How to Detect Myocarditis From Immune Checkpoint Inhibitors

Myocarditis is an unpredictable and potentially fatal complication of treatment with immune checkpoint inhibitors (ICIs). Researchers have developed a new biomarker strategy that enables clinicians to identify which patients are experiencing this adverse event.

“Immune checkpoint inhibitors have revolutionized the treatment of various cancers, [but] patients who develop the rare complication of myocarditis often present late with at least a 50% chance of death,” said senior author Salim Hayek, MD, medical director of the University of Michigan Health Frankel Cardiovascular Center Clinics.

“Diagnosing immune checkpoint inhibitor myocarditis is challenging, given that there is no one test that can differentiate it from other causes of cardiac injury. By the time patients present to the hospital, it is often too late,” Hayek said

“It is thus essential to have a screening strategy to monitor and risk-stratify patients with possible ICI myocarditis, diagnose the patients early enough to intervene and mitigate severe cardiovascular complications,” he told Medscape Medical News.

Hayek said that the findings of the new study from his team provide the framework for doing that. In their article, they describe a series of biomarkers that are elevated among patients who develop ICI-related myocarditis. He told Medscape Medical News that several institutions have already adopted monitoring protocols in which these biomarkers are regularly checked in these patients.

The study was published in JACC: CardioOncology.

It is estimated that the incidence of myocarditis is 1% to 2%, but it is associated with one of the highest fatality rates of all classes of immunotherapy-related adverse events, the authors note.

Hayek and colleagues conducted an observational cohort study of all adult patients who had been treated with single or dual ICIs at Michigan Medicine between June 2014 and December 2021 for any type of cancer (n = 2606).

Within the cohort, 27 (1.0%) patients (0.14 cases per 10,000 person-years) had been diagnosed with myocarditis attributed to ICI therapy.

Overall, the number of patients who received ICI therapy and the incidence of ICI myocarditis rose steadily from 2014 to 2021. The median time from the first dose of ICI to diagnosis of myocarditis was 28 days.

The main finding was that among nearly all patients who were diagnosed with myocarditis following ICI treatment, there were elevations in biomarkers, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine phosphokinase (CPK), and lactate dehydrogenase (LDH).

At diagnosis, among patients with myocarditis, there were elevations in high-sensitivity troponin T (100%), ALT (88.9%), AST (85.2%), CPK (88.9%), and LDH (92.6%). The findings were confirmed in an independent cohort of 30 patients with biopsy-confirmed ICI myocarditis.

Among a total of 95% of patients with ICI myocarditis, levels of at least three biomarkers were elevated, compared with 5% of patients without myocarditis.

However, among the noncardiac biomarkers, only CPK remained independently associated with the development of myocarditis after adjustment (adjusted hazard ratio [HR], 1.83 per doubling in CPK from baseline) and all-cause mortality (adjusted HR, 1.10). Elevations in CPK had a sensitivity of 99% and specificity of 23% for identifying myocarditis.

“We show that the vast majority of patients with ICI myocarditis exhibit early rises in these biomarkers, notably CPK,” said Hayek. “Thus, routinely measuring CPK during the first 60 days of ICI therapy is an effective strategy to screen for immune-related adverse events, notably myocarditis. We recommend that all patients who are noted to have an acute rise in CPK undergo high-sensitivity troponin testing, and if abnormal, undergo further downstream testing to risk-stratify for severe ICI myocarditis along with close monitoring for symptoms to potentially initiate immunosuppressive therapies.

“Conversely, our data support the practice of checking a CPK level in patients on ICI who present with cardiac symptoms and in whom ICI myocarditis is suspected,” he added. “A normal CPK level would make ICI myocarditis very unlikely, and other causes of cardiac injury should be considered.”

In-hospital mortality among patients with ICI myocarditis was 22.2%, and survival estimates at year 1 were 50% for patients with myocarditis and 66% for those without it (log-rank P = .10).

Most patients (88.9%) with myocarditis also showed evidence of noncardiac immune-related adverse events, such as hepatitis or myositis, the authors note.

“It makes sense that myocarditis related to immune checkpoint inhibitors does not occur in isolation, given a raging immune system is expected to affect several organs and particularly the muscles,” said co-author Joe-Elie Salem, MD, PhD, professor of medicine at Sorbonne Université in Paris. “A large variety of antigens targeted by autoreactive T-cells boosted by ICIs are shared between the myocardium and the peripheral muscles. Myositis, or muscle injury, is a central component of complications related to this class of drugs.”

Hayek was supported by the National Heart, Lung, and Blood Institute and the National Institute on Diabetes and Digestive and Kidney Diseases.

JACC CardioOncol. Published online December 4, 2022. Full text

Roxanne Nelson is a registered nurse and an award-winning medical writer who has written for many major news outlets and is a regular contributor to Medscape.

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