Discrepancies of cardio-muscular biomarkers in the diagnosis and prognostication of immune checkpoint inhibitor (ICI)-associated myocarditis

Abstract Background: Immune-checkpoint inhibitors (ICI) are approved for multiple cancers but can result in ICI-associated myocarditis, an infrequent but life-threatening condition. Elevations in cardiac biomarkers, troponin-I (cTnI), troponin-T (cTnT) and creatine-kinase (CK) are used for diagnosis. However, the temporal elevation of these biomarker elevations with course of disease and their association with outcomes have not been established. Methods: We analyzed the diagnostic accuracy and prognostic performances of cTnI, cTnT and CK in ICI-myocarditis (n=61) in two cardio-oncology units (APHP.Sorbonne, France & Heidelberg, Germany). Major adverse cardio-myotoxic events (MACE) were defined as heart failure, ventricular arrhythmia, atrioventricular/sinus block requiring pacemaker, respiratory muscle failure requiring mechanical ventilation, and related death. Diagnostic performances of troponins were also assessed in an international ICI-myocarditis registry (n=244 independent cases, 13 countries). Results: On presentation, cTnT, cTnI or CK were increased compared to upper reference limit (URL) in 51/52 (98%), 28/34 (82%, p=0.009 vs. cTnT), 33/48 (69%, p<0.0001 vs. cTnT), respectively. This higher rate of positivity for cTnT vs. cTnI was independently confirmed in an international registry. In patients surviving to 30 days, cTnI and CK had normalized in 20/34(59%) and 30/35(86%), respectively, while cTnT had reached normal values in only 5/42(12%), (p<0.0001). The highest value of cTnT/URL within the first 72h of admission performed best in predicting MACE (AUC:0.82) vs. CK/URL (AUC:0.74) and cTnI/URL (AUC:0.67), even after adjustment for age and sex. Maximal value of cTnT/URL≥32 within ≤72h of diagnosis was the best predictor cut-off for MACE (Hazard-ratio=9.4(95% CI 3.1, 28.3), p<0.0001) over a median follow-up of 4 months. cTnT was increased in all patients just before MACE (22/22, 100%) while cTnI and CK values were normal in 3/21(14%) and 6/24(25%) of patients (p<0.0001). Conclusions. Significant discrepancies between cTnT (compared to cTnI, and CK) circulating levels exist in ICI-myocarditis. cTnT is the best predictor of MACE and most suitable for diagnosis and surveillance. A ratio of cTnT/URL<32 within ≤72h of diagnosis identifies a subgroup at low-risk of MACE.