BACKGROUND Myocarditis is an uncommon, but potentially fatal, toxicity of immune checkpoint inhibitors (ICI). Myocarditis after ICI has not been well characterized. OBJECTIVES The authors sought to understand the presentation and clinical course of ICI-associated myocarditis. METHODS After observation of sporadic ICI-associated myocarditis cases, the authors created a multicenter registry with 8 sites. From November 2013 to July 2017, there were 35 patients with ICI-associated myocarditis, who were compared to a random sample of 105 ICI-treated patients without myocarditis. Covariates of interest were extracted from medical records including 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. RESULTS The prevalence of myocarditis was 1.14% with a median time of onset of 34 days after starting ICI (inter-quartile range: 21 to 75 days). Cases were 65 ± 13 years of age, 29% were female, and 54% had no other immune-related side effects. Relative to controls, combination ICI (34% vs. 2%; p < 0.001) and diabetes (34% vs. 13%; p = 0.01) were more common in cases. Over 102 days (interquartile range: 62 to 214 days) of median follow-up, 16 (46%) developed MACE; 38% of MACE occurred with normal ejection fraction. There was a 4-fold increased risk of MACE with troponin T of ≥1.5 ng/ml (hazard ratio: 4.0; 95% confidence interval: 1.5 to 10.9; p = 0.003). Steroids were administered in 89%, and lower steroids doses were associated with higher residual troponin and higher MACE rates. CONCLUSIONS Myocarditis after ICI therapy may be more common than appreciated, occurs early after starting treatment, has a malignant course, and responds to higher steroid doses.

Cancer and cardiovascular (CV) disease are the most prevalent diseases in the developed world. Evidence increasingly shows that these conditions are interlinked through common risk factors, coincident in an ageing population, and are connected biologically through some deleterious effects of anticancer treatment on CV health. Anticancer therapies can cause a wide spectrum of short-and long-term cardiotoxic effects. An explosion of novel cancer therapies has revolutionised this field and dramatically altered cancer prognosis. Nevertheless, these new therapies have introduced unexpected CV complications beyond heart failure. Common CV toxicities related to cancer therapy are defined, along with suggested strategies for prevention, detection and treatment. This ESMO consensus article proposes to define CV toxicities related to cancer or its therapies and provide guidance regarding prevention, screening, monitoring and treatment of CV toxicity. The majority of anticancer therapies are associated with some CV toxicity, ranging from asymptomatic and transient to more clinically significant and long-lasting cardiac events. It is critical however, that concerns about potential CV damage resulting from anticancer therapies should be weighed against the potential benefits of cancer therapy, including benefits in overall survival. CV disease in patients with cancer is complex and treatment needs to be individualised. The scope of cardio-oncology is wide and includes prevention, detection, monitoring and treatment of CV toxicity related to cancer therapy, and also ensuring the safe development of future novel cancer treatments that minimise the impact on CV health. It is anticipated that the management strategies discussed herein will be suitable for the majority of patients. Nonetheless, the clinical judgment of physicians remains extremely important; hence, when using these best clinical practices to inform treatment options and decisions, practitioners should also consider the individual circumstances of their patients on a case-by-case basis.

Aims Myocarditis is a potentially fatal complication of immune checkpoint inhibitors (ICI). Sparse data exist on the use of cardiovascular magnetic resonance (CMR) in ICI-associated myocarditis. In this study, the CMR characteristics and the association between CMR features and cardiovascular events among patients with ICI-associated myocarditis are presented. Methods and results From an international registry of patients with ICI-associated myocarditis, clinical, CMR, and histopathological findings were collected. Major adverse cardiovascular events (MACE) were a composite of cardiovascular death, cardiogenic shock, cardiac arrest, and complete heart block. In 103 patients diagnosed with ICI-associated myocarditis who had a CMR, the mean left ventricular ejection fraction (LVEF) was 50%, and 61% of patients had an LVEF ≥50%. Late gadolinium enhancement (LGE) was present in 48% overall, 55% of the reduced EF, and 43% of the preserved EF cohort. Elevated T2-weighted short tau inversion recovery (STIR) was present in 28% overall, 30% of the reduced EF, and 26% of the preserved EF cohort. The presence of LGE increased from 21.6%, when CMR was performed within 4 days of admission to 72.0% when CMR was performed on Day 4 of admission or later. Fifty-six patients had cardiac pathology. Late gadolinium enhancement was present in 35% of patients with pathological fibrosis and elevated T2-weighted STIR signal was present in 26% with a lymphocytic infiltration. Forty-one patients (40%) had MACE over a follow-up time of 5 months. The presence of LGE, LGE pattern, or elevated T2-weighted STIR were not associated with MACE. Conclusion These data suggest caution in reliance on LGE or a qualitative T2-STIR-only approach for the exclusion of ICI-associated myocarditis.

