Vemurafenib combined with cladribine and cytarabine results in durable remission of pediatric BRAF V600E-positive LCH.

Langerhans cell histiocytosis (LCH) is a disorder with a variety of clinical signs. The most severe forms affect "risk organs" (RO). The established role of BRAF V600E mutation in LCH led to a targeted approach. However, the targeted therapy can't cure the disease and the cessation leads to quick relapses. In our study, we combined cytarabine (Ara-C) and 2'-chlorodeoxyadenosine (2-CdA) with targeted therapy to achieve stable remission. Nineteen children were enrolled in the study: 13 RO+ and 6 RO-. Five patients received the therapy upfront, while the other 14 - as the second or third line. The protocol starts with 28 days of vemurafenib (20 mg/kg) which is followed by 3 courses of Ara-C and 2-CdA (100 mg/m2/every 12 h, 6 mg/m2/day, Days 1-5) with concomitant vemurafenib therapy. After that, vemurafenib therapy was stopped, and 3 courses of mono 2-CdA followed. All patients rapidly responded to vemurafenib: the median DAS decreased from 13 to 2 points in the RO+ group and from 4.5 to 0 points in the RO- group on Day 28. All patients except one received complete protocol treatment, and 15 of them didn't have disease progression. The 2-year relapse-free survival (RFS) for RO+ was 76.9% with a median follow-up of 21 months and 83.3% with a median follow-up of 29 months for RO-. Overall survival is 100%. Importantly, 1 patient experienced secondary MDS (sMDS) after 14 months from vemurafenib cessation. Our study demonstrates that combined vemurafenib plus 2-CdA and Ara-C is effective in a cohort of children with LCH, and the toxicity is manageable. This trial is registered at www.clinicaltrials.gov as NCT03585686.