Immune-related acute myocarditis in patients treated with immune checkpoints inhibitors: Systematic review with individual patient-level data meta-analysis.

Abstract

e24096 Background: Immune checkpoint inhibitors can sometimes lead to fatal outcomes or significant morbidity due to immune-related adverse events (IRAE). Cardiac IRAE, especially myocarditis, are among the most fatal IRAE. There are scarce of the trials addressing the optimal therapeutic approaches for patients with IR-myocarditis. Initial therapy with high-dose steroids (1000 mg of prednisolone for 3-5 days) may be beneficial for many patients with this IRAE and this approach is endorsed by NCCN guidelines. We conducted a systematic review with individual patient-level data meta-analysis of published clinical cases to assess impact of various initial therapeutic modalities and adherence to NCCN guidelines on outcomes of immune-related myocarditis, associated with checkpoint inhibitors. Methods: We searched PubMed database for all full-text articles and abstracts on the treatment of patients with cardiac-related IRAE treated with various PD-1/PD-L1 or CTLA-4 inhibitors for years between 2012 and 2020 in English. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) tool was used to ensure transparent reporting. Main study inclusion criteria were: 1) morphologically confirmed immune-related myocarditis or highly clinically suspected autoimmune myocarditis (based on Bonaca et\xa0al, 2019 criteria); 2) clear association of IRAE and administration of check-point inhibitors; 3) availability of individual patient and treatment data. Pooled analysis of outcomes and multiple logistic regression analysis were conducted. The primary outcome of this study was rate of major cardiac adverse events (MACE) due to immune-related autoimmune myocarditis according to adherence to NCCN guidelines. MACE was defined as death or persisting significant disabilities due to myocarditis (ie, chronic heart failure, rhythm abnormalities or deterioration leading to impossibility of further anticancer treatment). Results: We identified 277 articles and screened them for title and abstract. After the review process we selected 81 studies for further analysis which described treatment course for 111 patients. Overall, 26 and 85 patients were treated with high-dose and non-high dose steroids. Among patients treated high-dose steroids therapy and non-high dose steroids 10 (38.5%) and 57 (67.1%) of patients respectively experienced MACE (HR 0.185; 95% CI 0.07-0.47; p = 0.0091). Initial treatment failure was associated with high rate of morbidity; however, 9 patients were rescued with various immunosuppressive drugs (eg, tacrolimus, alemtuzumab, tocilizumab). Conclusions: Our results support use of high-dose pulse therapy as a preferred therapeutic approach for all patients with suspected or proven immune-related myocarditis.