BRAF V600E-positive mononuclear cells in blood at diagnosis portend treatment failure and neurodegeneration in pediatric LCH.

Langerhans cell histiocytosis (LCH) is a myeloid neoplastic disorder driven by mitogen-activated protein kinase (MAPK) activation in hematopoietic cells. Historically, LCH has been staged according to involvement of "risk organs" (bone marrow, liver, and spleen), based on risk of death. With improvements in supportive care and efficacy of MAPK pathway inhibitors, patients with LCH now rarely die. However, most patients with LCH with multisystem disease are not cured with current front-line chemotherapy, and treatment failure is associated with long-term morbidity, including LCH-associated neurodegeneration (LCH-ND). In this study, we evaluated the impact of extent of LCH at presentation, tumor genotype, and BRAFV600E in pretherapy peripheral blood mononuclear cells (PBMCs) and bone marrow on systemic and central nervous system outcomes in a cohort of 385 pediatric patients with LCH and 115 adults with LCH, followed up for a median of 4 years (range, 0.02-18 years). Five-year event-free survival was 50.7% for pediatric patients and 32.7% for adult patients with LCH. In the pediatric cohort, presence of BRAFV600E PBMC was strongly associated with front-line treatment failure (hazard ratio [HR], 7.7). Remarkably, BRAFV600E PBMC at diagnosis also identified patients at the highest risk of developing LCH-ND (HR, 23.1). These findings support an updated model of pediatric LCH pathogenesis in which persistence of disease reservoir and cell of origin determine extent of disease and clinical risks. We, therefore, propose a major revision of pediatric LCH diagnostic staging, shifting from focus on historical risk of death to risks of systemic treatment failure and LCH-ND based on lesion location, lesion genotype, and peripheral LCH reservoir (eg, BRAFV600E PBMC).