Langerhans cell histiocytosis: NACHO update on progress, chaos, and opportunity on the path to rational cures

Kevin Bielamowicz, Department of Pediatrics, College of Medicine at the University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
Peter Dimitrion, Center for Cutaneous Biology and Immunology, Henry Ford Health, Detroit, Michigan, USA.
Oussama Abla, Division of Hematology/Oncology, Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada.
Simon Bomken, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
Patrick Campbell, Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
Matthew Collin, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
Barbara Degar, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Eli L. Diamond, Departments of Neurology and Medicine, Memorial Sloan Kettering Center, New York, New York, USA.
Olive S. Eckstein, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
Nader El-Mallawany, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
Mark Fluchel, Division of Pediatric Hematology/Oncology, Department of Pediatrics, Seattle Children's Hospital and University of Washington School of Medicine, Seattle, Washington, USA.
Gaurav Goyal, Division of Hematology-Oncology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Michael M. Henry, Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, Arizona, USA.
Michelle Hermiston, Department of Pediatrics, University of California, San Francisco, San Francisco, California, USA.
Michael Hogarty, Division of Hematology and Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Michael Jeng, Department of Pediatrics, Pediatric Hematology/Oncology, Lucile Packard Children's Hospital, Stanford University, Palo Alto, California, USA.
Rima Jubran, Division of Pediatric Hematology/Oncology, Children's Hospital Los Angeles, Los Angeles, California, USA.
Joseph Lubega, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
Ashish Kumar, Division of Bone Marrow Transplant and Immune Deficiency, University of Cincinnati College of Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Stephan Ladisch, Center for Cancer and Immunology Research, Children's National Medical Center and George Washington University School of Medicine, Washington, District of Columbia, USA.
Kenneth L. McClain, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
Miriam Merad, Marc and Jennifer Lipschultz Precision Immunology Institute, New York, New York, USA.
Qing-Sheng Mi, Center for Cutaneous Biology and Immunology, Henry Ford Health, Detroit, Michigan, USA.
D Williams Parsons, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
Erin Peckham-Gregory, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
Jennifer Picarsic, University of Cincinnati College of Medicine and Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Zachary D. Prudowsky, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
Barrett J. Rollins, Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Peter H. Shaw, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Birte Wistinghausen, Center for Cancer and Immunology Research, Children's National Medical Center and George Washington University School of Medicine, Washington, District of Columbia, USA.
Carlos Rodriguez-Galindo, Department of Global Pediatric Medicine and Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
Carl E. Allen, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.

Document Type

Journal Article

Publication Date

4-30-2024

Journal

Cancer

DOI

10.1002/cncr.35301

Keywords

Langerhans cell histiocytosis; clinical trials; mitogen‐activated protein kinase (MAPK) pathway; myeloid neoplasia

Abstract

Langerhans cell histiocytosis (LCH) is a myeloid neoplastic disorder characterized by lesions with CD1a-positive/Langerin (CD207)-positive histiocytes and inflammatory infiltrate that can cause local tissue damage and systemic inflammation. Clinical presentations range from single lesions with minimal impact to life-threatening disseminated disease. Therapy for systemic LCH has been established through serial trials empirically testing different chemotherapy agents and durations of therapy. However, fewer than 50% of patients who have disseminated disease are cured with the current standard-of-care vinblastine/prednisone/(mercaptopurine), and treatment failure is associated with long-term morbidity, including the risk of LCH-associated neurodegeneration. Historically, the nature of LCH-whether a reactive condition versus a neoplastic/malignant condition-was uncertain. Over the past 15 years, seminal discoveries have broadly defined LCH pathogenesis; specifically, activating mitogen-activated protein kinase pathway mutations (most frequently, BRAFV600E) in myeloid precursors drive lesion formation. LCH therefore is a clonal neoplastic disorder, although secondary inflammatory features contribute to the disease. These paradigm-changing insights offer a promise of rational cures for patients based on individual mutations, clonal reservoirs, and extent of disease. However, the pace of clinical trial development behind lags the kinetics of translational discovery. In this review, the authors discuss the current understanding of LCH biology, clinical characteristics, therapeutic strategies, and opportunities to improve outcomes for every patient through coordinated agent prioritization and clinical trial efforts.

Department

Pediatrics

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