BRAF inhibitor: targeted therapy in hairy cell leukemia.

In this issue of Blood, Dietrich et al report that the low-dose BRAF inhibitor, vemurafenib, is highly effective in refractory hairy cell leukemia. Despite enormous progress that has been made with purine nucleoside analogs as the initial treatment of patients with hairy cell leukemia, the relapse rate and eventual development of refractory disease mandate the continued search for effective new therapies. The discovery of the presence of the BRAF V600E mutation in the overwhelming majority of patients with classic hairy cell leukemia prompted the logical application of inhibitors of this oncogene for treating patients with relapsed or refractory disease. Extensive work had previously been done to define a dose and schedule of vemurafenib for the treatment of malignant melanoma. Encouraging results indicated that this agent produced responses in patients with melanoma, but relapse and resistance were frequently encountered. Likewise, studies using the same dose and schedule of vemurafenib in patients with hairy cell leukemia have recently shown that responses are observed, but unfortunately relapses are also routinely encountered. Simply extrapolating the dose and schedule of this agent based on treatment plans established for patients with malignant melanoma underestimates the need to design specific therapeutic intervention based on the biology of the target in the patient with leukemia. The current report provides important information on the dose-response relationship of vemurafenib in patients with refractory hairy cell leukemia, showing that the response rate and kinetics of response are independent of dosing. Furthermore, Dietrich et al show that abrogation of phosphorylation of extracellular signal-related kinase (ERK) as a downstream target was consistently observed with low-dose administration. Identification of a genomic target in patients with hairy cell leukemia with a potential pharmacodynamics end point enables a rational approach to optimizing treatment. In the figure, the BRAFV600E pathway results in the expression of phospho-ERK (pERK). In recurrent or resistant melanoma, it is postulated that the reexpression of pERK and abnormalities in the MAPK pathway may be involved in the pathogenesis of progressive disease. This pharmacodynamics end point will need to be further validated in other studies of hairy cell leukemia. Investigation of this oncogenic pathway will hopefully provide insight into new therapeutic strategies for treatment. Alternatively, other modalities may be incorporated into combination approaches to The activated BRAF pathway provides oncogenic signaling to the leukemic hairy cell through the MEK-ERK cascade. Vemurafenib is an inhibitor of BRAF in this pathway. The activity of pERK is reduced as a consequence of BRAF inhibition. The reduced pERK results in decreased cell proliferation. This is measured by immunohistochemical analysis and is used as a pharmacodynamics biomarker of BRAF inhibition. P, indicates a phospho-group; RTK, receptor tyrosine kinase. Professional illustration by Patrick Lane, ScEYEnce Studios.