Immune checkpoint inhibitors (ICIs) are approved for a wide range of malignancies. They work by priming the immune system response to cancer and have changed the landscape of available cancer treatments. As anticipated, modulation of the regulatory controls in the immune system with ICIs results in diverse immune-related adverse events, targeting any organ or gland. These toxicities are rarely fatal and generally regress after treatment discontinuation and/or prescription of corticosteroids. Recently, several cases of ICI-related cardiotoxicity have been reported with complications ranging from cardiogenic shock to sudden death. The true incidence of ICI-associated myocarditis is likely underestimated, due to a combination of factors including the lack of specificity in the clinical presentation, the potential of overlap with other cardiovascular and general medical illnesses, the challenges in the diagnosis, and a general lack of awareness of this condition. Currently, there are no clear guidelines for surveillance, diagnosis, or management of this entity. There are multiple unresolved issues including, but not limited to, identifying those at risk of this uncommon toxicity, elucidating the pathophysiology, determining if and what type of surveillance is appropriate, optimal work-up of suspected patients, and methods for resolution of myocarditis. Here we describe a clinical vignette and discuss the salient features and management strategies of ICI-associated myocarditis. The Oncologist 2018;23:518-523 KEY POINTS• The incidence of immune checkpoint inhibitor (ICI)-associated myocarditis is unclear and has been reported to range from 0.06% to 1% of patients prescribed an ICI.• Myocarditis may be difficult to diagnose.• The risk factors for ICI-associated myocarditis are not well understood but may include underlying autoimmune disease and diabetes mellitus. • The prevalence of myocarditis has been reported to be higher with combination immune therapies.• Myocarditis with ICI's typically occurs early, with an elevated troponin, may present with an normal left ventricular ejection fraction and may have a fulminant course.• The optimal management of myocarditis associated with ICI's is unclear but most cases are treated with high-dose steroids. PATIENT STORYA 41-year-old woman with no cardiac risk factors but a prior history of Hashimoto's thyroiditis was diagnosed with metastatic melanoma. She presented with mild dyspnea 6 days after completing four cycles of combined immune checkpoint inhibitor (ICI) therapy with ipilimumab and nivolumab. On exam, she was tachycardic and mildly volume overloaded but was otherwise stable. Sinus tachycardia was noted on electrocardiogram (ECG); there were no conduction abnormalities (Fig. 1A). Cardiac troponin I (cTn) was mildly elevated with normal level of N-terminal-pro brain natriuretic peptide (NT-proBNP). A chest computed tomography (CT) scan did not show evidence of pneumonitis but did show cardiomegaly and pulmonary congestion. An echocardiogram revealed global left...

The discipline of Cardio-Oncology has seen tremendous growth over the past decade. It is devoted to the cardiovascular (CV) care of the cancer patient, especially to the mitigation and management of CV complications or toxicities of cancer therapies, which can have profound implications on prognosis. To that effect, many studies have assessed CV toxicities in patients undergoing various types of cancer therapies; however, direct comparisons have proven difficult due to lack of uniformity in CV toxicity endpoints. Similarly, in clinical practice, there can be substantial differences in the understanding of what constitutes CV toxicity, which can lead to significant variation in patient management and outcomes. This document addresses these issues and provides consensus definitions for the most commonly reported CV toxicities, including cardiomyopathy/heart failure and myocarditis, vascular toxicity, and hypertension, as well as arrhythmias and QTc prolongation. The current document reflects a harmonizing review of the current landscape in CV toxicities and the definitions used to define these. This consensus effort aims to provide a structure for definitions of CV toxicity in the clinic and for future research. It will be important to link the definitions outlined herein to outcomes in clinical practice and CV endpoints in clinical trials. It should facilitate communication across various disciplines to improve clinical outcomes for cancer patients with CV diseases.