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BRAF Mutation Correlates With High-Risk Langerhans Cell Histiocytosis and Increased Resistance to First-Line Therapy
Sébastien Héritier1, Jean-François Emile1, Mohamed-Aziz Barkaoui1
1Sébastien 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 Peuchmaur, Université Paris Diderot, Sorbonne Paris Cité; Hélène Pacquement, Institut Curie Medical Center; Guy Leverger, Université Pierre et Marie Curie; Fleur Cohen-Aubart and Julien Haroche, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris; Roger Lacave, Tenon Hospital, Assistance Publique-Hôpitaux de Paris; Valérie Taly, Institut National de la Santé et de la Recherche Médicale, Unités Mixte de Recherche S1147, Centre National de la Recherche Scientifique SNC 5014, Université Paris Sorbonne Cité, Paris; Sébastien Héritier, Jean-François Emile, Zofia Hélias-Rodzewicz, and Jean Donadieu, Université de Versailles Saint-Quentin-en-Yvelines, Université Paris-Saclay; Jean-François Emile, Ambroise Paré Hospital, Assistance Publique-Hôpitaux de Paris, Boulogne-Billancourt; Caroline Thomas and Anne Moreau, Centre Hospitalo-Universitaire de Nantes, Nantes; Florence Renaud, Centre Hospitalier Régional Universitaire, Université de Lille; Anne Lambilliotte and Françoise Mazingue, Centre Hospitalo-Universitaire de Lille, Lille; Catherine Chassagne-Clément, Centre Léon Bérard; Frédérique Dijoud, Hôpital Femme-Mère-Enfant, Hospices Civils de Lyon; Kamila Kebaili, Institut d'Hémato-Oncologie Pediatrique, Lyon; Valérie Rigau, Gui de Chauliac Hospital; Eric Jeziorski, Hôpital Arnaud de Villeneuve, Montpellier; Geneviève Plat, Centre Hospitalo-Universitaire de Toulouse, Toulouse; Nathalie Aladjidi, Centre Hospitalo-Universit
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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