BRAF inhibition in hairy cell leukemia with low dose vemurafenib

Sascha Dietrich, Andreas Pircher, Volker Endris, Frédéric Peyrade, Clemens-Martin Wendtner, George A. Follows, Jennifer Hüllein, Alexander Jethwa, Elena Ellert, Tatjana Walther, Xiyang Liu, Martin J.S. Dyer, Thomas Elter, Tilman Brummer, Robert Zeiser, Michael Hermann, Michael Herold, Wilko Weichert, Claire Dearden, Torsten Haferlach, Martina Seiffert, Michael Hallek, Christof von Kalle, Anthony D. Ho, Anita Gaehler, Mindaugas Andrulis, Michael Steurer and Thorsten Zenz

Key points

  • Low doses of the BRAF-inhibitor (BRAFi) vemurafenib are highly effective in refractory hairy cell leukaemia.

  • Abrogation of BRAF V600E induced ERK phosphorylation was consistently seen with 240 mg of vemurafnib bid.


The activating mutation of the BRAF serine/threonine protein kinase (BRAF V600E) is the key driver mutation in hairy-cell leukemia (HCL) suggesting opportunities for therapeutic targeting. We analyzed the course of 21 HCL patients treated with vemurafenib outside of trials with individual dosing regimens (240mg-1920mg/d; median treatment duration 90days). Vemurafenib treatment improved blood counts in all patients, with platelets, neutrophils and hemoglobin recovering within 28, 43, and 55 days (median). Complete remission was achieved in 40% (n=6/15 of evaluable patients) and median event free survival was 17 months. Response rate and kinetics of response were independent of vemurafenib dosing. Retreatment with vemurafenib led to similar response patterns (n=6). Pharmacodynamic analysis of BRAF V600E downstream targets showed that vemurafenib (480mg/d) completely abrogated ERK phosphorylation of hairy cells in vivo. Typical side effects also occurred at low dosing regimens. We observed the development of AML M6 in one patient and the course suggested disease acceleration triggered by vemurafenib. The PI3K hotspot mutation (E545K) was identified in the AML clone providing a potential novel mechanism for paradoxical BRAF activation. These data provide proof of dependence of HCL on active BRAF signaling. We provide evidence that anti-tumor and side effects are observed with 480mg vemurafenib, suggesting that dosing regimens in BRAF driven cancers could warrant reassessment in trials with implications for cost of cancer care.

  • Submitted November 19, 2015.
  • Accepted February 13, 2016.