Predictors and Risk Score for Immune Checkpoint-Inhibitor-Associated Myocarditis Severity
John Power
(1)
,
Charles Dolladille
(2)
,
Benay Ozbay
(3)
,
Adriel Procureur
(2)
,
Stephane Ederhy
(2)
,
Nicolas Palaskas
(4)
,
Lorenz Lehmann
(5)
,
Jennifer Cautela
(6, 7)
,
Pierre-Yves Courand
(8, 9)
,
Salim Hayek
(10)
,
Han Zhu
(11)
,
Vlad Zaha
(12)
,
Richard Cheng
(13)
,
Joachim Alexandre
(14, 15)
,
François Roubille
(16, 17)
,
Lauren Baldassarre
(18)
,
Alan Baik
(19)
,
Michal Laufer-Perl
(20)
,
Yuichi Tamura
(21)
,
Aarti Asnani
(22)
,
Sanjeev Francis
(23)
,
Elizabeth Gaughan
(24)
,
Peter Rainer
(25, 26)
,
Guillaume Bailly
(27)
,
Danette Flint
(28)
,
Dimitri Arangalage
(29)
,
Eve Cariou
(30)
,
Roberta Florido
(31)
,
Anna Narezkina
(1)
,
Yan Liu
(32)
,
Shahneen Sandhu
(33)
,
Darryl Leong
(34)
,
Nahema Issa
(35)
,
Nicolas Piriou
(36)
,
Lucie Heinzerling
(37, 38)
,
Giovanni Peretto
(39)
,
Shanthini Crusz
(40)
,
Nausheen Akhter
(41)
,
Joshua Levenson
(3)
,
Isik Turker
(13)
,
Assie Eslami
(42, 43)
,
Charlotte Fenioux
(44)
,
Pedro Moliner
(45, 46, 47, 48)
,
Michel Obeid
(49)
,
Wei-Ting Chang
,
Stephen Ewer
(50)
,
Seyed Ebrahim Kassaian
(51)
,
Douglas Johnson
(52)
,
Anju Nohria
(53)
,
Osnat Itzhaki Ben Zadok
(53)
,
Javid Moslehi
(19)
,
Joe-Elie Salem
(2)
1
UC San Diego -
University of California [San Diego]
2 CIC Paris-Est - Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière]
3 UPMC - University of Pittsburgh Medical Center [Pittsburgh, PA, États-Unis]
4 The University of Texas M.D. Anderson Cancer Center [Houston]
5 Heidelberg University Hospital [Heidelberg]
6 Hôpital Nord [CHU - APHM]
7 AMU - Aix Marseille Université
8 HCL - Hospices Civils de Lyon
9 UCBL - Université Claude Bernard Lyon 1
10 University of Michigan [Dearborn]
11 Stanford University
12 University of Texas Southwestern Medical Center [Dallas]
13 University of Washington [Seattle]
14 ANTICIPE - Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers
15 CHU Caen
16 PhyMedExp - Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046]
17 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
18 YSM - Yale School of Medicine [New Haven, Connecticut]
19 UC San Francisco - University of California [San Francisco]
20 TAU - Tel Aviv University
21 IUHW Hospital - International University of Health and Welfare Hospital
22 BIDMC - Beth Israel Deaconess Medical Center [Boston]
23 Maine Medical Center
24 University of Virginia
25 Medical University of Graz = Medizinische Universität Graz
26 St. Johannes Hospital Duisburg
27 Hôpital Lariboisière-Fernand-Widal [APHP]
28 DHMC - Dartmouth Hitchcock Medical Center
29 AP-HP - Hôpital Bichat - Claude Bernard [Paris]
30 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
31 University of Utah
32 University of Texas at Austin [Austin]
33 Peter MacCallum Cancer Centre
34 Mac Master University
35 CHU Bordeaux - Centre Hospitalier Universitaire de Bordeaux
36 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
37 University Hospital Erlangen = Uniklinikum Erlangen
38 LMU - Ludwig Maximilian University [Munich] = Ludwig Maximilians Universität München
39 IRCCS San Raffaele Scientific Institute [Milan, Italie]
40 Barts Health NHS Trust [London, UK]
41 Northwestern University [Evanston]
42 HEGP - Hôpital Européen Georges Pompidou [APHP]
43 UPCité - Université Paris Cité
44 Hôpital Henri Mondor
45 Bellvitge University Hospital = Bellvitge Hospital Universitari
46 ICO-Girona - Catalan Institute of Oncology [Girona]
47 IDIBELL - Institut d'Investigació Biomèdica de Bellvitge = Bellvitge Biomedical Research Institute
48 CIBERCV - Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares [Spain]
