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

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, BRAF V600E) 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.