Myocarditis in Patients Treated With Immune Checkpoint Inhibitors

Abstract

BACKGROUND Myocarditis is an uncommon, but potentially fatal, toxicity of immune checkpoint inhibitors (ICI). Myocarditis after ICI has not been well characterized. OBJECTIVES The authors sought to understand the presentation and clinical course of ICI-associated myocarditis. METHODS After observation of sporadic ICI-associated myocarditis cases, the authors created a multicenter registry with 8 sites. From November 2013 to July 2017, there were 35 patients with ICI-associated myocarditis, who were compared to a random sample of 105 ICI-treated patients without myocarditis. Covariates of interest were extracted from medical records including the occurrence of major adverse cardiac events (MACE), defined as the composite of cardiovascular death, cardiogenic shock, cardiac arrest, and hemodynamically significant complete heart block. RESULTS The prevalence of myocarditis was 1.14% with a median time of onset of 34 days after starting ICI (inter-quartile range: 21 to 75 days). Cases were 65 ± 13 years of age, 29% were female, and 54% had no other immune-related side effects. Relative to controls, combination ICI (34% vs. 2%; p < 0.001) and diabetes (34% vs. 13%; p = 0.01) were more common in cases. Over 102 days (interquartile range: 62 to 214 days) of median follow-up, 16 (46%) developed MACE; 38% of MACE occurred with normal ejection fraction. There was a 4-fold increased risk of MACE with troponin T of ≥1.5 ng/ml (hazard ratio: 4.0; 95% confidence interval: 1.5 to 10.9; p = 0.003). Steroids were administered in 89%, and lower steroids doses were associated with higher residual troponin and higher MACE rates. CONCLUSIONS Myocarditis after ICI therapy may be more common than appreciated, occurs early after starting treatment, has a malignant course, and responds to higher steroid doses.

Autoimmune hemolytic anemia associated with the use of immune checkpoint inhibitors for cancer: 68 cases from the Food and Drug Administration database and review

“…In a multicenter registry, a prevalence of 1.14% was reported. 26 In a corporate pharmacovigilance database, an incidence of only 0.06% of myocarditis following nivolumab and of 0.27% for the combination of nivolumab and ipilimumab was reported. 27 When adverse immune renal side effects of immune CPI were reviewed, the incidence varied depending on criteria and severity between 2.2% in earlier studies and 9.9% and 29% in later studies.…”

Reply

“…An additional question is whether the dose of immunosuppression used may affect the antitumor response of immune checkpoint inhibitors. In our study (1), we found that higher doses of steroids for the treatment of myocarditis was associated with a lower rate of adverse cardiac events. Specifically, we found that those treated with a methylprednisolone-equivalent dose of 2.06 mg/kg had a lower rate of major adverse cardiac events than those treated with 0.8 mg/kg.…”

“…We thank Dr. Cao for his comments on our paper (1) and for asking a critical question: Does the use of systemic immunosuppression reduce the antitumor efficacy of immune checkpoint inhibitors? There are no data on whether immunosuppression for myocarditis from immune checkpoint inhibitors reduces the antitumor efficacy of these agents, but there are significant data when all immune-related adverse events (irAEs) are combined.…”

“…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.…”

MRI in cardio‐oncology: A review of cardiac complications in oncologic care

“…Unfortunately, inflammatory reactions known as immunerelated adverse events (irAEs) including myocarditis have emerged as potentially life-threatening side effects to these promising therapies. [80][81][82][83] With increasing popularity in the use of ICIs for a myriad of cancers, cases of immune checkpoint inhibitor associated myocarditis are accumulating. [81][82][83] Correspondingly, a growing number of reports have demonstrated the role of MRI as the primary noninvasive modality to evaluate myocarditis in the cancer population.…”