49 CHUV - Centre Hospitalier Universitaire Vaudois = Lausanne University Hospital [Lausanne]
50 University of Wisconsin School of Medicine and Public Health
51 MedStar WHC - MedStar Washington Hospital Center [Washington, DC, USA]
52 Vanderbilt University Medical Center [Nashville]
53 Mass General Brigham-Salem Hospital
2 CIC Paris-Est - Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière]
3 UPMC - University of Pittsburgh Medical Center [Pittsburgh, PA, États-Unis]
4 The University of Texas M.D. Anderson Cancer Center [Houston]
5 Heidelberg University Hospital [Heidelberg]
6 Hôpital Nord [CHU - APHM]
7 AMU - Aix Marseille Université
8 HCL - Hospices Civils de Lyon
9 UCBL - Université Claude Bernard Lyon 1
10 University of Michigan [Dearborn]
11 Stanford University
12 University of Texas Southwestern Medical Center [Dallas]
13 University of Washington [Seattle]
14 ANTICIPE - Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers
15 CHU Caen
16 PhyMedExp - Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046]
17 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
18 YSM - Yale School of Medicine [New Haven, Connecticut]
19 UC San Francisco - University of California [San Francisco]
20 TAU - Tel Aviv University
21 IUHW Hospital - International University of Health and Welfare Hospital
22 BIDMC - Beth Israel Deaconess Medical Center [Boston]
23 Maine Medical Center
24 University of Virginia
25 Medical University of Graz = Medizinische Universität Graz
26 St. Johannes Hospital Duisburg
27 Hôpital Lariboisière-Fernand-Widal [APHP]
28 DHMC - Dartmouth Hitchcock Medical Center
29 AP-HP - Hôpital Bichat - Claude Bernard [Paris]
30 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
31 University of Utah
32 University of Texas at Austin [Austin]
33 Peter MacCallum Cancer Centre
34 Mac Master University
35 CHU Bordeaux - Centre Hospitalier Universitaire de Bordeaux
36 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
37 University Hospital Erlangen = Uniklinikum Erlangen
38 LMU - Ludwig Maximilian University [Munich] = Ludwig Maximilians Universität München
39 IRCCS San Raffaele Scientific Institute [Milan, Italie]
40 Barts Health NHS Trust [London, UK]
41 Northwestern University [Evanston]
42 HEGP - Hôpital Européen Georges Pompidou [APHP]
43 UPCité - Université Paris Cité
44 Hôpital Henri Mondor
45 Bellvitge University Hospital = Bellvitge Hospital Universitari
46 ICO-Girona - Catalan Institute of Oncology [Girona]
47 IDIBELL - Institut d'Investigació Biomèdica de Bellvitge = Bellvitge Biomedical Research Institute
48 CIBERCV - Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares [Spain]
49 CHUV - Centre Hospitalier Universitaire Vaudois = Lausanne University Hospital [Lausanne]
50 University of Wisconsin School of Medicine and Public Health
51 MedStar WHC - MedStar Washington Hospital Center [Washington, DC, USA]
52 Vanderbilt University Medical Center [Nashville]
53 Mass General Brigham-Salem Hospital
John Power
- Fonction : Auteur
- PersonId : 1168201
- ORCID : 0000-0003-4254-4447
Charles Dolladille
- Fonction : Auteur
- PersonId : 1309756
- ORCID : 0000-0003-0449-6261
Benay Ozbay
- Fonction : Auteur
- PersonId : 813498
- ORCID : 0000-0002-2039-5770
Stephane Ederhy
- Fonction : Auteur
- PersonId : 772992
- ORCID : 0000-0002-0792-2521
- IdRef : 095495304
Pedro Moliner
- Fonction : Auteur
Wei-Ting Chang
- Fonction : Auteur
Joe-Elie Salem
- Fonction : Auteur
- PersonId : 777251
- IdHAL : joe-elie-salem
- ORCID : 0000-0002-0331-3307
- IdRef : 160947227
Résumé
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.