in multivariable analysis. Elevations in CPK had a sensitivity of 99% and specificity of 23% for identifying myocarditis.

The authors concluded that although its incidence is rare, ICI myocarditis is associated with poor outcomes. Thus, identifying patients with myocarditis is crucial to provide early intervention and treatment. Acute ICI myocarditis co-occurs with other irAEs. Thus, evidence of possible irAEs such as elevated AST, ALT, and CPK during the first three months of ICI therapy should prompt further evaluation for ICI myocarditis, and normal levels of these biomarkers could rule out clinically significant acute ICI myocarditis. The study was published on December 20, 2022 in the journal JACC: CardioOncology.

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