MEK inhibitors are effective in Erdheim–Chester disease regardless of MAPK pathway mutations

We read with interest the Letter by Acosta-Medina et al, recently published in Leukemia [ 1 ]. The authors investigate the impact of pathogenic variants of genes involved in the MAPK-ERK pathway on the response to MEK inhibitors (MEKi) in a cohort of 20 patients with Erdheim-Chester disease (ECD). In the last decade, targeted treatments such as BRAF inhibitors (BRAFi) and MEKi have revolutionized the management of patients with ECD [ 2 ]. While BRAFi are considered to be effective only in patients harboring the BRAF V600E mutation [ 3 ], responses to MEKi have been reported regardless of the underlying mutation [ 4 ]. Interestingly, in this report, the authors suggest that responses to MEKi differ significantly between ECD patients with MAPK-ERK pathway mutations ( i.e ., BRAF , MAP2K1 , NRAS ) and those without. Notably, the latter group included two patients with CSF1R mutations, one with a FLT3::MEF2C fusion, and two with no identifiable variants based on their Next-Generation Sequencing (NGS) panel. While we acknowledge the importance of stratifying ECD patients on their molecular status, the study results are insufficient to draw definitive conclusions regarding wild-type (WT) patients. We herein present data on MEKi efficacy from a cohort of ECD patients treated at two referral centers, one in France (Pitié-Salpêtrière Hospital, Paris) and one in Italy (Meyer Children’s Hospital IRCCS, Florence). The MAPK-ERK pathway mutation status was determined in all patients using NGS, following the latest consensus recommendations on ECD [ 5 ]. We evaluated the response rate in 80 biopsy-proven ECD patients who received MEKi for at least three months (Fig. 1A ). None of these patients were enrolled in a clinical trial for MEKi. Among them, 34 (43%) had mutations involving BRAF , 28 (35%) MAP2K1 , one (1%) KRAS , and one (1%) NRAS ; in 16 patients (20%), no mutations were identified. MEKi were used as first-line treatment in 37 patients (46%), as second line in 30 (38%), and as third line in 13 (16%) (Table 1 ). Among patients with MAPK-ERK pathway mutations (n = 64), objective metabolic responses (defined as previously reported [ 6 , 7 , 8 ]) were observed in 39 patients (61%), 19 (30%) had stable disease while six (9%) experienced disease progression. Response rates were strikingly similar among the 16 WT patients: of them, 10 (63%) responded, five (31%) had stable disease and one (6%) progressed (Fisher’s exact test for response rate difference p = 1.000) (Fig. 1B ). Fig. 1: Study inclusion and results. A Flow-chart of patients’ inclusion. B Response to MEKi in the 80 ECD patients based on their mutational status. MEKi MEK inhibitors, NA not available, MOF multi-organ failure. Full size image Table 1 Clinical characteristics of the 80 included patients. Full size table Therefore, in contrast with Acosta-Medina’s findings, our data show that patients without identifiable MAPK-ERK mutations can also benefit from MEKi. As compared with Acosta-Medina’s, our cohort was much larger. Additionally, our patients had a varied clinical phenotype and received MEKi at different lines of treatment, therefore reflecting everyday practice. Overall, our data further supports the current consensus recommendations [ 5 ] that consider empiric MEKi treatment a reasonable approach for patients without BRAF WT or other MAPK-ERK mutations, particularly among the most severe patients ( i.e ., central nervous system and/or heart involvements). Our study has limitations, as it focused on the assessment of response at three months, while it is necessary for a slowly progressive and chronic disease like ECD to have a long-term follow-up evaluation. In addition, long-term assessment of treatment-related toxicity is necessary. Finally, given the limited sample sizes, we could not assess differences in response between patients who received front-line MEKi and those who had previous lines of therapy. In conclusion, MEKi seem to be effective for ECD patients irrespective of the MAPK/ERK underlying mutations. Long-term follow-up studies are needed to carefully ascertain the safety and efficacy of such agents in ECD.