The results of a study on the effectiveness 37 and safety of treatment with vemurafenib and cytarabine/2-chloro-2′-deoxyadenosine combination in patients with Langerhans cell histiocytosis with <i>BRAFV600E</i> mutation

Here, we report on a new treatment protocol for patients with BRAF-positive Langerhans cell histiocytosis (LCH). To achieve remission in the affected patients, we used vemurafenib (a targeted drug) in combination with cytarabine (Ara-C) and cladribine (2-CdA). The study included 27 patients: 18 children with multisystem LCH with risk organ involvement (RO+) and 9 – with multisystem LCH without risk organ involvement (RO–). The treatment started with a 28-day cycle of vemurafenib, with subsequent discontinuation. On Day 29, Аra-C + 2-СdA chemotherapy cycle № 1 was initiated. Vemurafenib treatment was again started on Day +1 after the Ara-C + 2-CdA cycle. The interval between the cycles was 28 days. Similarly, the next two Аra-C + 2-СdA chemotherapy cycles (№ 2 and № 3) were carried out. Then therapy with vemurafenib was stopped and 3 cycles of 2-CdA were administered. All the patients responded to the treatment quickly: on Day 28, disease activity score decreased from 15 to 2 in the RO+ group and from 4 to 0 in the RO– group. The two-year relapse-free survival in the RO+ group was 82 % (95 % confidence interval 66–100), and 89 % (95 % confidence interval 71–100) in the RO– patients. The overall survival in both groups was 100 %. Our study demonstrates the safety and effectiveness of the treatment with vemurafenib and intermediate-dose 2-CdA and Ara-C in children with multisystem RO+ and refractory LCH. This prospective non-randomized multicenter study was approved by the Independent Ethics Committee (Minutes No. 3e/1-18) and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation. It is registered at clinicaltrials.gov under the number NCT03585686. The first patient was enrolled on 22 June 2018, the data collection was stopped on 30 April 2023.