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Cited by 243Cancer Immunotherapy and BiomarkersInflammatory Myopathies and DermatomyositisViral Infections and Immunology Research

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

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Salem, Joe-Elie, Bretagne, Marie, Abbar, Baptiste, Leonard-Louis, Sarah, Ederhy, Stéphane, Redheuil, Alban, Boussouar, Samia, Nguyen, Lee S. +35 more·2023·Cancer Discovery
DOI 10.1158/2159-8290.cd-22-1180

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Abstract

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

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  • Abatacept alone or in combination with ruxolitinib has demonstrated clinical benefits in treating patients with ICI myocarditis and murine models.

    “Additionally, as previously discussed, abatacept alone or in combination with ruxolitinib has demonstrated clinical benefits in treating patients with ICI myocarditis and murine models (Figure 2). 51,254,260”

    From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [254]

    The Introduction reports that abatacept attenuated myocardial immune infiltration in a mouse model, and the Discussion reports lower mortality in patients treated with a strategy that included abatacept and ruxolitinib. The patient benefit cannot be attributed to those drugs alone because the strategy also included corticosteroids and respiratory-muscle management; the paper does not report a demonstrated benefit from the drug combination in mice. No page numbers are available in our copy. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Myotoxicity-related fatality occurred in 3% of patients receiving abatacept plus ruxolitinib compared with 60% in a group receiving clinician-based choice of immunosuppression.

    “Myotoxicity-related fatality occurred in only 3% of patients, compared with 60% in a group that received clinician-based choice of immunosuppression.”

    From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [254]

    The Abstract reports myotoxicity-related fatality of 3.4% (1/30) in the later cohort versus 60% in the first 10 patients. But the 3.4% applies to a broader strategy that included respiratory-muscle screening and management, not specifically to patients receiving both abatacept and ruxolitinib; the Cardio-myotoxicities outcomes section says ruxolitinib was used in 17 of 22 severe cases in the later cohort. The Study Cohort section describes the earlier group as treated under expert-consensus guidelines, rather than as a clinician-choice comparison group. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • In a study of 30 consecutive patients with ICI myocarditis, the combination of abatacept with ruxolitinib led to a dramatic improvement in survival.

    “in a study of 30 consecutive patients with ICI myocarditis, the combination of an appropriate dose of abatacept (based on receptor occupancy) with ruxolitinib led to a dramatic improvement in survival of patients.”

    From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [254]

    The Study Cohort and Cardio-myotoxicities outcomes sections describe 30 consecutive patients treated under a revised protocol, with lower mortality than in the preceding 10 patients. But the protocol also included corticosteroids and respiratory-muscle screening and management; ruxolitinib was used in 17 of the 22 severe cases, not all 30 patients. The observational study associates the combined strategy with improved survival but cannot establish that abatacept plus ruxolitinib caused it. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Recent studies implemented pathogenic T cells as potential diagnostic or therapeutic targets for autoimmune myocarditis including ICI myocarditis, demonstrating promising outcomes at both clinical and preclinical levels.

    “Recent studies implemented pathogenic T cells as potential diagnostic or therapeutic targets for autoimmune myocarditis including ICI myocarditis, demonstrating promising outcomes at both clinical and preclinical levels. 51,64,238,254,260,311,312”

    From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [254]

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Authors
Salem, J.-E., Bretagne, M., Abbar, B., Leonard-Louis, S., Ederhy, S., Redheuil, A., Boussouar, S., Nguyen, L. S., Procureur, A., Stein, F., Fenioux, C., Devos, P., Gougis, P., Dres, M., Demoule, A., Psimaras, D., Lenglet, T., Maisonobe, T., De Chambrun, M. P., Hekimian, G., Straus, C., Gonzalez-Bermejo, J., Klatzmann, D., Rigolet, A., Guillaume-Jugnot, P., Champtiaux, N., Benveniste, O., Weiss, N., Saheb, S., Rouvier, P., Plu, I., Gandjbakhch, E., Kerneis, M., Hammoudi, N., Zahr, N., Llontop, C., Morelot-Panzini, C., Lehmann, L., Qin, J., Moslehi, J. J., Rosenzwajg, M., Similowski, T., & Allenbach, Y.
Affiliations
  • Inserm (FR)
  • 3Sorbonne Université, INSERM, Department of Neuropathology, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.
  • 4Sorbonne Université, INSERM, UNICO-GRECO Cardio-oncology Program, Department of Cardiology, GRC27, AP-HP, Hôpital Saint-Antoine, Paris, France.
  • 8Sorbonne Université, INSERM, Department of Neurology, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.
  • 9Sorbonne Université, INSERM, Institute of Cardiometabolism and Nutrition, Department of Medical Intensive Care Unit, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.
  • 7Sorbonne Université, INSERM, Department R3S (Respiration, Réanimation, Réhabilitation, Sommeil), AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.
  • 12Sorbonne Université, INSERM, Department of Internal Medicine, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.
  • 16Sorbonne Université, ACTION Study Group, INSERM UMR_S 1166, Institute of Cardiometabolism and Nutrition, and Hôpital Pitié-Salpêtrière (AP-HP), Boulevard de l'hôpital, Paris, France.
  • 1Sorbonne Université, INSERM, UNICO-GRECO Cardio-oncology Program, Department of Pharmacology, GRC27, CIC-1901, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.
  • University Hospital Heidelberg (DE)
  • University of California, San Francisco (US)
  • 11Sorbonne University, INSERM UMRS959, Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Paris, France.
ORCID
Venue
Cancer Discovery
Publisher
American Association for Cancer Research (AACR)
Published
2023-02-23
Volume
13
Issue
5
Pages
1100-1115
ISSN
  • 2159-8274 (ISSN-L)
  • 2159-8290
DOI
10.1158/2159-8290.cd-22-1180
OpenAlex
W4321598981
Cited by
243
References
3
Citations by year
2026: 79 · 2025: 65 · 2024: 70 · 2023: 28
FWCI
29.51
Type
journal article
Language
en
Open access
Licence
other-oa
Locations
  • Cancer Discovery (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
No funding
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Epidemiology › Inflammatory Myopathies and Dermatomyositis
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Viral Infections and Immunology Research
Keywords
immune checkpoint inhibitor-associated myocarditis, respiratory muscle failure, mechanical ventilation, abatacept, ruxolitinib, JAK inhibitors, monocytes, screening method
MeSH terms
Abatacept, Antineoplastic Agents, Immunological, Myotoxicity, Immune Checkpoint Inhibitors, Humans, Myocarditis, Myositis, Nitriles, Pyrazoles, Pyrimidines, Respiratory Muscles

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