<i>BRAF</i> 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).

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Journal
Blood
Published
2025-04-03
DOI
https://doi.org/10.1182/blood.2024026671
Citations
7
Primary Topic
Histiocytic Disorders and Treatments
Type
article
Field-Weighted Citation Impact
8.15
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article

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

Tsz‐Kwong Man, Carl E. Allen, Michael E. Scheurer, Kenneth L. McClain et al.
7 citations
Blood
Histiocytic Disorders and Treatments
8.15
article

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

Tsz‐Kwong Man, Carl E. Allen, Michael E. Scheurer, Kenneth L. McClain, Erin C. Peckham‐Gregory, Stephen J. Simko, Zachary D. Prudowsky, Akanksha Batajoo, Deborah Schiff, John Hicks, Nitya Gulati, Nader Kim El‐Mallawany, D. Williams Parsons, Harshal Abhyankar, Howard Lin, Choladda V. Curry, Ryan Fleischmann, Vivekanudeep Karri, Angshumoy Roy, Jennifer Picarsic, Kevin E. Fisher, Kenneth Heym, Daria Vakula, Brooks Scull, Miriam Mérad, Olive S. Eckstein, Jessica Velazquez, Daniel Zinn
article en
7 citations

Abstract

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).

BloodVol. 146(2)
Dartmouth–Hitchcock Medical Center (US), University of Pittsburgh (US), Baylor College of Medicine (US), Cornell University (US), University of California San Diego (US), Rady Children's Hospital-San Diego (US), Cook Children's Medical Center (US), Tisch Hospital (US), Children's Hospital of Pittsburgh (US), Children's Hospital at Dartmouth Hitchcock (US), Texas Children's Hospital (US), Children's Cancer Center (US), Baylor Genetics (US), Icahn School of Medicine at Mount Sinai (US)
Good health and well-being
Openalex Percentile: Top 2%
Histiocytic Disorders and Treatments
8.15
DOISourceOpenAlex
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