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Authors' Contributions 1.JF -Substantial contributions to acquisition, analysis and interpretation of data, drafting the work, final approval of the version to be published and agreement to be accountable for all aspects of the work. 2.AO -Substantial contributions to the conception and design of the work, analysis and interpretation of data, revising it critically for important intellectual content, final approval of the version to be published and agreement to be accountable for all aspects of the work. 3.TP -Substantial contributions to the conception and design of the work, revising it critically for important intellectual content, final approval of the version to be published and agreement to be accountable for all aspects of the work. 4.SW -Substantial contributions to the conception and design of the work, analysis and interpretation of data, revising it critically for important intellectual content, final approval of the version to be published and agreement to be accountable for all aspects of the work. 5.AL -Substantial contributions to the conception and design of the work, revising it critically for important intellectual content, final approval of the version to be published and agreement to be accountable for all aspects of the work. 6.NL -Substantial contributions to the conception and design of the work, revising it critically for important intellectual content, final approval of the version to be published and agreement to be accountable for all aspects of the work. 7.AB -Substantial contributions to the conception and design of the work, revising it critically for important intellectual content, final approval of the version to be published and agreement to be accountable for all aspects of the work. 8.RP -Substantial contributions to the conception and design of the work, revising it critically for important intellectual content, final approval of the version to be published and agreement to be accountable for all aspects of the work. 9.LK -Substantial revising it critically for important intellectual content, final approval of the version to be published and agreement to be accountable for all aspects of the work. 10.SG -Substantial contributions to the conception and design of the work, revising it critically for important intellectual content, final approval of the version to be published and agreement to be accountable for all aspects of the work. 11.IP -Substantial contributions to the conception and design of the work, revising it critically for important intellectual content, final approval of the version to be published and agreement to be accountable for all aspects of the work. 12.IQ -Substantial contributions to revising it critically for important intellectual content, final approval of the version to be published and agreement to be accountable for all aspects of the work. 13.RJ -Substantial contributions to the conception and design of the work, revising it critically for important intellectual content, final approval of the version to be published and agreement to be accountable ...

BACKGROUND: Central nervous system Langerhans cell histiocytosis (CNS-LCH) brain involvement may include mass lesions and/or a neurodegenerative disease (LCH-ND) of unknown etiology. The goal of this study was to define the mechanisms of pathogenesis that drive CNS-LCH. METHODS: Cerebrospinal fluid (CSF) biomarkers including CSF proteins and extracellular BRAFV600E DNA were analyzed in CSF from patients with CNS-LCH lesions compared with patients with brain tumors and other neurodegenerative conditions. Additionally, the presence of BRAFV600E was tested in peripheral mononuclear blood cells (PBMCs) as well as brain biopsies from LCH-ND patients, and the response to BRAF-V600E inhibitor was evaluated in 4 patients with progressive disease. RESULTS: Osteopontin was the only consistently elevated CSF protein in patients with CNS-LCH compared with patients with other brain pathologies. BRAFV600E DNA was detected in CSF of only 2/20 (10%) cases, both with LCH-ND and active lesions outside the CNS. However, BRAFV600E+ PBMCs were detected with significantly higher frequency at all stages of therapy in LCH patients who developed LCH-ND. Brain biopsies of patients with LCH-ND demonstrated diffuse perivascular infiltration by BRAFV600E+ cells with monocyte phenotype (CD14+CD33+CD163+P2RY12−) and associated osteopontin expression. Three of 4 patients with LCH-ND treated with BRAF-V600E inhibitor experienced significant clinical and radiologic improvement. CONCLUSION: In LCH-ND patients, BRAFV600E+ cells in PBMCs and infiltrating myeloid/monocytic cells in the brain is consistent with LCH-ND as an active demyelinating process arising from a mutated hematopoietic precursor from which LCH lesion CD207+ cells are also derived. Therapy directed against myeloid precursors with activated MAPK signaling may be effective for LCH-ND.

Background Existing therapies for recurrent or refractory histiocytoses, including Langerhans cell histiocytosis (LCH), juvenile xanthogranuloma (JXG), and Rosai-Dorfman disease (RDD), have limited effectiveness. We report our experience with using clofarabine as therapy in children with recurrent or refractory histiocytic disorders, including LCH (11 patients), systemic JXG (4 patients), and RDD (3 patients). Methods Patients treated with clofarabine for LCH, JXG, or RDD by Texas Children’s Hospital physicians or collaborators between May 2011 and January 2013 were reviewed for response and toxicity. Results Patients were treated with a median of 3 chemotherapeutic regimens prior to clofarabine. Clofarabine was typically administered at 25 mg/m2/day for five days. Cycles were administered every 28 days for a median of six cycles (range: 2–8 cycles). Seventeen of eighteen patients are alive. All surviving patients showed demonstrable improvement after 2–4 cycles of therapy, with eleven (61%) complete responses, four (22%) partial responses, and two patients still receiving therapy. Five patients experienced disease recurrence, but three of these subsequently achieved complete remission. All patients with JXG and RDD had complete or partial response at conclusion of therapy. Side effects included neutropenia in all patients. Recurring but sporadic toxicities included prolonged neutropenia, severe vomiting, and bacterial infections. Conclusion Clofarabine has activity against LCH, JXG, and RDD in heavily pretreated patients, but prospective multi-center trials are warranted to determine long-term efficacy, optimal dosing, and late toxicity of clofarabine in this population.

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