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BRAF Mutation Correlates With High-Risk Langerhans Cell Histiocytosis and Increased Resistance to First-Line Therapy

Sébastien Heritier 1 Jean-François Emile 2 Mohamed-Aziz Barkaoui 3 Caroline Thomas 4 Sylvie Fraitag 5 Sabah Boudjemaa 3 Florence Renaud 6 Anne Moreau 7 Michel Peuchmaur 8 Catherine Chassagne-Clément 9 Frédérique Dijoud 10 Valérie Rigau 11 Despina Moshous 12 Anne Lambilliotte 13 Françoise Mazingue 14 Kamila Kebaili 15 Jean Miron 1 Eric Jeziorski 16 Genevieve Plat 17 Nathalie Aladjidi 18 Alina Ferster 19 Hélène Pacquement 20 Claire Galambrun 21 Laurence Brugières 22 Guy Leverger 23 Ludovic Mansuy 24 Catherine Paillard 25 Anne Deville 26 Corinne Armari-Alla 27 Anne Lutun 28 Marion Gillibert-Yvert 29 Jean-Louis Stephan 30 Fleur Cohen-Aubart 31 Julien Haroche 31 Isabelle Pellier 32 Frédéric Millot 33 Brigitte Lescoeur 34 Virginie Gandemer 35 Christine Bodemer 36 Roger Lacave 37 Zofia Helias-Rodzewicz 2 Valérie Taly 38 Frederic Geissmann 39 Jean Donadieu 23 
8 EA_3102 - Pathologie pédiatrique
Hôpital Robert Debré, UPD7 - Université Paris Diderot - Paris 7 : EA3102, IFR02
Abstract : PURPOSE: Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia with a broad spectrum of clinical manifestations and outcomes in children. The somatic BRAF(V600E) mutation occurs frequently, but clinical significance remains to be determined. PATIENTS AND METHODS: BRAF(V600E) mutation was investigated in a French LCH cohort. We analyzed associations between mutation status and clinical presentation, extent of disease, reactivation rate, response to therapy, and long-term permanent sequelae. RESULTS: Among 315 patients with successfully determined BRAF status, 173 (54.6%) carried a BRAF(V600E) mutation. Patients with BRAF(V600E) manifested more severe disease than did those with wild-type BRAF. Patients with BRAF(V600E) comprised 87.8% of patients (43 of 49) with multisystem LCH with risk organ involvement (liver, spleen, hematology), 68.6% of patients (35 of 51) with multisystem LCH without risk organ involvement, 43.9% of patients (86 of 196) with single-system LCH, and 42.1% of patients (8 of 19) with lung-involved LCH (P < .001). BRAF(V600E) mutation was also associated with organ involvement that could lead to permanent, irreversible damage, such as neurologic (75%) and pituitary (72.9%) injuries. Compared with patients with wild-type BRAF, patients with BRAF(V600E) more commonly displayed resistance to combined vinblastine and corticosteroid therapy (21.9% v 3.3%; P = .001), showed a higher reactivation rate (5-year reactivation rate, 42.8% v 28.1%; P = .006), and had more permanent, long-term consequences from disease or treatment (27.9% v 12.6%; P = .001). CONCLUSION: In children with LCH, BRAF(V600E) mutation was associated with high-risk features, permanent injury, and poor short-term response to chemotherapy. Further population-based studies should be undertaken to confirm our observations and to assess the impact of BRAF inhibitors for this subgroup of patients who may benefit from targeted therapy.
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Submitted on : Thursday, October 3, 2019 - 3:32:06 PM
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Sébastien Heritier, Jean-François Emile, Mohamed-Aziz Barkaoui, Caroline Thomas, Sylvie Fraitag, et al.. BRAF Mutation Correlates With High-Risk Langerhans Cell Histiocytosis and Increased Resistance to First-Line Therapy. Journal of Clinical Oncology, 2016, 34 (25), pp.3023-3030. ⟨10.1200/JCO.2015.65.9508⟩. ⟨inserm-02304878⟩



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