Downloaded from http://journals.lww.com/immunotherapy-journal by BhDMf5ePHKbH4TTImqenVKNoQAGGabrfpzZGOAIhTvoPhdgQa305o1kKuSKUElhR on 02/13/2019 Autoimmune Myocarditis Caused by Immune Checkpoint Inhibitors Treated With Antithymocyte Globulin Varun Jain,*† Mahsa Mohebtash,‡ Maria E. Rodrigo,* George Ruiz,‡ Michael B. Atkins,†§ and Ana Barac*†∥ Summary: The immune checkpoint inhibitors have brought about a paradigm shift in the treatment of many cancers and are being used as the first line therapy in increasing number of aggressive malig- nancies, including metastatic melanoma. Their adverse effects, mostly mediated by an uncontrolled overactivation of the immune system, may compromise the therapeutic benefit. Combination immune checkpoint therapies in particular, have higher therapeutic efficacy, but have also been associated with a higher incidence of severe immune-related adverse effects including autoimmune lym- phocytic myocarditis. Recent clinical reports of this rare and life threatening condition indicated rapid progression of severe hemo- dynamic and electrical instability, with or without acute decom- pensated heart failure, reduced ejection fraction and shock, pointing to the need for early recognition, diagnosis and prompt manage- ment. Current guidelines for management of other immune-related adverse effects recommend high-dose glucocorticoids, with consid- eration of immunomodulators, such as infliximab in patients with severe colitis. However, knowledge about the treatment approaches in immune-related myocarditis remains extremely scarce. Here we report a case of severe, steroid refractory, lymphocytic myocarditis that occurred after the first cycle of combination immunotherapy with the programmed cell death protein-1 inhibitor, nivolumab, and the cytotoxic T-lymphocyte-associated protein 4 blocker, ipilimu- mab, for metastatic melanoma. We discuss treatment approaches including the role for transvenous pacemaker, advanced heart fail- ure support, and interdisciplinary decision making. Key Words: immune checkpoint inhibitor, autoimmune myocardi- tis, complete heart block, antithymocyte globulin, nivolumab, ipi- limumab, cardiotoxicity (J Immunother 2018;41:332–335) CASE PRESENTATION A 67-year-old man, with history of melanoma of the right thigh treated with wide local excision in 2010, presented with new onset back pain over several weeks. Imaging revealed T11 vertebral lesions and multiple brain, lung, and liver metastases. He underwent surgical laminectomy with fusion and stereotactic radiosurgery of brain metastases followed by the initiation of systemic combination immunotherapy with ipilimumab (3 mg/kg) and nivolumab (1 mg/kg). Six days after the treatment he developed generalized skin rash (Fig. 1), hypotension, and acute kidney injury, and received 1 mg/kg of pre- dnisone (105 kg rounded at 120 mg) daily with some improvement. His initial electrocardiogram (EKG) was normal and echocardiography showed normal left ventricular (LV) systolic function with an ejection fraction of 60%. Over the next 10 days he developed progressive shortness of breath, cough, and dyspnea on exertion, and was rehospitalized for acute decompensated heart failure. His initial laboratory revealed elevated cardiac biomarkers with NT-ProBNP 7953; troponin, 27.9; lactic acid, 3.6; creatinine, 1.3; and liver transaminases AST, 114; ALT, 166. Creatine kinase was mildly elevated at 605. Serial EKG’s showed new intraventricular conduction delay which progressed into episodes of nonsustained ventricular tachycardia (Fig. 2A). Repeat echocardiogram demonstrated severe LV hypokinesis and LV ejection fraction (LVEF) decline to 20%. Coronary angiogram revealed no evidence of coronary artery disease. Within 48 hours, arrhythmia progressed into a complete heart block (Fig. 2B) requiring transvenous pacing. On admission to the hospital, pre- dnisone was changed to methylprednisolone 500 mg twice daily. Despite high-dose steroid treatment, the patient developed cardio- genic shock requiring inotropic and ventilatory support and was transferred to advanced heart failure and transplant center for invasive cardiac monitoring and support. Right heart catheter- ization with endomyocardial biopsy was performed and demon- strated diffuse cardiomyocyte necrosis with significant lymphocytic infiltration and predominance of CD3 + and CD20 - T cells on immunohistochemical staining, consistent with lymphocytic myo- carditis (Figs. 3A–C). Because of ongoing shock and hypotension despite hemodynamic support, antithymocyte globulin (ATG) was added to the steroid regimen, following the institutional heart transplant rejection protocol, with the initial intravenous dose of 1.5 mg/kg and subsequent daily doses ranging from 0.5 to 1.5 mg/kg, adjusted based on the absolute CD3 count. The patient received a total of 6 doses of ATG, with stabilization of the hemodynamic status and significant improvement of cardiac function to LVEF of 40% over the following 2 weeks. His hospital course was complicated by gastrointestinal bleed, ventilator-associated pneumonia and sepsis, all of which were treated. Complete heart block persisted and, after bacteremia resolved, transvenous pacemaker was removed and per- manent pacemaker implanted. He was transferred out of the intensive care unit with plan for rehabilitation. Before discharge he unfortu- nately deteriorated and experienced seizures, leading to pursuit of palliative care and inpatient hospice. DISCUSSION Immunotherapy with cytotoxic T-lymphocyte-associated antigen (CTLA-4) and programmed cell death protein-1 (PD-1) immune checkpoint inhibitors is effective in patients with advanced melanoma. Checkpoint inhibitors are increasingly being used for other tumor types including non–small-cell lung carcinoma, renal cell carcinoma, uro- thelial carcinoma, head and neck squamous cell carcinoma, and the Hodgkin lymphoma. 1,2 Ipilimumab, a monoclonal antibody against CTLA-4 was the first immune checkpoint inhibitor approved by Food and Drug Administration in 2011 after it showed objective responses in 11% of the patients and prolonged median overall survival compared with a peptide vaccine. 3,4 Nivolumab, a monoclonal antibody against PD-1, was Food and Drug Administration approved in 2014 having showed an improvement in objective response rate of 32% versus 11% and median overall survival Received for publication December 8, 2017; accepted March 9, 2018. From the *MedStar Georgetown University/Washington Hospital Center; †Georgetown University; §Lombardi Comprehensive Can- cer Center; ∥MedStar Heart and Vascular Institute, Washington, DC; and ‡MedStar Union Memorial Hospital, Baltimore, MD. Reprints: Ana Barac, MedStar Washington Hospital Center, 110 Irving Street NW, Suite 1F1218, Washington, DC 20010 (e-mail: ana.barac@ medstar.net). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. CLINICAL STUDY 332 | www.immunotherapy-journal.com J Immunother  Volume 41, Number 7, September 2018 Copyright r 2018 Wolters Kluwer Health, Inc. All rights reserved.