Immune Checkpoint Inhibitors-associated Myocarditis

Anmol Pitliya, M.D.
By Anmol Pitliya, M.D. on

In a recently published study in the Journal of American College of Cardiology, it was suggested that myocarditis following administration of immune checkpoint inhibitors (ICI) for various cancers is underestimated. Myocarditis occurs early in the course of treatment (~ 30 days), with the majority of cases presenting within 3 months of initiation of therapy. ICI-associated myocarditis responded to high doses (1000 mg) of steroids.

Immune checkpoint inhibitors are monoclonal antibodies developed to target certain immune checkpoints including CTLA-4 (ipilimumab), PD-1 (nivolumab and pembrolizumab), and PD-L1 (atezolizumab, avelumab, durvalumab) in order to trigger anticancer immune responses. They are used in the treatment of progressive, advanced and/or metastatic malignancies. Prior to this study, Johnson et al. had presented a case series of two patients that developed myocarditis after treatment with ICI therapy and subsequently died. They were both treated with 1 mg per kg methylprednisolone.  However, to further understand the presentation and clinical course of ICI-associated myocarditis, Mahmood et al. conducted a case-control study in which data was captured from 35 cases and 105 controls. Cases comprised of patients with ICI-associated myocarditis and were chosen by creating a multicenter registry with 8 sites. Controls comprised of ICI-treated patients without myocarditis who were randomly selected from the same sites. The major adverse cardiac events (MACE) endpoint was defined as a composite of cardiovascular death, cardiogenic shock, cardiac arrest, and hemodynamically significant heart block. In the majority of patients, echocardiogram was normal prior to administration of ICI therapy.

“Most patients were treated with steroids, and the dose of steroids administered was important as lower doses of steroids were associated with a higher troponin and an increased rate of major adverse cardiovascular events.”- Dr. Tomas Neilan, M.D.

Approximately 1.1% of patients treated with ICI developed myocarditis. This was found to be significantly higher than previously reported in other studies. The incidence of myocarditis was more common in individuals with cardiovascular risk factors, particularly diabetes. Surveillance was done using serum troponin which was abnormal in 94% of cases. Troponin levels were found to be predictive of cardiac adverse events.

Commenting on these findings, Dr. Tomas Neilan, the director of  cardio-oncology program at Massachusetts General Hospital, stated that “The rate of major adverse cardiovascular outcomes was 46% despite being treated at academic teaching centers. This rate of adverse outcomes was markedly higher than any prior series of patients with myocarditis. The occurrence of major adverse cardiac events was 0.52%.”

The investigators acknowledged that the controls were not tested to exclude myocarditis, leading to underestimation of the occurrence of myocarditis.  Additionally, Mahmood et. al. discussed the possibility of cases with ICI-associated myocarditis presenting to other facilities which might have led to an underestimation of the incidence rate.

Dr. Tomas Neilan stressed  the importance of the dose of steroid use stating that ‘most patients were treated with steroids, and lower doses of steroids were associated with a higher troponin and an increased rate of major adverse cardiovascular events.’

Source: Myocarditis in Patients Treated With Immune Checkpoint Inhibitors, March 19, 2018 DOI: 10.1016/j.jacc.2018.02.037

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