BRAF Inhibition Successful in Relapsed/Refractory BRAF V600E–Mutant Hairy Cell Leukemia


Key Points

  • Vemurafenib treatment produced responses in nearly all patients.
  • Median relapse-free survival was 19 and 6 months in patients with complete and partial responses in the Italian study; 1-year progression-free survival was 73% in the U.S. study.

In two phase II studies reported in The New England Journal of Medicine, Tiacci et al found that the BRAF inhibitor vemurafenib (Zelboraf) produced responses in nearly all patients with BRAF V600E–positive hairy cell leukemia who relapsed after treatment with a purine analog or who had disease refractory to purine analogs.

Study Details

In two single-group multicenter studies, 26 evaluable patients in Italy and 24 in the United States received vemurafenib 960 mg twice daily. Patients in both studies had received a median of three prior therapies, and 56% and 41% had disease refractory to their most recent therapy. Vemurafenib was given for a median of 16 weeks in the Italian study and 18 weeks in the U.S. study. The primary endpoints were complete response rate in the Italian study and overall response rate in the U.S. study.


Overall response rates were 96%, including complete response in 35%, after a median of 8 weeks in the Italian study and 100%, including complete response in 42%, after a median of 12 weeks in the U.S. study. After a median follow-up of 23 months in the Italian study, median relapse-free survival was 19 months in patients with complete response and 6 months in those with partial response, and median treatment-free survival was 25 and 18 months. In the U.S. trial, progression-free survival was 73%, and overall survival was 91% at 1 year.

Persistence of phosphorylated ERK-positive leukemic cells in bone marrow was frequently observed at the end of treatment, suggesting that bypass reactivation of MEK and ERK could be a resistance mechanism.

Adverse Events

The most common drug-related adverse events of any grade were rash/erythema (46% and 62% in the two studies) and arthralgia/arthritis (43% and 31%). Secondary cutaneous tumors, which were treated with simple excision occurred in 7 (14%) of the 50 patients.

The most common treatment-related grade 3 events were rash/erythema (7%), arthralgia/arthritis (7%), and pancreatitis (7%) in the Italian study and rash/erythema (19%), photosensitivity reaction (8%), alkaline phosphatase elevation (8%), and asthenia (8%) in the U.S. study; no grade 4 events were observed. Dose reductions were required in 58% and 50% of patients, usually due to rash or arthralgia/arthritis.

The investigators concluded: “A short oral course of vemurafenib was highly effective in patients with relapsed or refractory hairy cell leukemia.”

Brunangelo Falini, MD, of the University of Perugia, is the corresponding author of The New England Journal of Medicine article.

Enrico Tiacci, MD, of the University of Perugia, and Jae H. Park, MD, of Memorial Sloan Kettering Cancer Center, and Dr. Falini, Omar Abdel-Wahab, MD, of Memorial Sloan Kettering Cancer Center, and Martin S. Tallman, MD, of Memorial Sloan Kettering Cancer Center, contributed equally to The New England Journal of Medicine article.

The study was funded by Associazione Italiana per la Ricerca sul Cancro and others. For full disclosures of the study authors, visit

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