RESUMO
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.
RESUMO
Current mortality is low in cases of childhood acute leukemia. Dilated cardiomyopathy induced by anthracyclines remains the main cause of morbidity and mortality during mid-term and long-term follow-up. The aim of our study was to analyze the profile of left ventricular alterations in children treated with anthracyclines and to analyze risks and protective factors, including physical activity. Children and young adults with acute leukemia treated with anthracyclines between 2000 and 2018 during childhood were included. The physical activity performed by the patients before and after treatment was quantified in metabolic equivalent tasks, MET.h, per week. An echocardiographic assessment was performed, including strain analysis. Thirty-eight patients with a median age of 5 [3-8] years were included. Dilated cardiomyopathy was diagnosed in 3 patients and longitudinal strain abnormalities were observed in 11 patients (28.9%). Radiotherapy, cumulative anthracycline doses > 240 mg/m2, and the practice of physical activity > 14 MET.h per week (after leukemia treatment) were independently associated with strain abnormalities. In multivariate analysis, radiotherapy was significantly associated with an increased risk of LV GLS abnormalities (OR = 1.26 [1.01-1.57], p = 0.036), and physical activity > 14 MET.h/week after oncological treatment was significantly associated with a reduction in the risk of LV GLS abnormalities (OR of 0.03 [0.002-0.411], p = 0.009). The strain assessment of left ventricular function is an interesting tool for patient follow-up after leukemia treatment. Moderate and steady physical activity seems to be associated with fewer longitudinal strain abnormalities in patients treated with anthracyclines during childhood.