Noncardiac Biomarker Could Aid in Predicting Myocarditis, Mortality in Some Cancer Patients

Salim Hayek, MD

A study from Michigan Medicine suggests assessment of creatine phosphokinase could help identify increased risk of myocarditis and all-cause mortality in patients with cancer treated with immune checkpoint inhibitors (ICI).

An observational cohort study of adults who received ICI over a 7-year period beginning in 2014, results indicate a 100% increase in creatine phosphokinase was associated with an 83% increase in risk of myocarditis and 10% increase in risk of all-cause mortality, with further analysis providing insight into the sensitivity and specificity of the biomarker for identifying myocarditis.

“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 senior investigator Salim Hayek, MD, medical director of the University of Michigan Health Frankel Cardiovascular Center Clinics, in a statement from University of Michigan Health.

As rates of cancer diagnoses have increased in recent decades, so too has the number of therapeutic options for patients. With these increases, the growing risk of cardiotoxicity associated with many forms of cancer therapy has become a chief concern for cardiologists. With this as a backdrop, Hayek and a team of collaborators from University of Michigan Health launched the current research endeavor to examine where routinely measured biomarkers might improve management and identify those at increased risk of ICI myocarditis.

Investigators designed their study as an observational cohort study of adult patients who received at least one dose of ICI at a Michigan Medicine medical center between June 2014-December 2021. Further limiting their study to those with available information related to systematic serial testing for aspartate aminotransferase, alanine aminotransferase, creatine phosphokinase, and lactate dehydrogenase during ICI therapy, investigators identified a cohort of 2606 patients for inclusion in the study.

The study cohort had a mean age of 64±13 years, 60.7% were men, and 1.0% or 0.14 (95% CI, 0.09-0.21) cases per 10,00 person-years had a diagnosis of myocarditis attributed to ICI therapy. Of these, 5 were classified as definite, 4 were classifiable as probable, and 18 were classified as possible. Investigators pointed out the overall number of patients receiving ICI therapy and the incidence of myocarditis increased steadily each year during the study period. Additionally, the median time from the first dose of ICI to diagnosis of myocarditis was 28.0 (1-209) days, with 55.6% of patients developing myocarditis within 30 days after initiating ICI therapy.

Results of the investigators’ analyses demonstrated the majority of patients who developed myocarditis had elevated high-sensitivity troponin T (100%), alanine aminotransferase (88.9%), aspartate aminotransferase (85.2%), creatine phosphokinase (88.9%), and lactate dehydrogenase (92.6%). Investigators noted these findings were confirmed in an independent cohort of 30 patients with biopsy-confirmed ICI myocarditis.

Further analysis revealed 95% of patients with ICI myocarditis had elevations in at least 3 biomarkers compared to just 5% of the cohort without myocarditis. Additional analysis of noncardiac biomarkers revealed only creatine phosphokinase was associated with increased risk of developing myocarditis and all-cause mortality in multivariable analyses. Of note, these analyses assessed 100% increase in biomarker. Investigators pointed out elevations in creatine phosphokinase had a sensitivity of 99% and a specificity of 23% for identifying ICI myocarditis.

“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 study investigator Joe-Elie Salem, MD, PhD, professor of medicine at Sorbonne Université in Paris, in the aforementioned statement. “A large variety of antigens targeted by auto-reactive 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.”

This study, “Biomarker Trends, Incidence, and Outcomes of Immune Checkpoint Inhibitor–Induced Myocarditis,” was published in JACC: CardioOncology