BACKGROUND BRAF-V600E is the genetic lesion underlying hairy cell leukemia. We assessed the safety and activity of the oral BRAF inhibitor vemurafenib in patients with hairy cell leukemia who relapsed after or were refractory to purine analogues. METHODS We conducted in Italy and USA two phase-2 single-arm multicenter studies of vemurafenib (960 mg twice daily) given for a median of 16 and 18 weeks, respectively. Primary endpoints were complete remission rate and overall response rate. Patient enrollment was completed (n=28) in the Italian trial in April 2013 and is still open (n=26/36) in the American trial. RESULTS Drug-related adverse events were usually of grade 1-2, and those most frequently requiring dose reductions were rash and arthralgia/arthritis; secondary cutaneous tumors (treated with simple excision) developed in 6/50 patients. Overall response rates were 96% (25/26 evaluable Italian patients) and 100% (24/24 evaluable American patients), obtained after a median of 8 weeks and 12 weeks, respectively. Complete response rates were 34.6% (9/26) and 41.7% (10/24), respectively. In the Italian trial, after a median follow-up of 23 months, the median relapse-free and treatment-free survivals were respectively 19 and 25 months in complete responders, and 6 and 18 months in partial responders. In the American trial, 1-year progression-free and overall survival were 73% and 91%, respectively. Frequent persistence of phospho-ERK+ bone marrow leukemic cells at the end of treatment suggests bypass MEK-ERK reactivation as a resistance mechanism. CONCLUSIONS A short oral course of vemurafenib proved safe and highly effective in relapsed/refractory hairy cell leukemia patients (Funded by AIRC, ERC, Roche/Genentech and others; EudractCT number: 2011-005487-13, ClinicalTrials.gov number NCT01711632).

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