Immune checkpoint inhibitor-associated myocarditis: a novel risk score
John R. Power, Charles Dolladille, Benay Özbay, Adrien Procureur, Stéphane Éderhy, Nicolas L. Palaskas, Lorenz Lehmann, Jennifer Cautela, Pierre‐Yves Courand, Salim S. Hayek, Han Zhu, Vlad G. Zaha, Richard K. Cheng, Joachim Alexandre, François Roubille, Lauren A. Baldassarre, Yen-Chou Chen, Alan H. Baik, Michal Laufer‐Perl, Yuichi Tamura, Aarti Asnani, Sanjeev Francis, Elizabeth M Gaughan, Peter P. Rainer, Guillaume Bailly, Danette Flint, Dimitri Arangalage, Eve Cariou, Roberta Florido, Anna Narezkina, Yan Liu, Shahneen Sandhu, Darryl P. Leong, Nahéma Issa, Nicolas Piriou, Lucie Heinzerling, Giovanni Peretto, Shanthini Mary Crusz, Nausheen Akhter, Joshua Levenson, Isik Turker, Assié Eslami, Charlotte Fenioux, Pedro Moliner, Michel Obéid, Wei Ting Chan, Stephen M Ewer, Seyed Ebrahim Kassaian, Douglas B. Johnson, Anju Nohria, Osnat Itzhaki Ben Zadok, Javid J. Moslehi, Joe‐Elie Salem, International ICI-Myocarditis Registry, Anita Deswal, Franck Thuny, Anissa Bouali, Andrew Hughes, Lisa Moser, Maxime Faure, Rocio Baro Vila, Jesús Jiménez, Seyed Ebrahim Kassaian, Elise Paven, Elena Galli, Teresa López‐Fernández, Lucia Cobarro, Manhal Habib, Kazuko Tajiri, Fanny Rocher, Théodora Bejan‐Angoulvant, Mehmet Asım Bilen, Susmita Parashar, Avirup Guha, Wenjing Song, David W. Koenig, Kirsten D. Mertz, Carrie Lenneman, Andrew Haydon, Chloé Lesiuk, Romain Trésorier, Yazeed Samara, Christian Grohé, P.Y. Dietrich, Sean Tierney, Elie Rassy, Elvire Mervoyer, Shigeaki Suzuki, Satoshi Fukushima, Avirup Guha, Maxime Robert‐Halabi, Ryota Morimoto, Kazuko Tajiri, Robert Copeland-Halperin, Michael Layoun, Jun Wang, Suran L. Fernando, Eugenia Rota, Yumi Katsume, Yukiko Kiniwa
Abstract
BACKGROUND AND AIMS: 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. The main aim of this study was to determine predictors and construct a risk score associated with negative outcomes in patients admitted for ICI myocarditis. METHODS: A multicentre registry collected data retrospectively from 17 countries between 2014 and 2023. A multivariable Cox regression model was used to determine risk factors for the primary composite outcome: time to severe arrhythmia, heart failure, respiratory muscle failure, and/or cardiomyotoxicity-related death. Covariates included demographics, comorbidities, cardiomuscular 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 years), 30-day 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 (hazard ratio [HR] 3.6, 95% confidence interval [CI] 1.7-7.7), presence of cardiomuscular symptoms (HR 2.6 [1.5-4.2]), low QRS voltage on presenting electrocardiogram (HR for ≤0.5 mV vs >1 mV 1.9 [1.1-3.1]), left ventricular ejection fraction (LVEF) < 50% (HR 1.7 [1.1-2.6]), and incremental troponin elevation (HR 1.8 [1.4-2.4], 2.9 [1.8-4.7], and 4.6 [2.3-9.3], for 20, 200, and 2000-fold above upper reference limit, respectively). A prognostic risk score developed using these parameters showed good performance; 30-day primary outcome incidence increased gradually from 4% (risk score = 0) to 81% (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 cardiomyotoxic events. CONCLUSIONS: ICI-associated myocarditis can manifest with high morbidity and mortality. Myocarditis severity is associated with magnitude of troponin, thymoma, low QRS voltage, depressed LVEF, and cardiomuscular symptoms. A risk score incorporating these features performed well. CLINICAL TRIAL REGISTRATION: NCT04294771 and NCT05454527.