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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 16 Eric Jeziorski 17 Genevieve Plat 18 Nathalie Aladjidi 19 Alina Ferster 20 Hélène Pacquement 21 Claire Galambrun 22 Laurence Brugières 23 Guy Leverger 24 Ludovic Mansuy 25 Catherine Paillard 26 Anne Deville 27 Corinne Armari-Alla 28 Anne Lutun 29 Marion Gillibert-Yvert 30 Jean-Louis Stephan 31 Fleur Cohen-Aubart 32 Julien Haroche 32 Isabelle Pellier 33 Frédéric Millot 34 Brigitte Lescoeur 35 Virginie Gandemer 36 Christine Bodemer 37 Roger Lacave 38 Zofia Helias-Rodzewicz 2 Valérie Taly 39 Frederic Geissmann 40 Jean Donadieu 24
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, American Society of Clinical Oncology, 2016, 34 (25), pp.3023-3030. ⟨10.1200/JCO.2015.65.9508⟩. ⟨inserm-02304878⟩



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