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.

Plasma exchange plus glucocorticoids in the treatment of immune checkpoint inhibitor‐induced myocarditis: A case series and review

“…Owing to the lack of specific signs and symptoms at onset, early detection is prone to underand/or misdiagnosis. 8,9 In this study, we successfully cured four patients using plasma exchange plus systemic glucocorticoids. reducing their ability to maintain tumor cell dormancy.…”

Cardiac Troponins for Diagnosis and Prognostic Assessment of Immune Checkpoint Inhibitor Myocarditis and Myositis: The Emerging Importance of Peripheral Vision

“…The recent publication “Cardio-muscular biomarkers in the diagnosis and prognostication of immune checkpoint inhibitor myocarditis” in Circulation by Lehmann et al 4 leverages recognized differences between the biology of cTnI and cTnT isoforms to provide novel insights into diagnosis and risk assessment of this important complication. This study identifies one of the first clinical use cases capitalizing on recent recognition that cTnT, but not cTnI, is reexpressed in skeletal muscle in patients with active myositis.…”

“…In this study, cTnT emerged as a powerful risk stratification tool for major adverse cardiomyotoxic events (MACE; inclusive of respiratory failure, heart failure, ventricular arrythmias, pacemaker implantation, and sudden cardiac death). 4 In a cohort of 60 patients with clinically diagnosed ICI myocarditis, cTnT measured with a high-sensitivity (hs) assay was superior to hs-cTnI or creatinine kinase for assessing risk for MACE. Elevation ≥32 times the 99th percentile (upper reference limit) for cTnT was the optimal threshold for identifying an increased risk of MACE with an adjusted hazard ratio of 11.1 (95% CI, 3.2–38.0) and associated sensitivity of 86% and specificity of 74%, with 50% of patients with MACE developing respiratory failure.…”

“…The report by Lehmann et al 4 points to hs-cTnT as an excellent diagnostic test on the basis of its overall sensitivity for skeletal muscle myocyte injury that provides pathophysiologic insight beyond myocarditis into the severity of myositis that may be a major contributor to MACE in the form of respiratory failure. The potential advantage of incomplete cardiomyocyte specificity compared with the hs-cTnI assays in the assessment of ICI myocarditis is recognized by assigning hs-cTnT a prominent role in prognostication and assessment of both cardiac and skeletal muscle injury in the absence of an acute coronary syndrome.…”

“…As the ICI indications continue to grow, practicing cardiovascular physicians are likely to encounter patients at risk for immune-related adverse events and ICI myocarditis. Although the role of measuring both cTnT and cTnI for prognosis of suspected ICI myocarditis, together with the proposed cutoff values, will need additional validation, the results by Lehmann et al 4 shine a spotlight on the importance of understanding the full spectrum of immune-related adverse events, including ICI myocarditis, in patients receiving ICIs (Figure). Further studies are needed to determine whether assessment of hs-cTnT and hs-cTnI may help to identify patients presenting with less severe myocarditis and predominant myocyte injury (myasthenia gravis–like syndrome or myositis), and how the results may affect the decisions about the choice of immunosuppressive agents, duration of treatment, and even consideration of rechallenge with ICI after recovery.…”