In the 9 years since ipilimumab was approved as the first immune checkpoint inhibitor, these medications have revolutionized cancer treatment. As of 2020, immune checkpoint inhibitors are approved as first- or second-line therapy for at least 50 cancers and are being evaluated in more than 3,000 active clinical trials.¹ Immune checkpoint inhibitors are monoclonal antibodies that inhibit the receptors mediating immune tolerance on T-cells (CTLA-4 and PD-1) or on tumor cells (PD-L1). By releasing the brakes that keep the immune system quiescent, they lead to cell-mediated cytotoxicity. A predictable consequence of lost immune tolerance is that host tissues can become unintended targets of these T-cells. Rash, colitis, myositis, arthritis, and pneumonitis are commonly found autoimmune toxicities; however, the heart, liver, nervous system, and kidneys can also be affected and are generally more severe reactions.²

In addition to the rare and often fulminant cardiotoxicity of myocarditis, emerging data suggest that pericardium and cardiac vasculature are also targeted.³ However, myocarditis has the highest mortality (up to 50%), which underscores the importance of its diagnosis and treatment.3 Myocarditis is estimated to occur in 1.1% of individuals receiving either single or combination immune checkpoint inhibitor therapy with a median time to onset of 30 days.⁴ Risk factors for immune checkpoint inhibitor-associated myocarditis are not well defined. Combination immune checkpoint inhibitor therapy (anti-CTLA-4 in conjunction with anti-PD-1 therapy) appears to portend a 4.7-fold increased risk of developing myocarditis compared to single therapy.⁵ Theoretical risk factors such as previous myocardial injury, pre-existing autoimmune diseases, and genetic predisposition await further studies to be proven.

Immune checkpoint inhibitor-associated myocarditis can present with arrhythmias, HF, or ACS symptoms. Clinical suspicion is of paramount importance in the diagnosis, which is reached by exclusion of the more common clinical entities such as myocardial infarction. Serum markers of cardiomyocyte injury (troponin, creatine kinase-myocardial band) are almost always elevated, and brain natriuretic peptide might be elevated in more than half of the cases (though it is chronically elevated in patients with cancer).^4,6 Similarly, troponin T could be elevated due to immune checkpoint inhibitor-associated skeletal muscle inflammation, giving it less positive predictive value compared to troponin I.⁶ Abnormal electrocardiographic findings are common and may range from isolated atrial or ventricular extrasystole, non-specific ST-T changes to sustained life-threatening ventricular tachycardia or complete heart block.⁷ Regional wall motion abnormalities or decreased systolic function can be seen on echocardiogram; however, strikingly, half of the patients retain normal echocardiographic left ventricular systolic function.⁴ Cardiac magnetic resonance imaging is superior to echocardiography, allowing tissue characterization in the presence of myocardial edema, inflammation, and fibrosis. Where cardiac magnetic resonance imaging is not feasible or safe, cardiac fluorodeoxyglucose positron emission tomography might be useful for assessing inflammation.⁴ Still, tissue diagnosis from an endomyocardial biopsy sample showing myocardial lymphocyte and macrophage infiltration remains the gold standard for diagnosis; however, its sensitivity might decrease with patchy inflammation or sampling error. Despite these drawbacks, because the diagnosis of immune checkpoint inhibitor-associated myocarditis could lead to discontinuation of immune checkpoint inhibitor therapy, tissue diagnosis should be pursued whenever feasible.⁶

More recently, there has been increased awareness of the risk of atherosclerosis progression in patients receiving immune checkpoint inhibitor therapy. Preclinical studies had previously shown that immune checkpoint proteins were negative regulators of atherosclerosis progression.⁸ Recently, Neilan and colleagues looked to see if this finding translated into patients receiving immune checkpoint inhibitor. In a case-crossover study of 2,842 patients treated with an immune checkpoint inhibitor, they found that the myocardial infarction rate during the 2-year period after starting an immune checkpoint inhibitor was increased 4.8-fold compared to the 2-year period before starting an immune checkpoint inhibitor. Supporting this clinical finding, in an imaging sub-study cohort of 40 patients, they found that the rate of total plaque volume progression by computed tomography increased threefold per year after start of immune checkpoint inhibitor therapy compared to the rate of increase before immune checkpoint inhibitor therapy.⁸ The rate of increase was lower in statin users compared to those not using statin, which underscores the importance of strict cardiovascular risk modification including statin use in these patients.

