Study reveals biomarkers associated with immune checkpoint inhibitor myocarditis

Immune Checkpoint Molecule Pd L1 Social

In a study published Tuesday in JACC: CardioOncology, researchers at the University of Michigan determined that myocarditis during cancer treatment with an immune checkpoint inhibitor (ICI) was associated with increased levels of three biomarkers implicated in skeletal muscle damage.

Researchers analyzed data from 2,600 patients with cancer who had been treated with immune checkpoint inhibitors at University of Michigan Health between June 2014 and December 2021. The vast majority of patients diagnosed with ICI myocarditis showed early signs of liver damage and muscle injury, even prior to hospitalization. Of these patients, 95% had at least three elevated biomarkers compared to just 5% of patients without myocarditis.

ICIs are monoclonal antibodies that target cytotoxic T lymphocyte antigen 4, programmed cell death protein 1, or programmed cell death ligand 1, modulating the immune system’s response to cancerous cells. While they are highly effective, the increased immune system activity spurred by ICIs can turn the body against itself, causing damage to organ systems. While myocarditis is a rare complication of ICI treatment, it is also the most severe, with a high mortality rate.

“While immune checkpoint inhibitors have revolutionized the treatment of various cancers, patients who develop the rare complication of myocarditis often present late with at least a 50% chance of death,” said Dr. Salim Hayek, senior author of the study and medical director of the University of Michigan Health Frankel Cardiovascular Center Clinics, in a statement.

Moreover, ICI-induced myocarditis may be difficult to distinguish from other causes of cardiac injury, adding to the gravity of the condition; at present, there is no definitive procedure for early diagnosis of ICI myocarditis, even with regular monitoring.

“By the time patients present to the hospital, it is often too late,” Hayek said. “Diagnosing patients early allows us to start immunosuppressive therapy sooner and give patients a better chance of survival.”

In the study, ICI myocarditis was associated with elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), creatine phosphokinase (CPK), and high-sensitivity troponin T (hsTnT) levels. CPK elevation was associated with both the development of myocarditis and all-cause mortality. Furthermore, levels of AST, ALT, and hsTnT -- all associated with skeletal muscle damage -- remained high for months in survivors of ICI myocarditis; however, levels of CPK declined rapidly once treatment was administered.

In the study, the authors found that an elevated CPK alone had a 99% sensitivity and 23% specificity for acute ICI myocarditis.

“The high sensitivity of these markers and the fact that they are already routinely measured make them ideal screening tools for ICI myocarditis,” the researchers noted. And, while ICI myocarditis is uncommon, its mortality rate makes it imperative that it be diagnosed correctly and early.

“Abnormalities in these biomarkers should prompt clinicians to test for cardiac injury using high-sensitivity troponin,” Hayek said in a statement. “Conversely, patient suspected of immune checkpoint myocarditis should have creatine phosphokinase levels measured. If low, or within normal limits, then the diagnosis of immune checkpoint myocarditis is highly unlikely.”

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