Disease extent, not lesion location, determines relapse risk in single-system skeletal Langerhans cell histiocytosis

ABSTRACT: Langerhans cell histiocytosis (LCH) confined to the skeleton has excellent survival, yet optimal management of multifocal bone disease and lesions at traditionally defined "special sites" remains uncertain due to limited prospective data. We report prospective results from an international pilot trial embedded within the Histiocyte Society LCH-III study (2001-2008) evaluating 6 months of vinblastine-prednisolone in children with single-system skeletal LCH. Among 455 enrolled patients, 381 were evaluable. Early response at week 6 was achieved in 83% of cases. Five-year overall survival was 100%, and event-free survival (EFS) was 71%. Multifocal bone lesions (MFB) were the dominant predictor of relapse (5-year EFS: 63% vs 87% without MFB; P< .001), whereas isolated central nervous system (CNS)-risk skeletal lesions did not independently affect EFS. In contrast, the cumulative incidence of central diabetes insipidus at 5 years was 5% overall but was significantly higher in patients with CNS-risk lesions, particularly when combined with MFB. These prospective data demonstrate that in single-system skeletal LCH, disease extent and lesion location confer distinct risks, with skeletal multiplicity determining relapse propensity, and anatomic location determining the risk of permanent endocrine sequelae. This study provides a prospective international benchmark for systemic therapy and supports risk-adapted treatment strategies that minimize long-term morbidity while avoiding unnecessary treatment escalation. This trial was registered at www.ClinicalTrials.gov as NCT00276757.