Immune Checkpoint Inhibitor-Associated Myocarditis

Abstract

Immune checkpoint inhibitors (ICIs) are approved for a wide range of malignancies. They work by priming the immune system response to cancer and have changed the landscape of available cancer treatments. As anticipated, modulation of the regulatory controls in the immune system with ICIs results in diverse immune-related adverse events, targeting any organ or gland. These toxicities are rarely fatal and generally regress after treatment discontinuation and/or prescription of corticosteroids. Recently, several cases of ICI-related cardiotoxicity have been reported with complications ranging from cardiogenic shock to sudden death. The true incidence of ICI-associated myocarditis is likely underestimated, due to a combination of factors including the lack of specificity in the clinical presentation, the potential of overlap with other cardiovascular and general medical illnesses, the challenges in the diagnosis, and a general lack of awareness of this condition. Currently, there are no clear guidelines for surveillance, diagnosis, or management of this entity. There are multiple unresolved issues including, but not limited to, identifying those at risk of this uncommon toxicity, elucidating the pathophysiology, determining if and what type of surveillance is appropriate, optimal work-up of suspected patients, and methods for resolution of myocarditis. Here we describe a clinical vignette and discuss the salient features and management strategies of ICI-associated myocarditis. The Oncologist 2018;23:518-523 KEY POINTS• The incidence of immune checkpoint inhibitor (ICI)-associated myocarditis is unclear and has been reported to range from 0.06% to 1% of patients prescribed an ICI.• Myocarditis may be difficult to diagnose.• The risk factors for ICI-associated myocarditis are not well understood but may include underlying autoimmune disease and diabetes mellitus. • The prevalence of myocarditis has been reported to be higher with combination immune therapies.• Myocarditis with ICI's typically occurs early, with an elevated troponin, may present with an normal left ventricular ejection fraction and may have a fulminant course.• The optimal management of myocarditis associated with ICI's is unclear but most cases are treated with high-dose steroids. PATIENT STORYA 41-year-old woman with no cardiac risk factors but a prior history of Hashimoto's thyroiditis was diagnosed with metastatic melanoma. She presented with mild dyspnea 6 days after completing four cycles of combined immune checkpoint inhibitor (ICI) therapy with ipilimumab and nivolumab. On exam, she was tachycardic and mildly volume overloaded but was otherwise stable. Sinus tachycardia was noted on electrocardiogram (ECG); there were no conduction abnormalities (Fig. 1A). Cardiac troponin I (cTn) was mildly elevated with normal level of N-terminal-pro brain natriuretic peptide (NT-proBNP). A chest computed tomography (CT) scan did not show evidence of pneumonitis but did show cardiomegaly and pulmonary congestion. An echocardiogram revealed global left...

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Among 101 severe cases of immune checkpoint inhibitor‐associated myocarditis, the median time to onset was 27 days (range, 5–155), with 64% of cases occurring after just one or two doses. Death occurred in 46 of the 101 cases, and fatality rates were highest with combination therapy.

Patients presenting with myocarditis often have an abnormal ECG and elevated levels of the cardiac biomarker troponin I . Monge et al suggest an ECG, two‐dimensional‐echocardiogram, and assessment of troponin I levels prior to treatment initiation, then assessment of troponin I levels at 2, 4, and 12 weeks post‐treatment, and then monthly .…”

“…Monge et al suggest an ECG, two‐dimensional‐echocardiogram, and assessment of troponin I levels prior to treatment initiation, then assessment of troponin I levels at 2, 4, and 12 weeks post‐treatment, and then monthly . Patients with an elevated troponin I level should be further evaluated (e.g., with cardiac magnetic resonance imaging [CMRI] or myocardial biopsy) for possible myocarditis . Immune checkpoint inhibitor therapy should be immediately discontinued if myocarditis is suspected, and treatment with high‐dose steroids may minimize myocardial injury .…”

“…Patients with an elevated troponin I level should be further evaluated (e.g., with cardiac magnetic resonance imaging [CMRI] or myocardial biopsy) for possible myocarditis . Immune checkpoint inhibitor therapy should be immediately discontinued if myocarditis is suspected, and treatment with high‐dose steroids may minimize myocardial injury .…”

A review of cancer immunotherapy toxicity

“…Therefore, guidelines recommend initial methylprednisolone pulse dosing (1 g/day for 3‐5 days) . In unstable patients and patients who do not respond to corticosteroids, additional immunosuppression should be considered, although the optimal agent is not known . Infliximab, antithymocyte globulin, intravenous immunoglobulin, mycophenolate mofetil, and tacrolimus can be used .…”

Reply

“…In addition, based on our findings (1) of a beneficial effect on myocarditis outcomes with a higher dose and the pathological findings in which features were similar to cardiac transplant rejection, we have adopted an initial treatment strategy of 1,000 mg of Solu-Medrol (~15 mg/kg) with a rapid taper based on clinical and biomarker response (4). Further research is needed to test whether this high dose of steroids affects tumor efficacy or improves myocarditis outcomes (5) and, additionally, consider the risk of opportunistic infections among patients on prolonged, especially high-dose, immune suppression.…”