Original Investigation
Myocarditis in Patients Treated With Immune Checkpoint Inhibitors

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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 (interquartile 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.

Key Words

cardio-oncology
checkpoint inhibitor
ipilimumab
myocarditis
nivolumab
pembrolizumab

Abbreviations and Acronyms

anti-CTLA4
anti-cytotoxic T-lymphocyte-associated protein 4
anti-PD1
anti-programmed cell death protein 1
anti-PDL1
anti-programmed death-ligand 1
AUC
area under the curve
CHB
complete heart block
ECG
electrocardiogram
ICI
immune checkpoint inhibitor
LVEF
left ventricular ejection fraction
MACE
major adverse cardiac events
MRI
magnetic resonance imaging

Cited by (0)

Dr. Mahmood has been supported by the Sarnoff Cardiovascular Research Foundation. Drs. Chen and Gupta are supported by National Institutes of Health (NIH)/National Cancer Institute (NCI) Cancer Center Support grant P30 CA008748. Dr. Thavendiranathan is supported by Canadian Institutes of Health Research New Investigator Award (FRN 147814). Dr. Neilan was supported in part through the Kohlberg Foundation, American Heart Association Fellow to Faculty Award 12FTF12060588, NIH/National Heart, Lung, and Blood Institute grants 1R01HL130539-01A1, 1R01HL137562-01A1, and K24HL113128-06, and NIH/Harvard Center for AIDS Research grant P30 AI060354. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Dr. Mahmood has received consultancy fees from OMR Globus, Alpha Detail, and Opinion Research Team. Dr. Nohria has received research support from Amgen; and has been a consultant for Takeda Oncology. Dr. Heinzerling has received consultancy, advisory board, and speaker fees from MSD, BMS, Roche, Novartis, Amgen, and Curevac. Dr. Sullivan has been a consultant to Merck and Novartis. Dr. Moslehi has served as a consultant/advisor for Novartis, Pfizer, Bristol-Myers Squibb, Takeda/Millennium, Ariad, Acceleron, Vertex, Incyte, Rgenix, Verastem, Pharmacyclics, StemCentRx, Heat Biologics, Daiichi-Sankyo, and Regeneron. Dr. Groarke has received research support from Amgen.

Dr. Neilan has received advisory fees from Takeda. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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