Treatment of immune checkpoint inhibitor-associated myocarditis requires a team approach with involvement of at least a cardiologist and an oncologist. Although there is no established prognostic risk stratification, higher cardiac biomarkers, early arrhythmogenicity, and hemodynamic instability portend high mortality risk.⁶ Such patients should be watched with close hemodynamic and telemetry monitoring in cardiac intensive care units. Unfortunately, treatment approaches at this time are based on anecdotal evidence and expert opinion and are extrapolated from treatment of non-cardiac immune-related adverse events as well as treatment of cardiac transplant rejection. American Society of Clinical Oncology Clinical Practice Guidelines recommend holding immune checkpoint inhibitor therapy starting with Grade 1 cardiotoxicity (asymptomatic biomarker elevation or imaging abnormality) and permanently discontinuing for Grade 2 or higher.⁹ They also recommend that all-grade toxicities should have early administration of high-dose corticosteroids (1-2 mg/kg of prednisone oral or intravenous depending on symptoms). In patients with no immediate response to this regimen, 1 g daily intravenous methylprednisolone with addition of mycophenolate, infliximab, or anti-thymocyte globulin is recommended.⁹ Some cardiologists, on the other hand, recommend an aggressive initial steroid strategy similar to that used in transplant rejection (intravenous methylprednisolone 500-1000 mg daily until clinical stability, followed by oral prednisolone at 1 mg/kg daily tapered over 4-6 weeks).^6,10 In steroid refractory cases as assessed by clinical course, abnormal biomarkers, and electrocardiography, alemtuzumab, infliximab, tocilizumab, or rituximab can be considered.¹¹ It should be noted that infliximab might potentially worsen HF and is contraindicated in patients with decompensated HF. Which patients, if any, can be re-challenged with an immune checkpoint inhibitor is currently unknown.

In conclusion, immune checkpoint inhibitor-associated myocarditis is a severe complication of CTLA-4, PD-1, and PD-L1 antibodies used in treatment of multiple cancer types. Its diagnosis relies on clinical suspicion and exclusion of acute manifestations of common chronic cardiac conditions. Most importantly, there needs to be increased suspicion of ACS in the differential diagnosis because this risk is also significantly increased in patients on immune checkpoint inhibitor therapy compared to risk-matched controls. Although acute atherosclerotic vascular events are treated according to current ACS guidelines, there is no standardized approach for management of immune checkpoint inhibitor myocarditis currently. As the number of cancers treated with immune checkpoint inhibitors expand, the number of cases of myocarditis is expected to increase. Further studies are needed to risk stratify patients in order to safely continue this revolutionary class of cancer therapeutics.

References

1. Robert C. A decade of immune-checkpoint inhibitors in cancer therapy. Nat Commun 2020;11:3801.
2. Postow MA, Sidlow R, Hellmann MD. Immune-Related Adverse Events Associated with Immune Checkpoint Blockade. N Engl J Med 2018;378:158-68.
3. Salem JE, Manouchehri A, Moey M, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol 2018;19:1579-89.
4. Mahmood SS, Fradley MG, Cohen JV, et al. Myocarditis in Patients Treated With Immune Checkpoint Inhibitors. J Am Coll Cardiol 2018;71:1755-64.
5. Johnson DB, Balko JM, Compton ML, et al. Fulminant Myocarditis with Combination Immune Checkpoint Blockade. N Engl J Med 2016;375:1749-55.
6. Hu JR, Florido R, Lipson EJ, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors. Cardiovasc Res 2019;115:854-68.
7. Pradhan R, Nautiyal A, Singh S. Diagnosis of immune checkpoint inhibitor-associated myocarditis: A systematic review. Int J Cardiol 2019;296:113-21.
8. Drobni ZD, Alvi RM, Taron J, et al. Association Between Immune Checkpoint Inhibitors with Cardiovascular Events and Atherosclerotic Plaque. Circulation 2020;Oct 2:[Epub ahead of print].
9. Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2018;36:1714-68.
10. Michel L, Rassaf T, Totzeck M. Cardiotoxicity from immune checkpoint inhibitors. Int J Cardiol Heart Vasc 2019;25:100420.
11. Geraud A, Gougis P, Vozy A, et al. Clinical Pharmacology and Interplay of Immune Checkpoint Agents: A Yin-Yang Balance. Annu Rev Pharmacol Toxicol 2020;Sep 1:[Epub ahead of print].

Clinical Topics: Cardio-Oncology, Dyslipidemia, Heart Failure and Cardiomyopathies, Nonstatins, Novel Agents, Statins, Heart Failure and Cardiac Biomarkers

Keywords: Cardio-oncology, Cardiotoxicity, Troponin T, Troponin I, Antilymphocyte Serum, Creatine Kinase, MB Form, CTLA-4 Antigen, Prednisone, Natriuretic Peptide, Brain, Myocarditis, Hydroxymethylglutaryl-CoA Reductase Inhibitors

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