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Biomarker Trends of Immune Checkpoint Inhibitor–Induced Myocarditis
Quick Takes
- Elevated levels of ALT, AST, CPK, and LDH are noncardiac biomarkers that are associated with immune checkpoint inhibitor (ICI) myocarditis. Notably, CPK has the strongest association and increases/decreases rapidly with acute episodes.
- Elevated hsTnT is universally seen in ICI myocarditis, although not particularly specific.
- Cardiac and noncardiac biomarkers can serve as good screening tests for suspect ICI myocarditis.
Study Questions:
What are the biomarker trends for patients with immune checkpoint inhibitor (ICI)–induced myocarditis and the association with incidence and outcomes?
Methods:
This was a single-center, observational cohort study of adult patients who received at least one dose of an ICI between June 2014 and December 2021. Demographic and clinical data were collected. Patients in this study completed serial noncardiac biomarker testing while on ICI therapy to monitor for immune-related adverse events (irAE). Noncardiac biomarkers included aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine phosphokinase (CPK), and lactate dehydrogenase (LDH). Post-discharge serial high-sensitivity troponin T (hsTnT) levels were obtained for a subset of patients with ICI myocarditis diagnosed after January 2021. Patients with ICI myocarditis were identified and compared to those without ICI myocarditis. The biomarker findings of the study were replicated in an independent, external cohort of patients with biopsy-confirmed ICI myocarditis.
Results:
This cohort included 2,606 patients who received an ICI. Of these patients, 27 patients (1.0%) were diagnosed with ICI myocarditis (5 classified as definite, 4 as probable, 18 as possible). The median time from first ICI dose to myocarditis diagnosis was 28.0 days (range, 1-209 days). Compared to patients without ICI myocarditis, those with the diagnosis were more likely to be older and male, and more likely to have coronary artery disease and heart failure. Baseline cancer diagnosis, choice of ICI, and noncardiac biomarker levels were similar between the groups. In-hospital mortality for ICI myocarditis was high (22.2%). After adjustments in a multivariable model, ICI myocarditis was associated with a higher risk of all-cause death (hazard ratio [HR], 1.66; 95% confidence interval [CI], 1.01-2.74), though patients with myocarditis who survived to hospital discharge had similar survival on follow-up, when compared to patients without ICI myocarditis.
At the time of diagnosis, all patients with myocarditis had an elevated hsTnT level. For the noncardiac biomarkers, elevated levels were compared between patients with (n = 27) and without (n = 2,579) myocarditis.
- Elevated ALT: 88.9% of patients with myocarditis vs. 30.0% without myocarditis
- Elevated AST: 85.2% vs. 30.0%
- Elevated CPK: 88.9% vs. 10.7%
- Elevated LDH: 92.6% vs. 15.1%
- ≥3 biomarkers elevated: 96.2% vs. 4.9%
- (Similar noncardiac biomarker elevations were noted in an external cohort of 30 patients with biopsy-proven ICI myocarditis.)
For patients with ICI myocarditis, average peak biomarker concentrations were higher compared to no myocarditis, median time to first elevated biomarker was 21-24 days, and post-hospital discharge hsTnT levels were persistently elevated for most patients up to 60 days.
Of note, CPK levels peaked the fastest (median -2 days, interquartile range [IQR], -4 to 6) and returned to normal levels the quickest (median 17 days, IQR 7 to 22) from time of myocarditis diagnosis. After multivariable analysis, only CPK was associated with increased risk for developing myocarditis (HR, 1.83; 95% CI, 1.59-2.10) and all-cause mortality (HR, 1.10; 95% CI, 1.01-1.20). CPK elevations had 99% sensitivity and 23% specificity for diagnosing ICI myocarditis.
Conclusions:
ICI myocarditis is associated with elevations in noncardiac biomarkers (notably CPK) and may serve as a useful screening tool for development of myocarditis.
Perspective:
While uncommon, myocarditis is an important and severe irAE of ICI therapy. Early identification of this disease process can lead to prompt therapy changes. The study adds significantly to our knowledge of the diagnosis of ICI myocarditis, utilizing a large registry with a control population and serial biomarker tests. The noncardiac biomarkers, and specifically CPK, emerge as useful clinical measures in patients getting ICI therapy, as they are commonly measured and provide an early signal for the potential development of myocarditis. Elevations in these biomarkers, especially when ≥3 are elevated, should prompt further investigation. Given the universal elevations in hsTnT in patients with ICI myocarditis, this can also serve as a useful test to rule out acute myocarditis in suspected cases, although specificity is lacking, and should be interpreted in the context of the other biomarkers and clinical data.
Clinical Topics: Cardio-Oncology, Heart Failure and Cardiomyopathies, Atherosclerotic Disease (CAD/PAD), Acute Heart Failure, Heart Failure and Cardiac Biomarkers
Keywords: Aspartate Aminotransferases, Biomarkers, Biopsy, Cardiotoxicity, Coronary Artery Disease, Creatine Kinase, Heart Failure, Immune Checkpoint Inhibitors, Lactates, Myocarditis, Oxidoreductases, Patient Discharge, Troponin T
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