The Efficacy and Safety of MEK Inhibitor Therapy in Adults with Histiocytic Disorders: A Meta-Analysis

Introduction

Understanding the molecular pathogenesis of histiocytic disorders led to the development of targeted therapies used in relapsed-refractory cases or when genetic testing is available. Unlike BRAF inhibitors (BRAFi), the safety and efficacy of MEK inhibitors (MEKi) have not been extensively reviewed. Such research would be especially useful for adult patients as treatment responses and prognoses differ significantly across individuals while recommendations for management are sparse. This meta-analysis summarizes the response to MEKi in adults with histiocytic disorders.

Methods:

PubMed and Embase were searched for studies investigating response rates of MEKi in patients with histiocytosis published since 2014. Searches resulted in 334 articles after duplicates were removed. Studies which specified a dose of MEKi and enrolled patients aged 21 years or older were included. Case reports, studies conducted on pediatric patients, studies that did not report a complete response rate within 1 year of treatment, and studies that included other neoplastic disorders were excluded. Meta-analysis was performed using the “metafor” package version 3.4-0 in R version 4.1.2.

Results:

The final search resulted in 8 clinical studies (N = 131). Sample sizes ranged from 3 to 26 patients. The median age of patients included ranged from 43 to 63 years old. Erdheim Chester Disease (ECD) was the most common histiocytic disorder, representing 44% of total patients, followed by Rosai-Dorfman disease (25%) and then Langerhans cell histiocytosis (22%). The median duration for which patients were followed ranged from 16 to 23 months. 75% of patients achieved a CR 1 year after treatment with MEKi (95% CI 66% - 82%), which was not statistically significant (p = 0.844). Similarly, 34% of patients achieved an overall response (OR) 1 year after treatment with MEKi (95% CI 22 - 49%; p =0.053). There was mild statistical heterogeneity for OR (I2 = 0.0%) and moderate heterogeneity for CR (I2 = 51.5%) across included studies according to the Cochrane Q test. There was substantial heterogeneity regarding how adverse effects and the associated severity were reported. However, rash, reduced ejection fraction or heart failure, and diarrhea were the most cited adverse effects.

Discussion:

Limited data exists on use of MEKi in histiocytic disorders. The lack of statistical significance in achieving CR or OR with MEKi can be attributed to small number of patients pooled for this study. This analysis may reflect the importance of genetic testing to guide targeted treatment in histiocytic disorders as opposed to a lack of efficacy for MEKi, as comparison data with other targeted therapies like BRAFi in the setting of MEK positivity is lacking. A quantitative analysis of adverse effect profiles was not possible due to the heterogeneity in which adverse effects and severity of adverse effects were reported. Future studies should focus on uniformly reporting the adverse effects of MEKi to better inform risk-benefit discussions.

No relevant conflicts of interest to declare.