Diagnostic BRAFV600E blood predicts treatment failure and neurodegeneration and redefines paradigms of pediatric LCH

• Pediatric LCH patients with BRAFV600E PBMC at diagnosis are at highest risk of treatment failure and LCH-associated neurodegeneration

• We propose a shift from survival-based staging to risk of treatment failure based on extent of disease and peripheral BRAFV600E PBMC

Langerhans cell histiocytosis (LCH) is a myeloid neoplastic disorder driven by MAPK activation in hematopoietic cells. Historically, LCH has been staged according to involvement of "risk organs" (ROpos; bone marrow, liver, spleen), based on risk of death. With improvements in supportive care and efficacy of MAPK pathway inhibitors, LCH patients now rarely die. However, most LCH patients with multi-system 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 pre-therapy peripheral blood mononuclear cells (PBMC) and bone marrow on systemic and CNS outcomes in a cohort of 385 pediatric LCH patients and 115 adults, followed for a median of 4 years (0.02-18). Five year event-free survival was 50.7% for pediatric patients and 32.7% for adult LCH patients. In the pediatric cohort, presence of BRAFV600E PBMC was strongly associated with front-line treatment failure (hazard ratio 7.7). Remarkably, BRAFV600E PBMC at diagnosis also identified patients at the highest risk of developing LCH-ND (hazard ratio 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 (e.g. BRAFV600E PBMC).