Myocarditis in Patients Treated With Immune Checkpoint Inhibitors
What is the presentation and clinical course of immune checkpoint inhibitor (ICI)-associated myocarditis?
The study cohort was comprised of 35 patients with ICI-associated myocarditis from a multicenter registry of eight sites. These patients were compared to a random sample of 105 ICI-treated patients without myocarditis. Myocarditis was diagnosed in two ways: 1) standard histological features present on endomyocardial biopsy or autopsy; and 2) a guideline-recommended scoring system for clinically suspected myocarditis that incorporates several variables including the clinical, biomarker, and imaging features. Covariates of interest extracted from medical records included the occurrence of major adverse cardiac events (MACE), defined as the composite of cardiovascular death, cardiogenic shock, cardiac arrest, and hemodynamically significant complete heart block. Hazards ratios for MACE with 95% confidence intervals were calculated using Cox regression analysis for the optimal troponin T values. All statistical tests were two-sided, and 5% was set as the level of significance.
The study authors reported that the prevalence of myocarditis was 1.14% with a median time of onset of 34 days after starting ICI (interquartile range, 21-75). The mean age of the study cohort was 65 ± 13 years of age, 29% were female, and 54% had no other immune-related side effects. The most common indications for ICI were melanoma and non-small cell lung cancer. All cases with ICI-associated myocarditis had ICIs permanently discontinued. Compared with controls, myocarditis cases were more likely to have received combination ICI at any stage in treatment and were more likely to be treated with combination ICI therapy at the time of statistical analysis, that is, a median of 281 days of follow-up for controls, and 209 days for myocarditis cases.
Of the combination therapies at the time of presentation, anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4) with anti-programmed cell death protein 1 (anti-PD1) was the most frequent in cases. However, overall, myocarditis was more commonly seen with concurrent single ICI therapy (66%). Relative to controls, combination ICI (34% vs. 2%; p < 0.001) and diabetes (34% vs. 13%; p = 0.01) were more common in cases. Before myocarditis, the pre-ICI left ventricular ejection fraction was ≥50% in all those with a baseline measurement. In comparison with controls, myocarditis cases had a higher prevalence of diabetes mellitus and sleep apnea, and a higher body mass index. Over 102 days (interquartile range, 62-214) of median follow-up, 16 (46%) developed MACE; 38% of MACE occurred with normal ejection fraction. There was a four-fold increased risk of MACE with troponin T of ≥1.5 ng/ml (hazard ratio, 4.0; 95% confidence interval, 1.5-10.9; p = 0.003). Steroids were administered in 89%, and lower steroid doses were associated with higher residual troponin and higher MACE rates.
The authors concluded that myocarditis after ICI therapy may be more common than appreciated, occurs early after starting therapy, has a malignant course, and responds to higher steroid doses.
This is an important retrospective case-based report because it throws a light on how best to manage a fulminant side effect of this new class of drugs used in cancer therapy. The next step would be to conduct studies to prevent and treat myocarditis after ICI therapy.
Clinical Topics: Arrhythmias and Clinical EP, Cardio-Oncology, Geriatric Cardiology, Heart Failure and Cardiomyopathies, Prevention, Implantable Devices, SCD/Ventricular Arrhythmias, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Sleep Apnea
Keywords: Biopsy, Body Mass Index, Carcinoma, Non-Small-Cell Lung, Cardiotoxicity, CTLA-4 Antigen, Diabetes Mellitus, Geriatrics, Heart Arrest, Heart Block, Heart Failure, Lung Neoplasms, Melanoma, Myocarditis, Secondary Prevention, Shock, Cardiogenic, Sleep Apnea Syndromes, Stroke Volume, T-Lymphocytes, Cytotoxic, Troponin, Troponin T
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