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Vemurafenib for Refractory Multisystem Langerhans Cell Histiocytosis in Children: An International Observational Study

Jean Donadieu 1 Islam Amine Larabi 2 Mathilde Tardieu 3 Johannes Visser 4 Caroline Hutter 5 Elena Sieni 6 Nabil Kabbara 7 Mohamed Barkaoui 8 Jean Miron 9 François Chalard 10 Paul Milne 11 Julien Haroche 12 Fleur Cohen 13 Zofia Hélias-Rodzewicz 14 Nicolas Simon 15 Mathilde Jehanne 16 Alexandra Kolenova 17 Anne Pagnier 18 Nathalie Aladjidi 19 Pascale Schneider 20 Genevieve Plat 21 Anne Lutun 22 Anne Sonntagbauer 23 Thomas Lehrnbecher 23 Alina Ferster 24 Viktoria Efremova 25 Martina Ahlmann 26 Laurence Blanc 27 James Nicholson 11 Anne Lambilliote 28 Houda Boudiaf 29 Andrej Lissat 30 Karel Svojgr 31 Fanette Bernard 32 Sarah Elitzur 33 Michal Golan 34 Dmitriy Evseev 35 Michael Maschan 35 Ahmed Idbaih 36, 37 Olga Slater 38 Milen Minkov 39 Valérie Taly 40 Matthew Collin 41 Jean-Claude Alvarez 42 Jean-François Emile 14 Sébastien Héritier 43 
Abstract : 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.
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Jean Donadieu, Islam Amine Larabi, Mathilde Tardieu, Johannes Visser, Caroline Hutter, et al.. Vemurafenib for Refractory Multisystem Langerhans Cell Histiocytosis in Children: An International Observational Study. Journal of Clinical Oncology, American Society of Clinical Oncology, In press, pp.JCO.19.00456. ⟨10.1200/JCO.19.00456⟩. ⟨inserm-02299433⟩



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