Long-term MAPK inhibition of childhood refractory-Langerhans cell histiocytosis: an observational study on 288 patients

We evaluated long-term outcomes of 288 children with refractory-Langerhans cell histiocytosis (R-LCH) from 26 countries prescribed off-label mitogen-activated protein kinase inhibitors (MAPKis) according to clinical indications. MAPKi indications were: 148 R-risk-organ-positive (R-RO+), 67 R-RO-negative (R-RO-), 13 lung destruction (lung), 9 sclerosing cholangitis (SC), 49 neurodegeneration (ND) and 2 diabetes insipidus (DI). Median ages at diagnosis and MAPKi onset were 1.3 and 2.3 years, respectively, with median follow-up of 3.7 years (1166 person-years). Agents were mostly prescribed as monotherapies: 184 vemurafenib, 115 dabrafenib, 3 encorafenib, 42 cobimetinib, 45 trametinib and/or 1 binimetinib; followed 51 times by various chemotherapies or hematopoietic stem-cell transplantation, or combined anti-BRAF-anti-MEK 28 times. Short-term responses (<8 weeks) ranged from 98% (R-RO+ and R-RO-), to 30% (lung) to none (ND, DI and SC), although long-term lung and ND responses could be observed. Skin rash was the most frequent adverse event (~55%); 7 others were 1 cardiomyopathy and 6 retinitis. Five developed MAPKi-unrelated tumors. Nine patients died. Five-year survival was 98%. After 113 patients with R-LCH discontinued MAPKi, 69 experienced disease reactivation. None of the various empirical maintenance therapies were able to prevent secondary reactivation. Among the 143 assessable patients without ND-LCH at MAPKi onset, 60 developed ND: 45% 5-year risk. MAPKis appeared to be safe and effective in children with R-RO+/RO-LCH, while other indications' responses were less frequent or occurred later. Further studies are needed to find effective maintenance-therapy approaches, particularly to prevent frequently observed secondary ND.