<i>BRAF</i> V600E-positive mononuclear cells in blood at diagnosis portend treatment failure and neurodegeneration in pediatric LCH
Abstract
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).
Article Details
Authors (28)
Howard Lin
1Department of Genetics and Genomics, Baylor College of Medicine, Houston, TX
Akanksha Batajoo
2Section of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX
Erin Peckham-Gregory
2Section of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX
Daniel Zinn
2Section of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX
Olive S. Eckstein
2Section of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX
Nader Kim El-Mallawany
2Section of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX
Nitya Gulati
Zachary D. Prudowsky
2Section of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX
Brooks Scull
2Section of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX
Jessica Velazquez
2Section of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX
Harshal Abhyankar
2Section of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX
Stephen J. Simko
2Section of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX
Daria Vakula
2Section of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX
Ryan Fleischmann
2Section of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX
Vivekanudeep Karri
2Section of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX
M. John Hicks
8Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX
Kevin E. Fisher
8Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX
Choladda V. Curry
8Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX
Angshumoy Roy
1Baylor College of Medicine, Pathology & Immunology, Houston, United States
Deborah Schiff
6Rady Children's Hospital and the University of California San Diego, San Diego, United States
Kenneth M. Heym
11Department of Pediatric Hematology and Oncology, Cook Children’s Medical Center, Fort Worth, TX
Michael E. Scheurer
D. Williams Parsons
1Department of Genetics and Genomics, Baylor College of Medicine, Houston, TX
Miriam Merad
Tsz-Kwong Man
2Section of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX
Kenneth L. McClain
12Section of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX
Jennifer Picarsic
3Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
Carl E. Allen
6Texas Children’s Cancer and Hematology Center, Texas Children’s Hospital, Houston, TX