Risk Factors and Emerging Therapies for Immune Checkpoint Inhibitor-related Myocarditis: A Narrative Review.

BACKGROUND

Immune checkpoint inhibitors (ICIs) represent a groundbreaking development in immunotherapy, offering significant promise in the treatment of various malignancies previously considered incurable. However, despite their potential benefits, the increasing use of ICIs is associated with a spectrum of immune-related adverse events (irAEs). Myocarditis is a rare and potentially underestimated complication that represents the highest mortality rate among irAEs.

OBJECTIVE

The review aims to evaluate the current understanding of ICI-myocarditis (ICI-M) through providing a detailed overview of diagnostic challenges, screening strategies, and, in particular, the risk factors and evolving treatment agents beyond corticosteroids.

MATERIALS AND

METHODS

A comprehensive literature review was conducted on PubMed, analyzing data from relevant clinical studies, case reports, preclinical models, and expert consensus guidelines. In addition, data from one ongoing clinical trial (ATRIUM trial) not yet indexed in PubMed were included to reflect emerging therapeutic developments.

RESULTS

Despite the low incidence of ICI-M (0.06%-1%), which is likely underestimated, the mortality rate is the highest among irAEs; the most identifiable risk factors include combination therapy with ICI agents (anti-PD1 and anti-CTLA-4), preexisting cardiovascular and autoimmune diseases, use of ICIs alongside other anticancer treatments, certain tumor types, older age, and female sex. Diagnosis of the condition is faced with challenges such as nonspecific clinical features and often requires multimodal evaluation including biomarkers, imaging, and biopsy. High-dose corticosteroids remain the first-line treatment; however, steroid-refractory cases are increasingly reported. Promising second-line options include mycophenolate mofetil, antithymocyte globulin, abatacept, and tacrolimus; however, there is a lack of prospective data to support their efficacy. Studies conducted on various preclinical models highlight potential therapeutic targets such as CXCR3.

CONCLUSION

ICI-M poses a significant challenge in cardio-oncology practice due to its underestimation, high mortality rate, and lack of robust clinical data evaluating standardized screening protocols and second-line treatment measures. Although several second-line agents show promise, the evidence supporting their usage is largely on the basis of expert consensus and case reports, hence representing a strong need for prospective studies offering direct comparisons. Likewise, preclinical studies show great promise in identifying the pathophysiology and potential therapeutic targets for ICI-M; however, translational studies are necessary to validate these findings.