Author + information
- Received December 14, 2017
- Revision received February 8, 2018
- Accepted February 8, 2018
- Published online April 16, 2018.
- Syed S. Mahmood, MD, MPHa,b,
- Michael G. Fradley, MDc,
- Justine V. Cohen, DOd,
- Anju Nohria, MDe,
- Kerry L. Reynolds, MDd,
- Lucie M. Heinzerling, MD, MPHf,
- Ryan J. Sullivan, MDd,
- Rongras Damrongwatanasuk, MDc,
- Carol L. Chen, MDg,
- Dipti Gupta, MD, MPHg,
- Michael C. Kirchberger, MDf,
- Magid Awadalla, MDb,
- Malek Z.O. Hassan, MDb,
- Javid J. Moslehi, MDh,
- Sachin P. Shah, MDi,
- Sarju Ganatra, MDi,
- Paaladinesh Thavendiranathan, MDj,
- Donald P. Lawrence, MDd,
- John D. Groarke, MB BCh, MPHe and
- Tomas G. Neilan, MD, MPHb,k,∗ ()
- aCardiology Division, New York-Presbyterian Hospital, Weill Cornell Medical Center, New York, New York
- bCardiac MR PET CT Program, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts
- cCardio-Oncology Program, H. Lee Moffitt Cancer Center & Research Institute and University of South Florida Division of Cardiovascular Medicine, Tampa, Florida
- dDivision of Oncology and Hematology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
- eCardio-Oncology Program, Division of Cardiology, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
- fDepartment of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nurnberg (FAU), Germany
- gCardiology Division, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York
- hCardio-Oncology Program, Vanderbilt University Medical Center, Nashville, Tennessee
- iCardiology Division, Lahey Hospital & Medical Center, Burlington, Massachusetts
- jTed Rogers Program in Cardiotoxicity Prevention, Peter Munk Cardiac Center, Division of Cardiology Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
- kCardio-Oncology Program, Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
- ↵∗Address for correspondence:
Dr. Tomas G. Neilan, Cardio-Oncology Program and Cardiac MR PET CT Program, Massachusetts General Hospital, 165 Cambridge Street Suite 400, Boston, Massachusetts 02114.
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.
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.
- Received December 14, 2017.
- Revision received February 8, 2018.
- Accepted February 8, 2018.
- 2018 American College of Cardiology Foundation
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