A Combination of Vemurafenib, Cytarabine and 2-chlorodeoxyadenosine in Children With LCH and BRAF V600E Mutation
Status:
Recruiting
Trial end date:
2021-12-01
Target enrollment:
Participant gender:
Summary
Langerhans cell histiocytosis (LCH) is a disease caused by clonal expansion, proliferation,
and dissemination of cells that are phenotypically close to Langerhans cells in different
tissues and organs. The clinical presentation of LCH varies greatly from one solid bone tumor
to multisystem lesion that involves liver, spleen and bone marrow.
The basis of LCH is the clonal proliferation of the pathological cells. These cells express
CD1a and CD207 markers on their surface and originate from myeloid progenitors. The main
event in life circle of these cells is the MEK-ERK cascade mutation. The most common mutation
is the substitution of valine for glutamic acid in position 600 of BRAF gene. The influence
of this mutation was confirmed by G.Badalyan-Very et al. in 2010. About 64% of all LCH are
caused by clonal proliferation due to BRAF V600E mutation.
Despite generally good results of therapy of monosystemic LCH, the treatment of LCH with risk
organs lesion is still a challenge: 5-years survival is as low as 40-50%.
Combination of cytarabine and 2-chlorodeoxyadenosine was supposed to improve the results, but
the cost was a very high toxicity, that limits the application of the regimen in patients
with severe infections.
Currently, there is a lot of information on BRAF V600E inhibitors in patients with LCH and
other histiocytic disorders. Most of them report the dramatic efficacy of BRAF V600E
inhibitors but after quick effect patients usually burden minimal disease activity ("plateau"
effect). However, discontinuation of the therapy results in quick disease reactivation.
Considering this a trial that combines targeted therapy (vemurafenib) and low-dose
chemotherapy (cytarabine and 2-chlorodeoxyadenosine) in order to achieve complete response
with manageable toxicity is proposed.
Phase:
Phase 2
Details
Lead Sponsor:
Federal Research Institute of Pediatric Hematology, Oncology and Immunology