LCH-III

International randomised trial (Gadner et al., Blood 2013), more than 400 patients randomised. In risk-organ-positive disease, adding methotrexate to vinblastine and prednisone did not change response, survival or reactivation; but 12 months of therapy gave 5-year survival of 84% against 62% and 69% in the identically stratified predecessor trials LCH-I and LCH-II, and reduced 5-year reactivation to 27% from 55% and 44%. In risk-organ-negative disease, 12 months of vinblastine-prednisone lowered 5-year reactivation to 37% versus 54% with 6 months (P = 0.03). One year of vinblastine-prednisone became the international standard and the backbone of LCH-IV, which tests further prolongation and the addition of 6-mercaptopurine. The trial predates the discovery that most LCH carries BRAF V600E or other MAPK mutations, which now drive targeted therapy for refractory disease.