Predictors and Risk Score for Immune Checkpoint-Inhibitor-Associated Myocarditis Severity

Abstract

Background: Immune-checkpoint inhibitors (ICI) are associated with life-threatening myocarditis but milder presentations are increasingly recognized. The same autoimmune process that causes ICI-myocarditis can manifest concurrent generalized myositis, myasthenia-like syndrome, and respiratory muscle failure. Prognostic factors for this "cardiomyotoxicity" are lacking.

Methods: A multicenter registry collected data retrospectively from 17 countries between 2014-2023. A multivariable cox regression model (hazard-ratio(HR), [^95%confidence-interval]) was used to determine risk factors for the primary composite outcome: severe arrhythmia, heart failure, respiratory muscle failure, and/or cardiomyotoxicity-related death. Covariates included demographics, comorbidities, cardio-muscular symptoms, diagnostics, and treatments. Time-dependent covariates were used and missing data were imputed. A point-based prognostic risk score was derived and externally validated.

Results: In 748 patients (67% male, age 23-94), 30-days incidence of the primary composite outcome, cardiomyotoxic death, and overall death were 33%, 13%, and 17% respectively. By multivariable analysis, the primary composite outcome was associated with active thymoma (HR=3.60[1.93-6.72]), presence of cardio-muscular symptoms (HR=2.60 [1.58-4.28]), low QRS-voltage on presenting electrocardiogram (HR for ≤0.5mV versus >1mV=2.08[1.31-3.30]), left ventricular ejection fraction (LVEF) <50% (HR=1.78[1.22-2.60]), and incremental troponin elevation (HR=1.86 [1.44-2.39], 2.99[1.91-4.65], 4.80[2.54-9.08], for 20, 200 and 2000-fold above upper reference limit, respectively). A prognostic risk score developed using these parameters showed good performance; 30-days primary outcome incidence increased gradually from 3.9%(risk-score=0) to 81.3%(risk-score≥4). This risk-score was externally validated in two independent French and US cohorts. This risk score was used prospectively in the external French cohort to identify low risk patients who were managed with no immunosuppression resulting in no cardio-myotoxic events.

Conclusions: ICI-myocarditis can manifest with high morbidity and mortality. Myocarditis severity is associated with magnitude of troponin, thymoma, low-QRS voltage, depressed LVEF, and cardio-muscular symptoms. A risk-score incorporating these features performed well.

Trial registration number: NCT04294771 and NCT05454527.

Keywords: Myocarditis; cardio-oncology; immunotherapy; mortality; myositis; risk-score.

Figure 1:. Cardiac workup and clinical event rate.

Results of diagnostics used in myocarditis workup (A), major cardio-myotoxic events overlap (B), time from first ICI dose to onset of myocarditis (C), and event-curve of first major cardio-myotoxic event at 30-days (D).

Figure 2:. Multivariable analysis of association with 30-days major cardio-myotoxic events.

Explanatory multivariable model for association with major cardio-myotoxic event (A). Predictive multivariable model for association with major cardio-myotoxic event using a stepwise selection procedure (B). Abbreviations: CI : confidence interval, coef: coefficient, ICI: immune checkpoint inhibitor, ms: millisecond, mV: millivolt, Ref: reference, ULN: upper limit of normal, VEGFi: Vascular Endothelial Growth Factor Inhibitor, Immunomodulator: non-steroidal immunomodulators only

Figure 3:. Risk score for major cardio-myotoxic events.

Components of the risk score of major cardio-myotoxic events at 30-days (A). Distribution of patients according to risk score (B). Cumulative incidence of major cardio-myotoxic events according to for risk score level (C). Cumulative incidence of components of the primary composite outcome of cardio-myotoxic events (D).