Syed S Mahmood1, Michael G Fradley2, Justine V Cohen3, Anju Nohria4, Kerry L Reynolds3, Lucie M Heinzerling5, Ryan J Sullivan3, Rongras Damrongwatanasuk2, Carol L Chen6, Dipti Gupta6, Michael C Kirchberger5, Magid Awadalla7, Malek Z O Hassan7, Javid J Moslehi8, Sachin P Shah9, Sarju Ganatra9, Paaladinesh Thavendiranathan10, Donald P Lawrence3, John D Groarke4, Tomas G Neilan11. 1. Cardiology Division, New York-Presbyterian Hospital, Weill Cornell Medical Center, New York, New York; Cardiac MR PET CT Program, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts. 2. Cardio-Oncology Program, H. Lee Moffitt Cancer Center & Research Institute and University of South Florida Division of Cardiovascular Medicine, Tampa, Florida. 3. Division of Oncology and Hematology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. 4. Cardio-Oncology Program, Division of Cardiology, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. 5. Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nurnberg (FAU), Germany. 6. Cardiology Division, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York. 7. Cardiac MR PET CT Program, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts. 8. Cardio-Oncology Program, Vanderbilt University Medical Center, Nashville, Tennessee. 9. Cardiology Division, Lahey Hospital & Medical Center, Burlington, Massachusetts. 10. Ted Rogers Program in Cardiotoxicity Prevention, Peter Munk Cardiac Center, Division of Cardiology Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada. 11. Cardiac MR PET CT Program, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts; Cardio-Oncology Program, Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. Electronic address: tneilan@mgh.harvard.edu.
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.
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.
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