Cardiac Toxicity Associated with Immune Checkpoint Inhibitors: Case Series and Review of the Literature

Agrawal, Nikhil; Khunger, Arjun; Vachhani, Pankit; Colvin, Teresa; Hattoum, Alexander; Spangenthal, Edward; Curtis, Anne B.; Dy, Grace K.; Ernstoff, Marc S.; Puzanov, Igor

doi:10.1159/000498985

Cited by 68 publications

(106 citation statements)

References 52 publications

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“…Other case series on ICI-induced cardiotoxicity suggest that cardiomyopathy, myocarditis, and conduction abnormalities are under-reported. 13 The manufacturer of both ipilimumab and nivolumab reported myocarditis (0.09%) from detailed clinical trial safety data but other cardiovascular irAEs were later described in case reports. [14][15][16][17] Several studies have also characterized cardiac irAEs and their incidence.…”

Section: Discussionmentioning

confidence: 99%

Cardiotoxicity associated with immune checkpoint inhibitors: A retrospective analysis of patients at an academic tertiary care center

Waheed

Fradley

DeRemer

et al. 2020

Preprint

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Background: Immune checkpoint inhibitors (ICIs) are a novel class of anticancer agents that have demonstrated clinical response for both solid and hematological malignancies. ICIs are associated with development of immune-related adverse events including cardiotoxicity. We estimated the incidence of ICI-related cardiotoxicity in patients treated with ICIs at a large, tertiary care center.Methods: All patients with a cancer diagnosis who received any ICI treatment in the University of Florida’s Integrated Data Repository from 2011-2017 were included. Cardiotoxicity was defined as a new ICD diagnosis code for cardiomyopathy, heart failure, arrhythmia, heart block, pericardial disease, or myocarditis after initiation of ICI treatment.Results: Of 102,701 patients with a diagnosis of malignancy, 424 patients received at least one ICI. Sixty-two (14.6%) patients were diagnosed with at least one possible form of cardiotoxicity after initiation of ICI therapy. Of the 374 patients receiving one ICI, 21 (5.6%) developed heart failure. Of the 49 patients who received two ICIs sequentially, three (6.1%) developed heart failure and/or cardiomyopathy. Cardiotoxicity was diagnosed at a median of 63 days after initial ICI exposure. One patient developed myocarditis 28 days after receiving nivolumab. Mortality in those who developed ICI-attributable cardiotoxicity was higher compared to those who did not (66.1% vs. 41.4%, odds ratio=2.77, 1.55-4.95, p=0.0006). There was no evidence that use of cardioprotective agents such as beta-blockers or statins was associated with lower rates of cardiotoxicity or mortality.Conclusions: This study suggests that the incidence of ICI-related cardiotoxicity may be higher than previously reported.

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Section: Discussionmentioning

confidence: 99%

Cardiotoxicity associated with immune checkpoint inhibitors: A retrospective analysis of patients at an academic tertiary care center

Waheed

Fradley

DeRemer

et al. 2020

Preprint

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“…Management of patients with ICI-associated myocarditis has so far been reported to include high-dose glucocorticoids in the majority of patients, with other immunosuppressants such as infliximab or IVIG in used in some steroidrefractory patients, and case reports with the successful use of ATG in patients with fulminant disease (7,13,14,(27)(28)(29)(30). In general, ICI therapy is discontinued in patients diagnosed with ICI-associated myocarditis, as this is categorized as a high-grade irAE (4,31).…”

Section: Presentation and Diagnosis Of Ici-associated Myocarditismentioning

confidence: 99%

“…Furthermore, CMR does not expose patients to ionizing radiation, iodinated contrast, or radioisotope, is not limited by the patient's body habitus, and produces images with high spatial and temporal resolution (33). Most of the cases of ICI-associated myocarditis who underwent CMR had positive diagnostic findings; however, there have been a couple reported cases of CMR without diagnostic findings of myocarditis in this disease state (7)(8)(9)15). A recent review by Ganatra and Neilan on ICI-associated myocarditis outlines an algorithm enlisting CMR as a tool to both establish diagnosis in patients and confirm abnormalities found in troponins, NT-proBNP, ECG, and echocardiogram (12).…”

Section: Role Of Cardiac Mri In Assessment Of Ici-associated Myocarditismentioning

confidence: 99%

“…Patients with ICI-associated myocarditis have been found to have a reduction in their LVEF, isolated RV dysfunction, or biventricular dysfunction, with a varying degree of abnormalities in regional wall abnormalities in some of these patients (7,8,10,23). The role of echocardiography in structural and functional assessment of LV and RV function in patients with myocarditis has been well established (37,38).…”

Section: Structural and Functional Analysismentioning

confidence: 99%

“…These irAEs include significant cardiotoxicity, although the true incidence of cardiovascular complications is unknown. The most commonly reported cardiac irAEs are myocarditis, followed by heart failure with systolic dysfunction, pericarditis, and arrhythmias (3,(5)(6)(7)(8)(9). Myocarditis is more common in patients receiving a combination of ICIs compared to a single agent (10).…”

Section: Introductionmentioning

confidence: 99%

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Clinical and Advanced MRI Techniques for Detection of Checkpoint Inhibitor Associated Myocarditis

