PURPOSE: Off-label use of vemurafenib (VMF) to treat BRAFV600E mutation-positive, refractory, childhood Langerhans cell histiocytosis (LCH) was evaluated. PATIENTS AND METHODS: Fifty-four patients from 12 countries took VMF 20 mg/kg/d. They were classified according to risk organ involvement: liver, spleen, and/or blood cytopenia. The main evaluation criteria were adverse events (Common Terminology Criteria for Adverse Events [version 4.3]) and therapeutic responses according to Disease Activity Score. RESULTS: LCH extent was distributed as follows: 44 with positive and 10 with negative risk organ involvement. Median age at diagnosis was 0.9 years (range, 0.1 to 6.5 years). Median age at VMF initiation was 1.8 years (range, 0.18 to 14 years), with a median follow-up of 22 months (range, 4.3 to 57 months), whereas median treatment duration was 13.9 months (for 855 patient-months). At 8 weeks, 38 complete responses and 16 partial responses had been achieved, with the median Disease Activity Score decreasing from 7 at diagnosis to 0 (P < .001). Skin rash, the most frequent adverse event, affected 74% of patients. No secondary skin cancer was observed. Therapeutic plasma VMF concentrations (range, 10 to 20 mg/L) seemed to be safe and effective. VMF discontinuation for 30 patients led to 24 LCH reactivations. The blood BRAFV600E allele load, assessed as circulating cell-free DNA, decreased after starting VMF but remained positive (median, 3.6% at diagnosis, and 1.6% during VMF treatment; P < .001) and was associated with a higher risk of reactivation at VMF discontinuation. None of the various empirical therapies (hematopoietic stem-cell transplantation, cladribine and cytarabine, anti-MEK agent, vinblastine, etc) used for maintenance could eradicate the BRAFV600E clone. CONCLUSION: VMF seemed safe and effective in children with refractory BRAFV600E-positive LCH. Additional studies are needed to find effective maintenance therapy approaches.

Azienda Ospedaliero Universitaria A Meyer Florence Italy

Cambridge University Hospitals Cambridge United Kingdom

Centre Hospitalier du Nord Zgharta Lebanon

Centre Hospitalier Universitaire d'Amiens Amiens France

Centre Hospitalier Universitaire de Bordeaux Bordeaux France

Centre Hospitalier Universitaire de Grenoble Grenoble France

Centre Hospitalier Universitaire de Lille Lille France

Centre Hospitalier Universitaire de Poitiers Poitiers France

Centre Hospitalier Universitaire de Rouen Rouen France

Centre Hospitalier Universitaire de Toulouse Toulouse France

Centre Hospitalier Universitaire Félix Guyon La Réunion France

Centre Hospitalier Universitaire La Pitié Salpêtrière Charles Foix Paris France

Centre Hospitalier Universitaire Pitié Salpêtrière Paris France

Centre Hospitalier Universitaire R Poincaré Garches France

Charité University Medicine Berlin Berlin Germany

Comenius University Children's Hospital Limbova 1 Bratislava Slovakia

Dmitriy Rogachev National Center for Pediatric Hematology Oncology and Immunology Moscow Russia

Great Ormond Street Hospital London United Kingdom

Hôpital Mustapha Mustapha Algeria

Hôpital Sainte Marguerite Marseille France

Hôpital Universitaire des Enfants Reine Fabiola Brussels Belgium

Hôpitaux Universitaires de Genève Geneva Switzerland

Medical University of Vienna Vienna Austria

Newcastle University Newcastle upon Tyne United Kingdom

Rafic Hariri University Hospital Beirut Lebanon

Schneider Children's Medical Center Petah Tikva Israel

The Edmond and Lily Safra Children's Hospital Tel Hahsomer Israel

Trousseau Hospital Paris France

Universitätsklinikum Frankfurt Frankfurt am Main Germany

Universitätsklinikum Münster Klinik für Kinder und Jugendmedizin Pädiatrische Hämatologie und Onkologie Münster Germany

Université Paris Saclay Boulogne Billancourt France

Université Paris Sorbonne Cité Paris France

University Hospital Minsk Belarus

University Hospital Motol Prague Czech Republic

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Clinicogenomic associations in childhood Langerhans cell histiocytosis: an international cohort study