Dottorato in FISIOPATOLOGIA ED IMAGING CARDIO-TORACO-VASCOLARE

Titolo della tesi: Cardiotoxicity Related to Immunotherapy for Solid Tumours: The Immune Checkpoint Inhibitors Era.

Background: Immune checkpoint inhibitors (ICIs) have demonstrated high efficacy in many solid tumour treatments. However, they are burdened with many side effects with high morbidity and, sometimes, mortality. Cardiovascular (CV) adverse events are those with the higher mortality but are reported as rare. Since available data are based on trials and pharmacovigilance studies, with the exclusion of patients with CV diseases and reporting only severe cases, the incidence of CV toxicity is believed to be higher. The present work aims to describe the incidence of CV toxicities in a real-world cohort of patients diagnosed with a solid tumour and candidates for immunotherapy, alone or in combination with other anti-neoplastic agents and identify eventual early predictors of cardiac adverse events. Methods: all the patients with a new diagnosis of solid tumour candidate for immunotherapy schemes first lines are consecutively recruited at the Oncology Outpatient Clinic of the Policlinico Umberto Primo Hospital, “La Sapienza” University of Rome. They undergo serial CV evaluations at baseline or T0 (before starting therapy), at T1 (before the third therapy cycle), and at T2 (before the ninth therapy cycle). CV evaluation comprises clinical visit, electrocardiogram (ECG), standard and advanced transthoracic echocardiogram (TTE), cardiac biomarkers (Hs-TnT, NT-proBNP) and oxidative stress parameters (H2O2, sNOX2dp) evaluation. Results: This work presents the preliminary data of the project on the first enrolled eight patients (50% males, mean age 68 10) with available data at T0, T1 and T2. The vast majority of patients underwent Pembrolizumab plus Axitinib (VEGFi) therapy. No myocarditis or pericarditis nor myocardial infarction occurred. All the patients developed new onset or decompensated hypertension requiring anti-hypertensive therapy. One patient, with a history of coronary artery disease treated with multiple angioplasty and stent procedures, was diagnosed with asymptomatic left ventricular apical thrombosis at T1 and started anticoagulants. The comparison between ECG, TTE, biomarkers, and stress oxidative markers does not show significant differences between the three evaluations. A trend of increasing oxidative stress at T1 and T2 and decreasing LV-GLS at T2 was observed but without statistical significance, probably due to the small sample size. Conclusions: Preliminary data on a small cohort of patients with solid tumours undergoing immunotherapy, in combination with VEGFi or alone, showed no significant changes in ECG, TTE and biomarkers across three times evaluations. However, serial CV evaluation allows for detecting a case of endo-ventricular thrombosis and promptly starting anticoagulants, thus holding the potential for early identification of CV toxicities.