Abatacept/Ruxolitinib and Screening for Concomitant Respiratory Muscle Failure to Mitigate Fatality of Immune-Checkpoint Inhibitor Myocarditis

Joe-Elie Salem (1, 2, 3) , Marie Bretagne (1, 2, 3) , Baptiste Abbar (1, 2, 3) , Sarah Leonard-Louis (1) , Stéphane Ederhy (2, 4) , Alban Redheuil (5) , Samia Boussouar (5) , Lee Nguyen (2, 1, 3) , Adrien Procureur (2, 1, 3) , Frederic Stein (2, 1, 3) , Charlotte Fenioux (2, 1, 3) , Perrine Devos (2, 1, 3) , Paul Gougis (2, 1, 3) , Martin Dres (6) , Alexandre Demoule (6) , Dimitri Psimaras (1) , Timothee Lenglet (1) , Thierry Maisonobe (1) , Marc Pineton de Chambrun (5) , Guillaume Hekimian (5) , Christian Straus (7) , Jesus Gonzalez-Bermejo (6) , David Klatzmann (8) , Aude Rigolet (1) , Perrine Guillaume-Jugnot (1) , Nicolas Champtiaux (1) , Olivier Benveniste (9, 1) , Nicolas Weiss (1) , Samir Saheb (1) , Philippe Rouvier (1) , Isabelle Plu (1) , Estelle Gandjbakhch (10, 1) , Mathieu Kerneis (10, 1) , Nadjib Hammoudi (10, 1) , Noel Zahr (2, 3, 1) , Claudia Llontop (6) , Capucine Morelot-Panzini (6) , Lorenz Lehmann (11, 12) , Juan Qin (13) , Javid Moslehi (13) , Michelle Rosenzwajg (8) , Thomas Similowski (6) , Yves Allenbach (1)

1 CHU Pitié-Salpêtrière [AP-HP]
2 GRC 27 - GRECO - Groupe de REcherche en Cardio Oncologie
3 CIC Paris-Est - Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière]
4 CHU Saint-Antoine [AP-HP]
5 IHU ICAN - Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière]
6 R3S - Service de Pathologies du sommeil
7 UMRS 1158 - Neurophysiologie Respiratoire Expérimentale et Clinique
8 I3 - Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière]
9 Centre de recherche en Myologie – U974 SU-INSERM
10 ICAN - Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases
11 Heidelberg University Hospital [Heidelberg]
12 DZHK - German Center for Cardiovascular Research
13 UC San Francisco - University of California [San Francisco]

Immune-checkpoint-inhibitor (ICI)-associated myotoxicity involves the heart (myocarditis) and skeletal muscles (myositis), which frequently occur concurrently and are highly fatal. We report the results of a strategy that included identification of individuals with severe ICI myocarditis by also screening for and managing concomitant respiratory muscle involvement with mechanical ventilation, as well as treatment with the CTLA4 fusion protein abatacept and the JAK inhibitor ruxolitinib. Forty cases with definite ICI myocarditis were included with pathologic confirmation of concomitant myositis in the majority of patients. In the first 10 patients, using recommended guidelines, myotoxicity-related fatality occurred in 60%, consistent with historical controls. In the subsequent 30 cases, we instituted systematic screening for respiratory muscle involvement coupled with active ventilation and treatment using ruxolitinib and abatacept. The abatacept dose was adjusted using CD86 receptor occupancy on circulating monocytes. The myotoxicity-related fatality rate was 3.4% (1/30) in these 30 patients versus 60% in the first quartile (P < 0.0001). These clinical results are hypothesis-generating and need further evaluation. Significance: Early management of respiratory muscle failure using mechanical ventilation and high-dose abatacept with CD86 receptor occupancy monitoring combined with ruxolitinib may be promising to mitigate high fatality rates in severe ICI myocarditis. See related commentary by Dougan, p. 1040. This article is highlighted in the In This Issue feature, p. 1027.

Domaines: Immunothérapie; Cardiologie et système cardiovasculaire

Joe-Elie Salem, Marie Bretagne, Baptiste Abbar, Sarah Leonard-Louis, Stéphane Ederhy, et al.. Abatacept/Ruxolitinib and Screening for Concomitant Respiratory Muscle Failure to Mitigate Fatality of Immune-Checkpoint Inhibitor Myocarditis. Cancer Discovery, 2023, 13 (5), pp.1100-1115. ⟨10.1158/2159-8290.CD-22-1180⟩. ⟨hal-04578810⟩