Treatment of Immune Checkpoint Inhibitor-associated Myocarditis

Abstract

Immune checkpoint inhibitors (ICIs) are a form immunotherapy where the negative regulators of host immunity are targeted, thereby leveraging the own immune system. ICIs have significantly improved cancer survival in several advanced malignancies, and there are currently more than 90 different cancer indications for ICIs. Most patients develop immune-related adverse events during ICI therapy. Most are mild, but a small subset of patients will develop severe and potentially fatal immune-related adverse events. A serious cardiovascular complication of ICI therapy is myocarditis. Although the incidence of myocarditis is low, mortality rates of up to 50% have been reported. The mainstay of ICI-associated myocarditis treatment is high-dose corticosteroids. Unfortunately, half of patients with myocarditis do not show clinical improvement after corticosteroid treatment. Also, high doses of corticosteroids may adversely impact cancer outcomes. There is an evidence gap in the optimal second-line treatment strategy. Currently, there is a paradigm shift in second-line treatment taking place from empirical corticosteroid-only strategies to either intensified initial immunosuppression where corticosteroids are combined with another immunosuppressant or targeted therapies directed at the pathophysiology of ICI myocarditis. However, the available evidence to support these novel strategies is limited to observational studies and case reports. The aim of this review is to summarize the literature, guidelines, and future directions on the pharmacological treatment of ICI myocarditis.

Fig. 1:

The underlying pathological processes of myocarditis associated with immune checkpoint inhibitor therapy and the mode of action of pharmaceutical interventions. ATG = Antithymocyte globulin; CTLA-4 = cytotoxic T lymphocyte antigen-4; ICI = immune checkpoint inhibitor; IMP = Inosine monophosphate, IVIG = intravenous immunoglobulin; JAK-STAT = Janus kinase-signal transducer and activator of transcription; LAG-3 = lymphocyte-activation gene 3; MHC = major histocompatibility complex; PD-1/PDL-1 = programmed death-1 receptor/programmed death-1 ligand (PDL-1); TNF = tumor necrosis factor.

Fig. 2:

graphical representation of five guidelines and consensus statements on the treatment of immune checkpoint inhibitor associated myocarditis. ABA = abatacept; ALE = alemtuzumab; ASCO = American Society of Clinical Oncology; ATG = Antithymocyte globulin; ESC = European Society of Cardiology; ESMO = European Society of Medical Oncology; IFX = infliximab; IVG = intravenous immunoglobulins; JAK = JAK-STAT inhibitor; MM = mycophenolate mofetil; MP = methylprednisolone; NCCN = National Comprehensive Cancer Network; PLX = plasma exchange; SITC = Society for Immunotherapy of Cancer.