Can Biomarkers Give Early Heads-Up on Immune Checkpoint Inhibitor Myocarditis?

In the quest to catch myocarditis earlier during immune checkpoint inhibitor (ICI) therapy for cancer, researchers have found a potential role for routinely measured biomarkers.

Of 2,606 consecutive ICI recipients at Michigan Medicine, the 1% who developed myocarditis often or always had elevated high-sensitivity troponin T (hsTnT; 100%), alanine aminotransferase (ALT; 88.9%), aspartate aminotransferase (AST; 85.2%), creatine phosphokinase (CPK; 88.9%), and lactate dehydrogenase (LDH; 92.6%) at diagnosis.

Between ICI recipients who did and did not have acute myocarditis, the proportion with elevations in at least three of the hepatic and skeletal muscle biomarkers was 95% versus 5%, according to the detailed medical chart review by Salim Hayek, MD, of the University of Michigan Frankel Cardiovascular Center in Ann Arbor, and colleagues.

"Thus, the absence of elevated ALT, AST, CPK, and LDH could assist clinicians in ruling out myocarditis ... The high sensitivity of these markers and the fact that they are already routinely measured make them ideal screening tools for ICI myocarditis," they wrote in JACC: CardioOncology.

Low hsTnT levels may also rule out ICI myocarditis, and isolated elevation in cardiac troponin is unlikely to be due to acute ICI myocarditis, Hayek and team noted.

ICIs have revolutionized cancer treatment by modulating the patient's immune response against cancerous cells. Considered relatively well-tolerated among cancer therapies, ICIs are nevertheless associated with immune-related adverse events such as myocarditis, which can range in presentation from zero symptoms to fulminant heart block and complete heart block. ICI myocarditis has a high fatality rate, despite a low estimated incidence of 1% to 2%.

"Diagnosing [ICI] 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 in a press release. "Diagnosing patients early allows us to start immunosuppressive therapy sooner and give patients a better chance of survival."

The study authors calculated a 22.2% in-hospital mortality rate for patients with ICI myocarditis. Kaplan-Meier survival estimates at year 1 were 50% and 66% for ICI users who did and did not develop myocarditis, respectively. There was a link between myocarditis and all-cause death (adjusted HR 1.66, 95% CI 1.01-2.74).

However, patients who survived the myocarditis hospitalization and had persistent elevations in biomarkers had similar long-term survival compared with peers without ICI myocarditis. This puts into question the clinical impact of the study's findings, Hayek and colleagues acknowledged.

"The investigators have provided a start. If that pushes us to more comprehensive evaluations of biomarkers, we may in the long run begin to develop insights into the diagnosis, treatment, and pathogenesis of ICI myocarditis," commented Allan Jaffe, MD, of the Mayo Clinic in Rochester, Minnesota, in an accompanying editorial.

"For now, there are some nuggets of clinical information that are helpful, but the large number of gaps require that all of us, in dealing with these patients, be aware that there is no solely reliable biomarker or test short of a biopsy or [cardiac MRI] to confirm myocarditis," Jaffe cautioned.

The observational cohort study by Hayek's team relied on the University of Michigan ICI registry and included 2,606 adults who received single or dual ICI therapy at Michigan Medicine from June 2014 to December 2021 and had longitudinal biomarker data.

ICI users had an average age of 64 years, and 60.7% were men. The most common malignancies diagnosed were malignant melanoma (40.4%) and metastatic lung cancer (24.5%). Pembrolizumab (Keytruda) monotherapy was administered to over half the cohort, and 14.6% received dual ICI therapy.

The 27 individuals diagnosed with ICI myocarditis were divided into five definite cases, four probable, and 18 possible. It took a median 28 days from the first dose of ICI to diagnosis of myocarditis, with 55.6% of patients developing myocarditis within 30 days.

Among the non-cardiac biomarkers, only CPK stayed independently associated with the development of myocarditis after adjustment (adjusted HR 1.83 per doubling in CPK from baseline, 95% CI 1.59-2.10) and all-cause mortality (adjusted HR 1.10, 95% CI 1.01-1.20). Elevations in CPK had a sensitivity of 99% and specificity of 23% for identifying myocarditis.

CPK levels also peaked the fastest, with a median time to peak concentration of 2 days prior to the diagnosis of myocarditis.

"It makes sense that myocarditis related to [ICIs] does not occur in isolation, given a raging immune system is expected to affect several organs and particularly the muscles," said study co-author Joe-Elie Salem, MD, PhD, of Sorbonne Université in Paris, in the press release. "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."

The present biomarker findings were confirmed in a separate cohort of 30 patients with biopsy-confirmed ICI myocarditis from Salem's institution.

Ultimately, all those who developed myocarditis stopped their ICI treatment. Only two patients opted to resume it after a median of 1.3 years, Hayek and colleagues reported.

They cautioned that their retrospective study lacked troponin data routinely collected from patients.

"Understandably, markers such as hsTnT were not obtained in a reproducible manner; they were obtained when the patients presented clinically and when testing was needed clinically. The sampling frequency was a conglomerate of varying times, and probably because of the complexity and frequency and variability, these times were not well described," Jaffe noted.

Another limitation of the study was its lack of baseline biomarker data, according to the editorialist.

"Every field progresses slowly, and a study such as this is a first step. However, several additional studies are necessary," Jaffe concluded.

Myocarditis is not the only heart-related side effect of ICIs. This summer, a report showed that over 10% of people on these therapies experienced major adverse cardiovascular events, including acute coronary syndrome, heart failure, stroke, and transient ischemic attack.

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