Pathophysiology, diagnosis and management of cardiac toxicity induced by immune checkpoint inhibitors and BRAF and MEK inhibitors

Abstract

Immune checkpoint inhibitors (ICIs) and BRAF and MEK inhibitors (BRAFi/MEKi) have drastically improved the outcome of melanoma patients. ICIs can induce myocarditis, a rare immune related adverse event (irAE) with an estimated lethality of 50%. BRAFi/MEKi may induce left ventricular ejection fraction decrease, hypertension or QT interval prolongation. While the BRAFi/MEKi induced cardiotoxicity is often reversible upon treatment discontinuation or dose adaptation and symptomatic therapy is often sufficient to restore cardiac function, the treatment of ICI-induced myocarditis mainly relies on high dose corticosteroids. There is no established therapy for steroid resistant myocarditis, yet various drugs have been reported to improve outcome. Shared epitopes between melanoma cells and cardiac tissue are thought to underlie the development of ICIs induced myocarditis. The mechanism of BRAFi/MEKi induced cardiotoxicity appears to be related to the Ras-Raf-MEK-ERK pathway in cardiomyocyte repair, survival and proliferation. With the emerging application of ICI-BRAFi/MEKi combinations, so called triplet therapies, differentiating between these two types of cardiotoxicity will become important for appropriate patient management.In this article we provide a summary of the existing literature on the pathophysiology, diagnosis and management of cardiotoxicity of melanoma therapies.

Prescription Patterns, Recurrence, and Toxicity Rates of Adjuvant Treatment for Stage III/IV Melanoma—A Real World Single-Center Analysis

“…While dabrafenib and trametinib toxicity is, in general, reversible and comprises pyrexia, unspecific symptoms, such as fatigue, headache and nausea, and, rarely, cardiac toxicity, immune-related adverse events (irAEs) can affect any organ, might require systemic corticosteroids or other immunosuppressive drugs, and can be long-lasting and irreversible [8]. In particular, myocarditis is a rare but potentially fatal complication of ICI [9].…”

Myocarditis Induced by Immunotherapy in Metastatic Melanoma—Review of Literature and Current Guidelines

“…Interestingly, targeted therapies used in melanoma treatment may also induce cardiotoxicity. BRAF/MEK inhibitors may cause reduction in left ventricular ejection fraction (5–11%), hypertension (11–30%) or QT interval prolongation (0–5%) [ 34 ]. The summary of the most important information about cases, which are mentioned above, is provided in supplementary data ( Table S1 in Supplementary Materials ).…”

“…Cardiac MRI can show regional or globally increased T2-weighted signal with gadolinium enhancement and/or myocardial injury through T1-based markers (including the presence of late gadolinium enhancement following a non-ischemic distribution) [ 15 , 34 ]. Moreover, cardiac MRI may quantitate tissue injury, including edema, hyperemia, and fibrosis, and can support the diagnosis of myocarditis (Lake Louis criteria) [ 57 , 58 ].…”

“…The consensus for the initial steroid dose is an equivalent dose of (methyl)prednisolone 1–2 mg/kg for grade 2 or higher cardiotoxicity ( Table 2 ) [ 77 , 78 ]. CTLA-4 agonist abatacept, alemtuzumab, tocilizumab, rituximab, anti-thymocyte globulin, intravenous immunoglobulins, tacrolimus, mycophenolate, azathioprine, methotrexate, cyclophosphamide, and infliximab or plasmapheresis have been used in steroid-refractory cases of myocarditis, although infliximab is not preferred at higher dosing given its association with cardiac failure [ 34 , 64 , 79 ]. Matzen et al compared fatality in identified cases and 55% treated with high-dose steroids only were fatal versus 43% fatality in cases treated with other immunosuppressive agents [ 16 ].…”

Cardiotoxicity Induced by Protein Kinase Inhibitors in Patients with Cancer

“…Protein KIs can lead to numerous cardiovascular toxicities including, but not limited to, hypertension, arrhythmias, cardiomyopathy or heart failure, fluid retention, thromboembolic events, and myocardial ischemia or infarction [ 40 , 41 , 42 , 43 , 44 , 45 , 46 , 53 , 54 , 57 , 58 ]. Considering the toxicity profile of KIs, the National Cancer Institute recommends that before starting therapy, each patient should be assessed for cardiovascular risk factors such as previous cardiovascular disease, blood pressure above 160/100 mmHg, diabetes, dyslipidemia, smoking, obesity (body mass index >30 kg/m 2 ), lack of physical activity, alcohol abuse, excessive salt consumption, and family history of cardiovascular disease [ 7 , 58 ].…”