Standard treatment for Langerhans Cell Histiocytosis (LCH) is chemotherapy, with high failure rates. Since MAP-kinase activating mutations are found in most cases, BRAF- and MEKinhibitors have been used successfully to treat patients with refractory or relapsed disease. However, data on long-term responses in children are limited and no data exist on their use as first-line therapy. We treated thirty-four patients (26 LCH, 2 Juvenile Xanthogranuloma, 2 Rosai-Dorfman Disease, 4 presumed single site-CNS histiocytosis) with either dabrafenib and/or trametinib, either as first line or after relapse or failure of chemotherapy. Sixteen patients aged 1.3-21 years, had disease that was recurrent or refractory to chemotherapy, 9 of whom had multisystem LCH with risk-organ involvement. With a median treatment duration of 4.3 years, 15 (94%) patients have sustained favorable responses. Eighteen patients aged 0.2-45 years received the inhibitor as first-line treatment. All of these have had sustained favorable responses, with a median treatment duration of 2.5 years. Three patients with presumed isolated CNS/pituitary-stalk histiocytosis demonstrated stabilization or improvement of disease. Overall, inhibitors were well tolerated. Five patients with single system LCH discontinued therapy and remain off therapy without recurrence. In contrast, all 4 patients with multisystem disease that discontinued therapy were restarted. Our data suggest that children suffering from histiocytoses can be treated safely, and effectively with dabrafenib or trametinib. Additional studies are needed however to determine the long term safety and optimal duration of therapy.
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