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.

TNF-α Inhibitors and Other Biologic Agents for the Treatment of Immune Checkpoint Inhibitor-Induced Myocarditis

“…However, the risk of tumor relapse should also be noted. Two patients experienced tumor relapse 3 months and 4 months after abatacept treatment, respectively (96,97). The duration of follow-up was only 1 month in another patient, the possibility of tumor relapse could not be excluded (94).…”

“…Methylprednisolone 1g/d and addition of mycophenolatemofetil had limited efficacy. Initiation of abatacept and ruxolitinib reversed the disease course and the patient fully recovered clinically, with ejection fraction restoring to 60% (97). Therefore, use of abatacept in ICI-induced myocarditis is worth expecting, especially considering its efficacy in concurrent myositis and myocarditis.…”

“…Like other immunosuppressant, further research is needed to assess the optimal drug mix, dosage and duration of abatacept, in order to mitigate the potential lethality associated with irAEs while preserving antitumor beneficial effects. CD86 receptor occupancy saturation might be a reference for the timing and dosage of abatacept (97). Two prospective clinical trials have been underway to assess the safety and efficacy of abatacept in ICI-induced myocarditis (NCT05335928 and NCT05195645).…”

Cardiotoxicity Induced by Immune Checkpoint Inhibitors: What a Cardio-Oncology Team Should Know and Do

“…In a mouse model of ICI-induced myocarditis, abatacept reduced immune system activation and increased survival [ 66 , 67 ]. Several clinical studies reported the administration of abatacept in ICI-induced myocarditis [ 68 , 69 , 70 ], with promising results obtained, in particular in the simultaneous treatment of myositis and myocarditis. However, the risk of cancer relapse should also be noted.…”

Overcoming the cardiac toxicities of cancer therapy immune checkpoint inhibitors

“…Immune modulators which have been shown in case reports or small case series to be effective in reversing near-lethal ICI-myocarditis. Drugs which have been investigated include tocilizumab (IL-6R antibody) (145), alemtuzumab (anti-CD52) (17) (146), abatacept (CTLA-4 agonist) (147), ruxolitinib (JAK inhibitor) (148), infliximab (TNFa antibody) (149), tofacitinib (JAK inhibitor) (150), mycophenolate mofitil (151), and antithymocyte globulin (152), and IV immunoglobulin. (153) However, the effectiveness of these therapies in ICI induced cardiac irAEs is unclear and they are therefore only reserved for patients with poor responses to corticosteroids.…”