Increased incidence of immune-mediated myocarditis in advanced skin malignancies treated with immune checkpoint inhibitors in the COVID-19 era

ABSTRACT

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced stage skin malignancies. Immunotherapy related adverse events (irAE) are toxicities associated with ICI therapy. Myocarditis is a rare life-threatening irAE. We attempt to characterize cases of myocarditis related to ICI therapy that have occurred since the start of the COVID-19 pandemic. Methods: We performed a single-center, retrospective cohort analysis of patients with advanced stage skin cancers who were treated with ICIs and identified cases of ICI-mediated myocarditis. ICI-mediated myocarditis was defined as evidence of myocardial injury in the setting of irAEs and exclusion of cardiovascular causes. Clinicopathologic variables and clinical outcomes were assessed in these patients. Results: A review of 361 patients that received ICI from 9/2014 - 10/2019 found 0 cases of ICI-mediated myocarditis. From 11/2019 - 12/2021, an additional 425 patients were identified of whom 11 (2.6%) developed ICI-mediated myocarditis. 10 patients had melanoma and 1 patient had Merkel cell carcinoma. 10/11 patients were male. 9/11 were treated with anti-PD-1 monotherapy and 2/11 were treated with ipilimumab with nivolumab. All patients had elevated high sensitivity troponin (median 361 pg/mL on presentation, reference range 0-19 pg/mL). 11/11 patients presented with elevated CPK (median 1734 IU/L, reference range 38-240 IU/L) and 8/11 presented with elevated ASTALT ratio (median 1.581) on routine screening which prompted further investigation. 1 patient tested positive for COVID-19 13 days after initial biochemical concern for myocarditis, and 5 patients had received COVID-19 vaccines between 2.5-11 months prior to myocarditis onset. All patients were treated with high dose steroids, and 4 were treated with abatacept. 2 patients died within 30 days after diagnosis of myocarditis and 2 patients later died from malignancy progression. 2 patients developed progressive disease and 1 was successfully rechallenged with ICI with no myocarditis recurrence. 2 patients remain on active surveillance, 2 continue on a steroid taper, and 1 was lost to follow up. All patients with at least 5 months of follow up from myocarditis onset (n = 5) had persistently elevated HS-troponin despite normalization of CPK levels. Conclusions: In this single center study, we noted an increase in the frequency of ICI-mediated myocarditis in patients with advanced skin cancers during the pandemic era (2.6% vs 0% prepandemic) which is higher than reported in the literature (0.04-1.14%). The impact of COVID-19 during this time is suspicious and warrants further investigation. Therefore, we suggest heightened awareness in the COVID-19 era that elevated CPK levels and ASTALT ratios merits further diagnostic investigation of ICI-mediated myocarditis.