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

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Heritier, Sébastien | Emile, Jean-François | Barkaoui, Mohamed-Aziz | Thomas, Caroline | Fraitag, Sylvie | Boudjemaa, Sabah | Renaud, Florence | Moreau, Anne | Peuchmaur, Michel | Chassagne-Clément, Catherine | Dijoud, Frédérique | Rigau, Valérie | Moshous, Despina | Lambilliotte, Anne | Mazingue, Françoise | Kebaili, Kamila | Miron, Jean | Jeziorski, Eric | Plat, Genevieve | Aladjidi, Nathalie | Ferster, Alina | Pacquement, Hélène | Galambrun, Claire | Brugières, Laurence | Leverger, Guy | Mansuy, Ludovic | Paillard, Catherine | Deville, Anne | Armari-Alla, Corinne | Lutun, Anne | Gillibert-Yvert, Marion | Stephan, Jean-Louis | Cohen-Aubart, Fleur | Haroche, Julien | Pellier, Isabelle | Millot, Frédéric | Lescoeur, Brigitte | Gandemer, Virginie | Bodemer, Christine | Lacave, Roger | Helias-Rodzewicz, Zofia | Taly, Valérie | Geissmann, Frederic | Donadieu, Jean

Edité par CCSD ; American Society of Clinical Oncology -

International audience. 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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