Long-term off-label MAPK inhibitor therapy in children with severe/refractory Langerhans cell histiocytosis: An international observational study of 277 cases.

Abstract

10011 Background: Long-term off-label use of MAP kinase inhibitors (MAPKi) to treat, refractory childhood Langerhans cell histiocytosis (LCH) was evaluated within the European consortium for histiocytosis network ( www.echo-histio.net ). Methods: 277 patients from 26 countries treated with MAPKi were classified according to the clinical indication: refractory risk organ positive/negative (RO+/RO-), isolated lung destruction (Lung), sclerosing cholangitis (SC), neurodegeneration (ND), and diabetes insipidus (DI). 252 patients had received one or several lines of chemotherapies prior to MAPKi: VBL/steroids (n = 243) then 2CdA/AraC (n = 48), 2CdA alone (n = 52), clofarabine (n = 5), VCR/AraC (n = 70) before being considered refractory. The 25 treated front line by MAPKi were newborn with aggressive disease (n = 7), or had chronic manifestations like ND, SC or DI. BRAF V600E was detected in 95% of the cases. Results: Median age at diagnosis was 1.3 years. MAPKi indication was RO+ (n = 138); RO– (n = 72); Lung (n = 7); SC (n = 9), ND (n = 45), DI (n = 2). Median age at MAPKi onset was 2.3 years, with median follow-up of 3.5 years (IQR 1.6-5.9). Vemurafenib (n = 177), Dabrafenib (n = 105), Encorafenib (n = 3), Cobimetinib (n = 41), Tramatinib (n = 41), and Binimetinib (n = 1) were prescribed mainly in monotherapy, sometimes (n = 44) with various chemotherapies or HSCT (n = 5). The short-term response (before wk 8) varied from 98% in RO+ and RO-, to 30% in Lung to a null response in ND, DI and SC, although some long-term response (after 6 months) was observed in Lung and ND. Skin rash was the most frequent adverse event (AE), affecting 55% of patients. Other AEs were observed in 7 (cardiomyopathy n = 1, retinitis n = 6). Five tumors or malignancies were observed not related to MAPKi; only in patients heavily treated by 2CdA, AraC or Clofarabine. Six deaths were observed; 5-year survival was 98%. MAPKi discontinuation for 111 patients led to LCH 66 reactivations. None of the various empirical maintenance therapies used was able to prevent secondary reactivation. Among the 133 assessable patients free of ND at MAPKi initiation, ND was observed in 52 with a 5-year risk of 55%. In some cases, ND was reversible after MAPKi dose adaptation. Conclusions: MAPKi appeared quick, safe and effective in children with refractory LCH while the response to Lung, SC, DI and ND was limited or delayed. Further studies are needed to find effective maintenance therapy. ND should be monitored in the follow up of patients treated by MAPKi.