IMMUNE CHECKPOINT INHIBITOR RELATED MYOCARDITIS: A SYSTEMATIC REVIEW TO MAP THE MOST EFFECTIVE TREATMENT APPROACH

Abstract

Introduction Immune checkpoint inhibitor (ICI) related myocarditis (ICIRM) is the commonest and most serious of ICI induced cardiotoxicities. Its rarity, severity and complexity hinder a consensus on treatment guidelines. We conducted a systematic review (SR) of real-world evidence aiming to formulate the most effective treatment approach for ICIRM. Methodology 5 databases (MEDLINE, Embase, Cochrane, Scopus, Google Scholar) were searched for 'immune checkpoint inhibitors' and 'myocarditis'. Only real-world studies were included. Baseline demographics, myocarditis diagnoses, disease characteristics, treatments, and outcomes were extracted by atleast 2 independent reviewers. Results A pooled analysis of 588 patients from 17 studies was done. Most common primary tumours were melanoma (n=62) and non-small cell lung cancer (n=51). PD-1 inhibitors (n=208) were the commonest monotherapy, followed by CTLA-4 (n=14) and PD-L1 (n=11) inhibitors. Combination therapy wise, PD-1/CTLA-4 (n=20) superseded PD-L1/CTLA-4 (n=2) inhibitors. ICIRM was diagnosed using composite criteria in 8/17 studies (clinical, ECG, troponin, cardiac MRI) with 9/17 incorporating histology (endomyocardial biopsy). Methylprednisolone (MP) was first line (1L) (17/17 studies), with evidence of combination intravenous immunoglobulin (IVIG) (8/17) more commonly than plasmapheresis (2/17). Differential dosage was identified in 8/17, whereas dose ranges in 3/17. 2/17 advocated1g intravenous MP (table 1). Lower mortality and incidence of major adverse cardiovascular event (MACE) were linked to higher steroid dose (3/17 and 3/17 studies respectively) and earlier initiation of steroids i.e., within <24 h after presentation (1/17 and 1/17 respectively). In the steroid refractory state, IVIG (4/17), anti-thymocyte globulin (ATG) (2/17) and plasmapheresis (1/17) were used only as 1L; tocilizumab in 1L (1/17), 2L (2/17) and 3L settings (1/17); tacrolimus, mycophenolate mofetil (MMF), abatacept, infliximab in 1L or 2L setting without any evidence of comparative benefit over each other or consensus over treatment sequencing. ICIs were subject to immediate cessation (9/17) except 1/17 which involved continuation if mild ICIRM. 2/17 considered ICI rechallenge, 1/17 in mild disease and 1/17 in 8 to 12 months. Biomarker surveillance utilised troponin I (7/17) more commonly than troponin T (5/17). Conclusion We reviewed 17 studies to identify a consensus on treatment strategies for ICIRM along with treatment-related factors promoting survival prognostication, including timing of steroid commencement and cessation of ICIs. Analysis is limited by the lack of individual patient data. We provide suggestions for future research regarding steroid usage characteristics, combination therapies, immunosuppressant treatment sequencing and comparative analysis if refractory disease.