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

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.

Fig 1.

Study cohort selection. LCH, Langerhans cell histiocytosis.

Fig 2.

Clinical presentation, disease extent, and disease severity, according to BRAF status. (A) Prevalence of mutant BRAF among patients with Langerhans cell histiocytosis (LCH), according to sex, age at diagnosis, organ involvement, and extent of disease. For age, sex, and involvement of individual organs, the significance was based on comparisons between patients with and without the characteristic. For the extent of disease [lung involvement (Lung+); multiple system (MS); risk organ involvement (RO+); no risk organ involvement (RO−); single system (SS)], the significance was based on comparisons between the all four categories. (B) Prevalence of BRAF mutation analyzed in subgroups of patients with LCH. Among patients with bone involvement (n = 262), BRAF^V600E prevalence was not different between patients with multifocal (54.3%) and those with unifocal (52.6%) bone lesions (P = .81). Among patients with skin lesions (n = 113), BRAF mutation was not observed in patients with localized skin lesions (solitary skin LCH), which was significantly different from the high prevalence among patients with multifocal skin lesions in SS LCH or skin lesions in MS LCH. (C) Maximum Disease Activity Score (DAS) measured during the clinical course for each patient is shown according to age at diagnosis and BRAF status. Blue symbols represent BRAF-mutated cases, and gold symbols represent BRAF wild-type (WT) cases. (Right) Distributions of disease severity are grouped according to three DAS ranges (≤ 2, 3 to 6, and > 6). These cutoff values are from previously published data that correlated DAS with LCH prognosis. P values in each panel were calculated by using Fisher’s exact test. Because multitests were performed, P < .002 was considered statistically significant. *P < .05; **P < .002.

Fig 3.

Outcome from Langerhans cell histiocytosis (LCH) according to BRAF status. (A) Cumulative incidence of reactivation curves. The green line shows the time (5 years) at which groups were compared. Boxes indicate percentages of reactivation observed in each group at that time. (B) Incidences of different types of permanent consequences (% indicates the patients in each subgroup/total patients with BRAF^V600E mutated LCH or wild-type (WT) BRAF LCH. BRAF status is indicated as mutated (BRAF) or WT. *P < .05; **P < .01.