Efficacy of MAPK inhibitors in children with neurodegenerative Langerhans cell histiocytosis: Results from the European Consortium for Histiocytosis

Neurodegenerative Langerhans cell histiocytosis (ND‐LCH) is a severe and debilitating complication of LCH with no effective treatment. In this study, we assessed the efficacy of MAPK inhibitors (MAPKi) in a large cohort of children with ND‐LCH. We included pediatric patients with ND‐LCH who received MAPKi between 2013 and 2025. Clinical and radiological responses were evaluated using validated and newly developed scoring systems. We included 60 patients and assessed the response to MAPKi in 54 (clinical n = 53, radiological n = 54). Of the 53 clinically evaluable patients, 44 (83%) presented with symptoms (impaired global functioning n = 39, 74%; neurological manifestations n = 38, 72%; and psychiatric disturbances n = 27, 51%). MAPKi were started at a median of 25 months (interquartile range [IQR] 5–67) from ND diagnosis. Clinical responses were observed in 29 patients (55%), while the remaining showed disease stabilization ( n = 21, 39%) or progression ( n = 3, 6%). Of the 54 patients with magnetic resonance imaging (MRI) follow‐up, radiological improvement was documented in 40 (74%), while 12 (22%) demonstrated stable findings, and 2 (4%) showed progression. We observed significant improvements in both clinical (P < 0.001) and MRI abnormalities (P < 0.001). None of the nine asymptomatic patients developed symptoms, while MRI lesions improved in six of them. Positive responses occurred irrespective of baseline disease severity and treatment delay. Adverse events, evaluable in 60 patients, were reported in 31 of them (52%) but were generally not severe and manageable. In conclusion, we demonstrated robust efficacy of MAPKi in ND‐LCH, with an acceptable safety profile. These findings support a promising therapeutic approach that warrants prospective validation in this challenging condition.