Cardiac Complications Associated With Checkpoint Inhibition: A Systematic Review of the Literature in an Important Emerging Area

Mir, Hassan R.; Alhussein, Muhammad Mustafa; Alrashidi, Sulaiman; Alzayer, Hussain; Alshatti, Ahmad; Valettas, Nicholas; Mukherjee, Som D.; Nair, Vidhya; Leong, Darryl P.

doi:10.1016/j.cjca.2018.03.012

Cited by 104 publications

(78 citation statements)

References 78 publications

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“…A troponin T level ≥1.5 ng/mL was associated with a fourfold increase in major adverse cardiac events during follow-up (hazard ratio 4.0; 95% confidence interval 1.5 to 10.9) 87. Case fatality rates are high in patients with ICI myocarditis, so early and aggressive treatment with immunosuppressive therapy (including very high dose corticosteroids) is critical 878889…”

Section: Clinical Presentation Of Checkpoint Inhibitor Associated Autmentioning

confidence: 99%

Autoimmune complications of immunotherapy: pathophysiology and management

Chan

Bass

2020

BMJ

100

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Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that target inhibitory molecules, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), or its ligand, programmed cell death protein ligand 1 (PD-L1), and lead to immune activation in the tumor micro-environment. ICIs can induce durable treatment responses in patients with advanced cancers, but they are commonly associated with immune related adverse events (irAEs) such as rash, colitis, hepatitis, pneumonitis, and endocrine and musculoskeletal disorders. Almost all patients experience some form of irAE, but high grade irAEs occur in approximately half of those on combination therapy (eg, anti-CTLA-4 plus anti-PD-1), and up to one quarter receiving ICI monotherapy. Fatal irAEs occur in approximately 1.2% of patients on CTLA-4 blockade and 0.4% of patients receiving PD-1 or PD-L1 blockade, and case fatality rates are highest for myocarditis and myositis. IrAEs typically occur in the first three months after ICI initiation, but can occur as early as one day after the first dose to years after ICI initiation. The mainstay of treatment is with corticosteroids, but tumor necrosis factor inhibitors are commonly used for refractory irAEs. Although ICIs are generally discontinued when high grade irAEs occur, ICI discontinuation alone is rarely adequate to resolve irAEs. Consensus guidelines have been published to help guide management, but will likely be modified as our understanding of irAEs grows.

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Section: Clinical Presentation Of Checkpoint Inhibitor Associated Autmentioning

confidence: 99%

Autoimmune complications of immunotherapy: pathophysiology and management

Chan

Bass

2020

BMJ

100

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“…The growing clinical use of ICIs in an increasing number of patients with different cancers was accompanied by publication of individual case reports and case series of patients suffering from severe cardiac side effects (12,(17)(18)(19)(20)(21). While the initial clinical trials with CTLA4 or PD-1/PD-L1 inhibitors did not indicate cardiac complications, a recent meta-analysis listed 99 cases of cardiac side effects in patients having received ICI (21). Myocarditis was the most frequent presentation (45 out of 99 cases of cardiac toxicity).…”

Section: Cardiac Side Effects Of Icismentioning

confidence: 99%

“…A total of 27% of the cardiac events were heart failure or cardiomyopathy without signs of myocarditis. Pericardial diseases were reported in 15% of patients with cardiac side effects, conduction diseases in 12% (21). Overall, indications for therapy with ICI was predominantly melanoma (41%), non-small cell lung cancer (26%), and multiple myeloma (9%) (21).…”

Section: Cardiac Side Effects Of Icismentioning

confidence: 99%

Cardio-toxicity of checkpoint inhibitors

Müller¹,

Spehlmann²,

Frey³

2018

J. Thorac. Dis

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Immune checkpoint inhibitors (ICIs): new challenges for cardio-oncology The increasing awareness of cardiac side effects of classical oncological therapies has resulted in multiple improvements in cardiac surveillance of cancer patients (1,2). Although classical chemotherapeutic drugs still result in considerable side effects (2), recent studies have shown that cardiovascular mortality is not increased in breast cancer patients any more (3,4). This most probably reflects an increased consideration of cardiac protection when applying chemotherapies, an improved understanding of mechanisms of cardiac damage, and early involvement of cardiologists in following up patients at risk. Similar to the advances in breast cancer therapy more than two decades ago, a novel class of anticancer drugs has started revolutionizing the treatment of numerous cancers by restoring immune resistance against cancer cells. These so-called ICIs comprise monoclonal antibodies against immune checkpoint molecules. The first substance, ipilimumab, a monoclonal antibody against cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), was introduced for melanoma treatment in 2010 and strikingly improved prognosis of this otherwise fatal disease by doubling the likelihood of long-term survival (5,6). Further antibodies were developed against programmed cell death 1 (PD-1) (nivolumab, pembrolizumab) and its ligand PD-L1 (atezolizumab, durvalumab, avelumab) and successfully applied in multiple solid tumors and hematological malignancies in the last years (7). However, these substances do not only restore antitumor immunity, but may also result in immune-related adverse events (IRAEs) (8,9). These IRAEs were found to be frequent, but responded in most cases well to high doses of steroids (10). Cardiotoxicity was overall low in clinical trials (11). A large safety database from the manufacturer of ipilimumab and nivolumab,

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“…2 Fulminant myocarditis is currently the most recognized irAE, but complete heart block, conduction abnormalities, pericarditis, stress-induced cardiomyopathy, and left ventricular dysfunction have also been reported. [3][4][5] Limited data are available on the incidence of cardiotoxicity after ICI initiation, and there is scarce evidence to guide prevention, surveillance, and treatment. [6][7][8] The reported incidence of ICI-induced myocarditis ranges from 0.06% to 1.14% of patients receiving ICIs.…”

Section: Introductionmentioning

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 newly diagnosed cardiovascular disease 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. Cardiovascular disease 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 new cardiovascular disease 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. Incident cardiovascular disease was diagnosed at a median of 63 days after initial ICI exposure. One patient developed myocarditis 28 days after receiving nivolumab. Mortality in ICI treated patients with a concomitant diagnosis of incident cardiovascular disease was higher compared to those who did not (66.1% vs. 41.4%, odds ratio = 2.77, 1.55-4.95, p = 0.0006). Conclusions This study suggests a high incidence of newly diagnosed cardiovascular disease after the initiation of ICI therapy.

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Cardiac Complications Associated With Checkpoint Inhibition: A Systematic Review of the Literature in an Important Emerging Area

Cited by 104 publications

References 78 publications

Autoimmune complications of immunotherapy: pathophysiology and management

Autoimmune complications of immunotherapy: pathophysiology and management

Cardio-toxicity of checkpoint inhibitors

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

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