Vemurafenib in Hairy-Cell Leukaemia

An alternative signalling pathway, as yet uncharacterised, may be affected by vemurafenib

A team of scientists from the University of Leicester, UK published on 16 January 2014 in the New England Journal of Medicine, findings that indicate that vemurafenib, a BRAF inhibitor that has been approved as a treatment for advanced melanomas, cleared the malignant cells from the blood of patient with hairy-cell leukaemia (HCL) who had exhausted all other treatment options. The treatment with vemurafenib led to a complete clinical recovery in a number of days.

The study was led by the University of Leicester and involved treatment of a patient at the Leicester Royal Infirmary. Through a genetic study of the patient's blood cells the research team identified a mutation in the BRAF gene. This knowledge enabled them to combat the disease with vemurafenib, which has had proven success as a BRAF inhibitor in melanomas. 

Leicester University

Left to right - This shows PhD student Jesvin Samuel, Dr Salvador Macip and Professor Martin Dyer.

©University of Leicester

According to the NEJM article, the BRAF V600E mutation is present in nearly all cases of HCL. This finding has led to the introduction of BRAF inhibitors for the treatment of chemotherapy-resistant HCL, and patients have had a good response to the oral inhibitor vemurafenib. Until now constitutive phosphorylation of both ERK and MEK has been considered to be a direct consequence of BRAF activation, with BRAF inhibition resulting in cell death through suppression of this pathway in HCL. However, data to support this theory are limited, since most patients present with pancytopenia. 

The research team evaluated a patient with purine analogue–refractory HCL who had biallelic BRAF V600E mutations and a high leukaemic burden during treatment with vemurafenib. Because of the high numbers of circulating HCL cells, it was possible to study the effects of vemurafenib directly in vivo. Vemurafenib induced complete clinical remission with reduction of the viability of CD103+ HCL cells during therapy. 

However, BRAF inhibition was not associated with any major changes in phosphorylation of either MEK or ERK in vivo, as shown by means of both immunoblot and flow cytometry, despite prolonged exposure to vemurafenib. According to Dr Salvador Macip from the University of Leicester's Department of Biochemistry, "what was most surprising was that the drug did not work in the way we expected it to. Whilst it successfully blocked BRAF and killed the cancerous cells, there was no ability to block the downstream cascade of signals.”

An alternative signalling pathway, as yet uncharacterised, may therefore be affected by vemurafenib, either directly or through BRAF inhibition, and it may have a strong impact in HCL cell survival in vivo.

The data from this study have implications for the design of possible combination treatments.


Samuel J, Macip S, Dyer M. Efficacy of Vemurafenib in Hairy-Cell Leukemia. N Engl J Med 2014; 370:286-288. doi: 10.1056/NEJMc1310849