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      Immune checkpoint inhibitor-induced myocarditis in cancer patients: a case report and review of reported cases

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          Abstract

          Background

          Immune checkpoint inhibitor (ICI) induced myocarditis is a rare, severe, and often fatal adverse event. Evidence to guide appropriate immunosuppressive therapy is scarce. We present a case of ICI-induced myocarditis and a review of ICI-induced myocarditis cases to determine the most effective immunosuppressive therapeutic strategy for ICI-induced myocarditis.

          Methods

          A systematic search of PubMed was carried out for treatment of ICI-induced myocarditis. Reference lists from identified articles were manually reviewed for additional cases.

          Results

          A total of 87 cases with ICI-induced myocarditis were identified. The majority were melanoma ( n = 39), lung cancer ( n = 19), renal cell cancer ( n = 10), and thymoma cancer patients ( n = 4). In 38 (44%) cases, patients received high-dose steroid treatment only. A total of 49 (56%) cases were treated with immunosuppressive agents other than steroid; a total of 13 different immunosuppressive agents were used, including alemtuzumab or abatacept. The median time to onset of symptoms after initiation of ICI was 16 days (range, 1–196 days); cardiotoxic symptoms developed after 2 cycles of ICI (range, 1–13 cycles). A total of 48% of cases were fatal. In cases treated with high-dose steroids only vs. cases treated with other immunosuppressive agents, fatality was 55% and 43% respectively. In 64 out of the 87 cases, tumor control was not described. In patients treated with high-dose steroids only, two patients had stable disease as best tumor response; in patients treated with other immunosuppressive agents, one complete response, one partial response and seven stable disease were noted as best tumor response. Overall, 11 studies were at low risk of bias (12.6%), 38 at moderate risk of bias (43.7%) and 38 at high risk of bias (43.7%).

          Conclusion

          Immune checkpoint inhibitor induced myocarditis is a serious and often fatal adverse event. High-dose prednisolone, alemtuzumab or abatacept are all possible treatments options for ICI-induced myocarditis, whereas infliximab increases the risk of death from cardiovascular causes, and should be avoided. Further research is needed.

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          Most cited references75

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          2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.

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            Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline

            Purpose To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events in patients treated with immune checkpoint inhibitor (ICPi) therapy. Methods A multidisciplinary, multi-organizational panel of experts in medical oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, urology, neurology, hematology, emergency medicine, nursing, trialist, and advocacy was convened to develop the clinical practice guideline. Guideline development involved a systematic review of the literature and an informal consensus process. The systematic review focused on guidelines, systematic reviews and meta-analyses, randomized controlled trials, and case series published from 2000 through 2017. Results The systematic review identified 204 eligible publications. Much of the evidence consisted of systematic reviews of observational data, consensus guidelines, case series, and case reports. Due to the paucity of high-quality evidence on management of immune-related adverse events, recommendations are based on expert consensus. Recommendations Recommendations for specific organ system-based toxicity diagnosis and management are presented. While management varies according to organ system affected, in general, ICPi therapy should be continued with close monitoring for grade 1 toxicities, with the exception of some neurologic, hematologic, and cardiac toxicities. ICPi therapy may be suspended for most grade 2 toxicities, with consideration of resuming when symptoms revert to grade 1 or less. Corticosteroids may be administered. Grade 3 toxicities generally warrant suspension of ICPis and the initiation of high-dose corticosteroids (prednisone 1 to 2 mg/kg/d or methylprednisolone 1 to 2 mg/kg/d). Corticosteroids should be tapered over the course of at least 4 to 6 weeks. Some refractory cases may require infliximab or other immunosuppressive therapy. In general, permanent discontinuation of ICPis is recommended with grade 4 toxicities, with the exception of endocrinopathies that have been controlled by hormone replacement. Additional information is available at www.asco.org/supportive-care-guidelines and www.asco.org/guidelineswiki .
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              Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases.

              In this position statement of the ESC Working Group on Myocardial and Pericardial Diseases an expert consensus group reviews the current knowledge on clinical presentation, diagnosis and treatment of myocarditis, and proposes new diagnostic criteria for clinically suspected myocarditis and its distinct biopsy-proven pathogenetic forms. The aims are to bridge the gap between clinical and tissue-based diagnosis, to improve management and provide a common reference point for future registries and multicentre randomised controlled trials of aetiology-driven treatment in inflammatory heart muscle disease.
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                Author and article information

                Contributors
                fd@oncology.au.dk
                Journal
                Cardiooncology
                Cardiooncology
                Cardio-oncology
                BioMed Central (London )
                2057-3804
                9 August 2021
                9 August 2021
                2021
                : 7
                : 27
                Affiliations
                [1 ]GRID grid.154185.c, ISNI 0000 0004 0512 597X, Department of Oncology, , Aarhus University Hospital, Palle Juul-Jensens, ; Boulevard 99, 8200 Aarhus N, Denmark
                [2 ]GRID grid.154185.c, ISNI 0000 0004 0512 597X, Department of Rheumatology, , Aarhus University Hospital, ; Aarhus, Denmark
                [3 ]GRID grid.154185.c, ISNI 0000 0004 0512 597X, Department of Cardiology, , Aarhus University Hospital, ; Aarhus, Denmark
                [4 ]GRID grid.154185.c, ISNI 0000 0004 0512 597X, Department of Pathology, , Aarhus University Hospital, ; Aarhus, Denmark
                Article
                114
                10.1186/s40959-021-00114-x
                8351114
                34365980
                80999f83-5c01-4580-84a5-d9375feed700
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 5 March 2021
                : 16 July 2021
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100010983, Health Research Fund of Central Denmark Region;
                Categories
                Review
                Custom metadata
                © The Author(s) 2021

                checkpoint immunotherapy,myocarditis,immunosuppressive therapy

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