Reversal of immune-checkpoint inhibitor fulminant myocarditis using personalized-dose-adjusted abatacept and ruxolitinib: proof of concept

Abstract

Immune-checkpoint inhibitors (ICI) have revolutionized cancer therapy but are associated with infrequent but lethal myocarditis, for which management remains uncertain. Abatacept, a CTLA-4 fusion protein targeting CD86 on antigen presenting cells and leading to global T-cell anergy, has been described as a potential treatment in individual reports. Yet, abatacept treatment dosage, schedule and optimal combination with other immunosuppressive therapies are unclear. We describe a 25-year-old man who developed pembrolizumab (anti-PD1)-induced myocarditis 14 days after first injection for thymoma treatment, which deteriorated into cardiogenic shock, with sustained ventricular arrhythmia, requiring urgent extracorporeal life support implantation, despite prompt initiation of corticosteroids and mycophenolate-mofetil. Using a strategy of serial measurement ensuring with a target of >80% CD86 receptor occupancy on circulating monocytes, abatacept dose was adjusted and combined with ruxolitinib and methylprednisolone. This strategy resulted in high-dose of abatacept: 60 mg/kg in three doses (20 mg/kg each) within the first 10 days, followed by two doses. Clinical improvement occurred within 7 days, with resolution of systolic cardiac dysfunction, and ventricular arrhythmias resulting in successful discharge from hospital. We reversed a case of nearly lethal ICI-myocarditis, using specific patient-dose adjusted abatacept, which may serve as basis for personalized treatment of patients with severe ICI-adverse events. Trial registration number: NCT04294771.

Keywords: autoimmunity; case reports; immunotherapy.

Conflict of interest statement

Competing interests: Written consent for publication was obtained from the patient. J-ES have participated to advisory boards or consultancy from BMS, Novartis, Banook, AstraZeneca and Beigene. Other authors have nothing to disclose regarding this manuscript. SE received modest consultant fees from AstraZeneca, Amgen, BMS, Banook, Celgene and EISAI. J-ES, JM and YA have patents related to the treatment of ICI related immune adverse events. JM has served on advisory boards for Bristol Myers Squibb, Takeda, Audentes, Deciphera, Janssen, Immuno-Core, Boston Biomedical, Amgen, Myovant, Kurome Therapeutics, Star Therapeutics, ProtinQure, Pharmacyclics, Pfizer, Mallinckrodt Pharmaceuticals, Silverback Therapeutics, Cytokinetics, and AstraZeneca. JM was supported by National Institutes of Health grants (R01HL141466, R01HL155990, and R01HL156021).

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Timechart of the evolution of tumor size, PD1 +T cells and pembrolizumab plasma concentration after injection, and through the myocarditis event. Thoracic CT-scanner images showing the thymoma 48 days before myocarditis (ie, 34 days before pembrolizumab) and 1-year follow-up after pembrolizumab (maximal tumor size in mm) with the different anticancer treatment’s subsequent sequences. Evolution over time of pembrolizumab circulating levels associated with proportion of T-cells expression PD1 (%) is also represented.

Figure 2

ICI-myocarditis case report evolution on immunossupressant drugs. Timechart evolution of the patient (103 kg) with the main clinical events, treatments received and abatacept immune-monitoring results (circulating levels and CD86RO). CD86RO, CD86 receptor occupancy on circulating monocytes; (C) ICU, (cardiac). 99th percentile normal upper value of troponin-T was 14 ng/L; Hemodynamic support included extracorporeal life support associated with norepinephrine for the first 48hours. *For graphical representation, negative values of CD86RO were represented as null (see the Methods section for CD86RO value computation). ICI, immune checkpoint inhibitor; ICU, intensive care unit; LVEF, left ventricular ejection fraction; MMF, mycophenolate mofetil.