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

Author:

Héritier Sébastien1,Emile Jean-François1,Barkaoui Mohamed-Aziz1,Thomas Caroline1,Fraitag Sylvie1,Boudjemaa Sabah1,Renaud Florence1,Moreau Anne1,Peuchmaur Michel1,Chassagne-Clément Catherine1,Dijoud Frédérique1,Rigau Valérie1,Moshous Despina1,Lambilliotte Anne1,Mazingue Françoise1,Kebaili Kamila1,Miron Jean1,Jeziorski Eric1,Plat Geneviève1,Aladjidi Nathalie1,Ferster Alina1,Pacquement Hélène1,Galambrun Claire1,Brugières Laurence1,Leverger Guy1,Mansuy Ludovic1,Paillard Catherine1,Deville Anne1,Armari-Alla Corinne1,Lutun Anne1,Gillibert-Yvert Marion1,Stephan Jean-Louis1,Cohen-Aubart Fleur1,Haroche Julien1,Pellier Isabelle1,Millot Frédéric1,Lescoeur Brigitte1,Gandemer Virginie1,Bodemer Christine1,Lacave Roger1,Hélias-Rodzewicz Zofia1,Taly Valérie1,Geissmann Frédéric1,Donadieu Jean1

Affiliation:

1. Sébastien Héritier, Mohamed-Aziz Barkaoui, Jean Miron, and Jean Donadieu, French Reference Center for Langerhans Cell Histiocytosis, Trousseau Hospital; Sébastien Héritier, Sabah Boudjemaa, Guy Leverger, and Jean Donadieu, Trousseau Hospital, Assistance Publique–Hôpitaux de Paris; Sylvie Fraitag, Despina Moshous, and Christine Bodemer, Necker Hospital, Assistance Publique–Hôpitaux de Paris; Michel Peuchmaur and Brigitte Lescoeur, Robert Debré Hospital, Assistance Publique–Hôpitaux de Paris; Michel...

Abstract

Purpose Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia with a broad spectrum of clinical manifestations and outcomes in children. The somatic BRAFV600E mutation occurs frequently, but clinical significance remains to be determined. Patients and Methods BRAFV600E 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 BRAFV600E mutation. Patients with BRAFV600E manifested more severe disease than did those with wild-type BRAF. Patients with BRAFV600E 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). BRAFV600E 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 BRAFV600E 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, BRAFV600E 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.

Publisher

American Society of Clinical Oncology (ASCO)

Subject

Cancer Research,Oncology

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