Arbune

Soufer

Baldassarre

2020

Curr Cardiovasc Imaging Rep

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Purpose of Review With the advent of immune checkpoint inhibitors (ICIs), cancer treatment has been revolutionized; however, these agents are associated with immune-related adverse events, including myocarditis, which ranges from mild to fulminant in severity. Currently, there are no established guidelines in diagnosing ICI-associated myocarditis, and the gold standard test for diagnosis of myocarditis in general is invasive endomyocardial biopsy (EMB). Cardiac magnetic resonance (CMR) imaging is a noninvasive test with the advantage of providing structural, functional and tissue characterization information. Additionally, it provides high spatial and temporal resolution without exposure to ionizing radiation, iodinated contrast, or radioactive isotopes. Recent Findings With an increasing number of reported cases of ICI associated myocarditis, understanding of the disease process and associated CMR findings is growing. Diagnostic testing with cardiac biomarkers, electrocardiogram, and echocardiogram can be nonspecific and EMB can have sampling errors. CMR as a diagnostic tool can provide functional assessment of biventricular ejection fraction, myocardial strain, tissue characterization of myocardial edema and inflammation as well as fibrosis. Furthermore, with advanced parametric mapping techniques, CMR provides even more sensitive and quantitative information about myocardial inflammation and fibrosis, including measurements of extracellular volume. Summary ICI-associated myocarditis is a serious immune adverse event, and CMR plays a vital role in establishing its diagnosis, providing prognostic information, and has the potential for use as a tool for screening and serial monitoring in patients exposed to ICIs.

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Immune Checkpoint Inhibitor–Induced Cardiotoxicity

Nielsen,

Juhl,

Nielsen

et al. 2024

JAMA Oncol

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ImportanceImmune checkpoint inhibitors (ICIs) improve outcomes in a wide range of cancers; however, serious adverse effects, including cardiovascular adverse effects (CVAEs), can occur.ObjectiveTo determine the incidence of CVAEs and analyze data on the management of myocarditis in patients exposed to ICIs.Data SourcesPubMed, Embase, and Cochrane Central Register of Controlled Trials from inception were searched on April 4, 2023.Study SelectionTwo separate studies were performed. Key inclusion criteria for study 1 were phases 1 to 4 trials involving adults with malignant neoplasms treated with an ICI and toxicity data; for study 2, publications (case reports and retrospective analyses) on clinical manifestations and treatment of patients with ICI-induced CVAEs. Studies with dose escalation or fewer than 11 patients in each group and all case reports, retrospective analyses, letters, reviews, and editorials were excluded from study 1. Studies not published in English were excluded from study 2.Data Extraction and SynthesisThe PRISMA guidelines and Cochrane Handbook for Systematic Reviews were followed. Data were extracted independently by 2 researchers. A meta-analysis of the incidence of CVAEs in clinical trials and a systematic review of the evidence for the management of myocarditis were performed. Data were pooled using a random-effects model.Main Outcomes and MeasuresIn study 1, the primary outcome was incidence CVAEs in clinical trials with ICIs and ICI combination therapies. Study 2 examined evidence supporting specific management strategies that may decrease the mortality rate of myocarditis. The primary outcomes were planned before data collection began.ResultsIn study 1, a total of 83 315 unique participants in 589 unique trials were included in the meta-analysis. Incidence of CVAEs induced by anti–programmed cell death 1 and/or programmed cell death ligand 1 was 0.80% (95% CI, 0%-1.66%) in clinical trials, with no differences between the compounds, except for cemiplimab, which was associated with a higher risk of CVAEs. Incidence of CVAEs following ipilimumab treatment was 1.07% (95% CI, 0%-2.58%). The incidence of myocarditis was significantly higher following treatment with dual ICIs. However, CVAE incidence was not higher with dual ICIs, ICI combination with chemotherapy, or tyrosine kinase inhibitors. Evidence from randomized clinical trials on recommended monitoring and treatment strategies for ICI-induced myocarditis was lacking. Study 2 showed that myocarditis-associated mortality occurred in 83 of 220 patients (37.7%). Prospective data from 40 patients with myocarditis indicated that systematic screening for respiratory muscle involvement, coupled with active ventilation, prompt use of abatacept, and the addition of ruxolitinib, may decrease the mortality rate.Conclusions and RelevanceImmune checkpoint inhibitor–induced CVAEs and/or myocarditis were recorded in 1.07% of patients in clinical trials. The CVAE mortality risk remains high, justifying the need for monitoring and management strategies for which evidence from randomized clinical trials is absent. Early recognition, ICI therapy cessation, prompt initiation of corticosteroid therapy, and escalation of therapy are all crucial elements for achieving optimal outcomes. Prospective clinical trials or at least prospective registration of treatments and outcomes are highly warranted.

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Cardiac Toxicity Associated with Immune Checkpoint Inhibitors: Case Series and Review of the Literature

Cited by 68 publications

References 52 publications

Cardiotoxicity associated with immune checkpoint inhibitors: A retrospective analysis of patients at an academic tertiary care center

Cardiotoxicity associated with immune checkpoint inhibitors: A retrospective analysis of patients at an academic tertiary care center

Clinical and Advanced MRI Techniques for Detection of Checkpoint Inhibitor Associated Myocarditis

Immune Checkpoint Inhibitor–Induced Cardiotoxicity

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