Fulminant Myocarditis with Combination Immune Checkpoint Blockade

2016/11/02 by Douglas B. Johnson, Justin M. Balko, Margaret Compton +36 · 2,303 citations
Biochemistry, Genetics and Molecular Biology · Medicine · #Blockade #CAR-T cell therapy research #Cancer #Cancer Immunotherapy and Biomarkers #Cancer research #Fulminant #Immune checkpoint #Immune system #Immunology #Immunotherapy #Internal medicine #Ipilimumab #Medicine #Melanoma #Melanoma and MAPK Pathways #Myocarditis #Myositis #Nivolumab #Oncology #Pembrolizumab #Tremelimumab

paper · pdf · doi:10.1056/nejmoa1609214

published in New England Journal of Medicine 375(18), 1749-1755 (Massachusetts Medical Society)

openalex publication_date 2016/11/02 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/06

Abstract

Immune checkpoint inhibitors have improved clinical outcomes associated with numerous cancers, but high-grade, immune-related adverse events can occur, particularly with combination immunotherapy. We report the cases of two patients with melanoma in whom fatal myocarditis developed after treatment with ipilimumab and nivolumab. In both patients, there was development of myositis with rhabdomyolysis, early progressive and refractory cardiac electrical instability, and myocarditis with a robust presence of T-cell and macrophage infiltrates. Selective clonal T-cell populations infiltrating the myocardium were identical to those present in tumors and skeletal muscle. Pharmacovigilance studies show that myocarditis occurred in 0.27% of patients treated with a combination of ipilimumab and nivolumab, which suggests that our patients were having a rare, potentially fatal, T-cell-driven drug reaction. (Funded by Vanderbilt-Ingram Cancer Center Ambassadors and others.) I mmune checkpoint inhibitors have transformed the treatment of several cancers by releasing restrained antitumor immune responses. 1 3] These toxic effects are more frequent and severe when ipilimumab and nivolumab are used in combination. Here, we report two cases of lethal myocarditis accompanied by myositis in patients treated with a combination of nivolumab and ipilimumab.

Cited by

• Immune-Related Adverse Events Associated with Immune Checkpoint Blockade
• Fundamental Mechanisms of Regulated Cell Death and Implications for Heart Disease
• Drug-induced cardiac toxicity and adverse drug reactions, a narrative review
• Deciphering the role of circulating inflammatory proteins in myocarditis: Novel strategies for targeted therapy
• Immune checkpoint inhibitor associated myocarditis occurs in both high-grade and low-grade forms
• 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS)
• Effects of immune‐related adverse events (irAEs) and their treatment on antitumor immune responses
• Immune checkpoint inhibitor–induced myocarditis is dependent on CD8 T cell–derived TNF and TNFR2 signaling
• Immune checkpoint inhibitors and acute kidney injury
• Multimodality imaging in the detection and management of coronary and peripheral arterial disease in patients with cancer receiving cardiotoxic antineoplastic treatments: A clinical consensus statement of the ESC Council of Cardio-Oncology and the European Association of Cardiovascular Imaging (EACVI) of the ESC
• Caught in the crossfire: cardiac complications of cancer therapy
• Drug allergy: A 2022 practice parameter update
• Reduced monocytic IL10 expression in PD1 inhibitor-treated patients is a harbinger of severe immune-related adverse events
• Evolving insights into the mechanisms of toxicity associated with immune checkpoint inhibitor therapy
• Identification of features and differences in PD-1 inhibitor-associated myocarditis and acute myocardial infarction using proteomic analysis: a clinical and preclinical study
• Life-threatening immune-related adverse events in the intensive care unit: a narrative review
• Systemic immune characteristics predicting toxicity to immune checkpoint inhibitors in patients with advanced breast cancer
• Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
• Automatic Bug Triage using Semi-Supervised Text Classification
• Preclinical mouse models of immune checkpoint inhibitor-associated myocarditis
• Metabolic reprogramming in cancer therapy-related cardiovascular toxicity: Mechanisms and intervention strategies
• Histopathologic Characterization of Myocarditis Associated With Immune Checkpoint Inhibitor Therapy
• Myocarditis
• 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure
• Risk factors associated with cardiovascular hospital admissions and all-cause mortality in cancer patients treated with immune checkpoint inhibitors
• Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade. [europepmc]
• CTLA-4: a moving target in immunotherapy. [europepmc]
• A neoantigen fitness model predicts tumour response to checkpoint blockade immunotherapy. [europepmc]
• Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. [europepmc]
• Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. [europepmc]
• Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. [europepmc]
• Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis. [europepmc]
• Myocarditis in Patients Treated With Immune Checkpoint Inhibitors. [europepmc]
• Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain. [europepmc]
• Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis. [europepmc]
• Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. [europepmc]
• Combination of CTLA-4 and PD-1 blockers for treatment of cancer. [europepmc]
• Fundamental Mechanisms of Regulated Cell Death and Implications for Heart Disease. [europepmc]
• Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors. [europepmc]
• Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations. [europepmc]
• Immune Checkpoint Inhibitor Myocarditis: Pathophysiological Characteristics, Diagnosis, and Treatment. [europepmc]
• Adverse cardiac effects of cancer therapies: cardiotoxicity and arrhythmia. [europepmc]
• Immune-related adverse events of checkpoint inhibitors. [europepmc]
• Molecular Pathways of Colon Inflammation Induced by Cancer Immunotherapy. [europepmc]
• Association Between Immune Checkpoint Inhibitors With Cardiovascular Events and Atherosclerotic Plaque. [europepmc]
• Management of Acute Myocarditis and Chronic Inflammatory Cardiomyopathy: An Expert Consensus Document. [europepmc]
• Hallmarks of response, resistance, and toxicity to immune checkpoint blockade. [europepmc]
• Defining cardiovascular toxicities of cancer therapies: an International Cardio-Oncology Society (IC-OS) consensus statement. [europepmc]
• Immune-checkpoint inhibitors: long-term implications of toxicity. [europepmc]
• Regulatory mechanisms of PD-1/PD-L1 in cancers. [europepmc]

Related

• Cardiovascular toxicities associated with immune checkpoint inhibitors
• Histopathologic Characterization of Myocarditis Associated With Immune Checkpoint Inhibitor Therapy
• Immune checkpoint inhibitor–induced myocarditis is dependent on CD8 T cell–derived TNF and TNFR2 signaling
• Durvalumab-Induced Myocarditis and Dilated Cardiomyopathy in a Patient With Non-small Cell Lung Cancer: A Diagnostic Conundrum.
• Acute demyelinating polyneuropathy induced by nivolumab