High incidence of immune checkpoint inhibitor therapy related subclinical cardiac dysfunction and myocarditis in patients with extracardiac immune related adverse events

Abstract

Background: Immune checkpoint inhibitors (ICI) have improved survival in patients with advanced cancers. The activation of immunity during ICI therapy may trigger cardiac and extracardiac immune-related adverse events (irAEs). However, the cardio-oncology guideline does not indicate serial echocardiography evaluations in patients under ICI therapy, which may underestimate the incidence of cancer therapy related cardiovascular toxicity (CTR-CVT).

Aim: To determine the incidence of CTR-CVT in cancer patients with extracardiac irAEs under ICI therapy compared to control patients. CTR-CVT was diagnosed based on the cardio-oncology guideline definition. 

Methods: We have analyzed patients scheduled for ICI therapy from the EcoR (Essen cardio-oncology Registry) database from the local cardio-oncology unit between July 2018 and March 2023. Data was collected from the cardio-oncology consultations before ICI therapy start (baseline), at 6 weeks, 6 months and 12 months after therapy start. Patients were divided in two groups: patients diagnosed with extracardiac irAEs (group 1) and patients without extracardiac irAEs (group 2).

Results: Out of 2540 patients, we identified 266 individuals (61 ± 14 years, 40.6% female, 86.5% patients with melanoma, 62% with metastatic disease) scheduled for ICI therapy. 104 patients (37.5%) developed extracardiac irAEs (most frequent 15.4% hepatitis, 13.5 % colitis, 7.1 % thyroiditis) and were compared to 162 patients without extracardiac irAEs. Patients in the two groups were not significantly different regarding age, gender, cardiovascular risk factors and history of cardiovascular disease. Patients with extracardiac irAEs had a 2-fold higher risk of cancer therapy related cardiac dysfunction (CTRCD): relative risk (RR) 2 (95% CI 1.46, 2.76), p < 0.001. Most of the patients (98.9%) suffered from a mild CTRCD. The incidence of myocarditis was 10.5% in patients with extracardiac irAEs, compared to 0% in patients without extracardiac irAEs. There were no differences regarding the incidence of arrhythmia and vascular toxicity between the two groups. Overall, patients with extracardiac irAEs showed 39% more cardiovascular toxicity, predominantly mild CTRCD, in 42% of cases diagnosed through a reduction in global longitudinal strain (GLS). This emphasizes the importance of the echocardiography assessment during the cardio-oncology monitoring under ICI therapy.

Conclusion: Patients under ICI therapy with extracardiac irAEs show a twofold higher incidence of mild CTRCD and a high incidence of myocarditis. The early diagnostic of CTR-CVT, including CTRCD and myocarditis cannot be performed in the absence of echocardiography data. This calls to a refining of cardio-oncology surveillance protocols in this patient group, urging the inclusion of echocardiography serial examination of patients with irAEs under ICI therapy. The CTR-CVT is of utmost relevance for the prognosis of cancer survivors.