ISSN 1866-8836
Клеточная терапия и трансплантация

PO-03. Targeted therapy for treatment of Langerhans cell histiocytosis reactivation in pediatric patients without “risk organ” involvement

Evgeniy A. Burtsev, Gleb O. Bronin            

Morozov City Children’s Hospital, Moscow, Russia

Contact: Dr. Evgeniy A. Burtsev, phone: +7 (916) 589-90-69, e-mail:

doi 10.18620/ctt-1866-8836-2023-12-3-1-176


Our aim was to evaluate the efficacy and toxicity profile of BRAF- and MEK-inhibitors for the treatment of Langerhans cells histiocytosis (LCH) reactivation in children without involvement of the “risk organs” (RO), i.e., liver, spleen and hematopoietic system.

Patients and methods

The study included 13 patients with established LCH reactivation after completion of the protocol therapy. Before administration of the targeted therapy, Sanger sequencing was performed to verify BRAF V600E mutation in all cases. Based on the results of gene sequencing, all patients were divided into 2 groups: patients who have BRAF V600E mutation (BRAF+) and patients without BRAF V600E mutation (BRAF-). BRAF+ patients were treated with the BRAF-inhibitor vemurafenib. BRAF- patients were treated with MEK-inhibitor cobimetinib. There were 6 patients in BRAF+ group. Two of them initially had a single-system LCH (SS-LCH), four of them exhibited multisystem LCH features (MS-LCH). The duration of treatment was six months for SS-LCH and 12 months for MS-LCH. Vemurafenib was administered in all cases at a dose of 20 mg/kg/day orally as monotherapy. Seven patients were included in the BRAF- group. MS-LCH was initially detected in three cases, four of them had SS-LCH. The duration of treatment was 6 months in all cases. Cobimetinib was administered as a monotherapy per os at a dose of 1 mg/kg/day. All patients of this group were additionally tested by NGS sequencing for other possible pathogenic variants. In 5 cases, mutations in MAP2K1 gene were detected (p.Q58_E62del in 3 patients; p.K57_G61del, in 1 patient; p.Q56_G61delinsR, in 1 case). Response assessment in both groups was performed with RECIST V1.1 (Response Evaluation Criteria in Solid Tumors) score. Toxicity assessment was carried out in accordance to the CTCAE v5.0 (Common Terminology Criteria for Adverse Events) score.


Five out of six patients achieved partial response (PR) in the BRAF+ group. There were no cases of progressive disease (PD) and no cases of grade 3-4 toxicity according to CTCAE V5.0 in this group. The most common side effect was photodermatitis detected in 3 patients. The skin toxicity was successfully resolved in all these cases after dose modification and topical treatment. PD within a three-month period after termination of the vemurafenib was seen in 2 children. In these cases, the treatment of reactivation included vemurafenib combined with chemotherapy. In the BRAF- group the PR was achieved in 4 out of 7 cases. No cases of PD were observed during the treatment. Usage of cobimetinib was associated with a high incidence of grade 1-2 toxicity assessed by CTCAE V5.0. Six out of seven patients encountered at least one form of toxicity. Diarrhea was noted in 6 patients, and skin rash in 4 patients, being the most common adverse effects. One case of grade 4 toxicity was recorded in the study, most likely, due to the individual drug intolerance. In this patient, cobimetinib was switched to another MEK-inhibitor trametinib without subsequent toxicity. PD after discontinuation of cobimetinib treatment was observed in 4 patients. In all cases of PD, the targeted therapy was resumed in combination with chemotherapy.


The use of targeted therapy allowed to achieve PR in 5 out of 6 patients in the BRAF+ group and in 4 out of 7 patients in the BRAF- group. PD was observed in two patients in the BRAF+ group after completion of the targeted therapy (median follow-up – 34 months). In the BRAF- group, reactivation of the disease was diagnosed in 4 patients (median follow-up was 37 months). In all cases of reactivation, appropriate targeted treatment was resumed in combination with chemotherapy.


Histiocytosis, targeted therapy, vemurafenib, cobimetinib.

Supplement 12-3

Download PDF version

doi 10.18620/ctt-1866-8836-2023-12-3-1-176

Back to the list