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

Abstract

International audiencePurpose 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. © 2016 by American Society of Clinical Oncology

How I manage pulmonary Langerhans cell histiocytosis

“…In children with LCH, the BRAF V600E mutation is associated with an increased risk of recurrence in systemic LCH, a high-risk disease (with risk organs) with increased resistance to first-line therapy [76,83].…”

Pulmonary Langerhans' Cell Histiocytosis in Adults

“…Basing on extrapolated observations made during randomised trials in children, various types of cytoreductive therapy (methotrexate, vinblastine, 6 mercaptopurine, etoposide) have been applied in adult LCH patients [3,[42][43][44][45][46][47][48][49]. However, the disease in adults runs a diverse clinical course and many drugs are differently tolerated.…”

“…The researches conducted among French LCH children have shown that detection of BRAF mutation was associated with a weaker response not only to the first-line treatment (vinblastine and steroids) but also a weaker response to a second-line treatment and a higher proportion of recurrence [16,19,49].…”

Adult-onset Langerhans cell histiocytosis of the sternum

“…Howarth et al reported that among all the patients with bone lesions included in their study, the most frequent osseous invasion sites were the skull (29.9%), proximal femur (12.4%), and ribs (11.1%) (7). Conversely, only 2/314 cases (0.6%) invaded the sternum; other involved organs included the skin (36.9-39%), lymph nodes (19%), liver (16%), spleen (13%), oral mucosa (13%), lung (10-14%), and central nervous system (6-16%) (7)(8)(9). Other symptoms of LCH reported were relatively nonspecific, including dyspnea (14%), malaise, painful scalp lump (9%), spontaneous pneumothorax (7%), and/or diabetes insipidus (6%) (7).…”