Myocarditis in the Setting of Cancer Therapeutics: Proposed Case Definitions for Emerging Clinical Syndromes in Cardio-Oncology

Abstract

Recent developments in cancer therapeutics have improved outcomes but have also been associated with cardiovascular complications. Therapies harnessing the immune system have been associated with an immune-mediated myocardial injury described as myocarditis. Immune checkpoint inhibitors are one such therapy with an increasing number of case and cohort reports describing a clinical syndrome of immune checkpoint inhibitor–associated myocarditis. Although the full spectrum of immune checkpoint inhibitor–associated cardiovascular disease still needs to be fully defined, described cases of myocarditis range from syndromes with mild signs and symptoms to fatal events. These observations in the clinical setting stand in contrast to outcomes from randomized clinical trials in which myocarditis is a rare event that is investigator reported and lacking in a specific case definition. The complexities associated with diagnosis, as well as the heterogeneous clinical presentation of immune checkpoint inhibitor–associated myocarditis, have made ascertainment and identification of myocarditis with high specificity challenging in clinical trials and other data sets, limiting the ability to better understand the incidence, outcomes, and predictors of these rare events. Therefore, establishing a uniform definition of myocarditis for application in clinical trials of cancer immunotherapies will enable greater understanding of these events. We propose an operational definition of cancer therapy-associated myocarditis that may facilitate case ascertainment and report and therefore may enhance the understanding of the incidence, outcomes, and risk factors of this novel clinical syndrome.

Keywords: oncology, medical; adjudication; immunotherapy; cardiovascular disease; myocarditis; immunosuppressive agents.

Conflict of interest statement

Dr Bonaca reports consulting for Amgen, AstraZeneca, Bayer, Janssen, Pfizer, Sanofi-Aventis, Merck as well as research funding from AstraZeneca, MedImmune, Merck, and Pfizer. Dr Salem was supported by Cancer ITMO of the French National Alliance for Life and Health Sciences (AVIESAN): “Plan Cancer 2014 to 2019”. Dr Wiviott reports ARENA, AstraZeneca, Aegerion, Allergan, Angelmed, Boehringer-Ingelheim, Boston Clinical Research Institute, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, Icon Clinical, Janssen, Lexicon, Merck, Servier, St Jude Medical, Xoma, and research grants from Amgen, Arena, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, Janssen, Merck and Sanofi-Aventis. Dr Wiviott’s spouse is an employee of Merck Research Laboratories. Dr Ederhy has received consultant and lecture fees from Eli Lilly, Daiichy-Sankyo, Celgene, Pfizer, EspeRare, Bristol-Myers Squibb, Janssen, Philips Healthcare, Bayer, Novartis, Amgen, and Ipsen. Dr Cohen has received consultant and lecture fees from, Amgen, AstraZeneca, Bayer Pharma, BMS-Pfizer alliance, Boehringer-Ingelheim and Novartis, and has received research grants from ARS, RESICARD, Bayer, and Boehringer-Ingelheim. Dr Di Carli has received consulting honoraria from Sanofi and General Electric and research grants from SpectrumDynamics. Dr Choueiri has been a consultant for AstraZeneca, Bayer, BMS, Cerulean, Eisai, Foundation Medicine Inc, Exelixis, Genentech, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Ipsen and has received research funding from AstraZeneca, Bayer, BMS, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, and Ipsen. Dr Kumbhani has received an honoraria from American College of Cardiology. Dr Heinzrling has been a principal investigator in clinical studies for Bristol-Myers Squibb, Merck, Roche, Amgen, GlaxoSmithKline, Curevac, and Novartis; had received consultancy and speaker fees from from Bristol-Myers Squibb, Merck, Roche, Amgen, Novartis, Curevac, and Pierre Fabre. Dr Lyon has received speaker, advisory board or consultancy fees and/or research grants from Pfizer, Novartis, Servier, Amgen, Clinigen Group, Takeda, Roche, Eli Lily, Eisai, Bristol Myers Squibb, Ferring Pharmaceuticals, and Boehringer Ingelheim. Dr Johnson has served on an advisory board for Array, Bristol-Myers Squibb, Genoptix, Incyte, Merck, and Novartis, and has received research funding from Bristol-Myers Squibb and Incyte. Dr Moslehi has served on an advisory board for Pfizer, Novartis, Bristol-Myers Squibb, Takeda, Regeneron, and Myokardia and received research funding from Pfizer and Novartis. The other authors report no conflicts.

© 2019 American Heart Association, Inc.

Figures

Figure 1

A proposed approach to diagnosis of myocarditis in the setting of ICI use. Abbreviations: ACS: Acute coronary syndrome AMICI : Acute myocarditis related to ICI AHF: acute heart failure AV: atrioventricular AF: atrial fibrillation Bm: biomarkers CMR: Cardiac magnetic resonance imaging ECG: Electrocardiogram EMB: Endo-myocardial biopsy ICI: immune checkpoint inhibitor LVEF: Left ventricular ejection fraction MI: myocardial infarction NIMI : non ischemic MI Sd: Syndrome TTE : Transthoracic echocardiography TTS : Takotsubo WMA: Wall motion abnormality

Figure 2

A proposed definition of myocarditis to be applied in clinical trials

Figure 3

Scope of ascertainment for cardiovascular events in oncology trials. Cardiac events should be adjudicated in a hierarchical manner excluding ischemia prior to establishing myocarditis. Simultaneous adjudication of heart failure and arrhythmia is recommended as event types may not be mutually exclusive Abbreviations: CV: Cardiovascular ECG: Electrocardiogram HF: Heart Failure HTN: Hypertension VTE: Venous thrombo-embolic