The BRAF Inhibitor Vemurafenib “Highly Effective” in Relapsed/Refractory Hairy-Cell Leukemia

The oral BRAF inhibitor vemurafenib produced high overall response rates, with mild toxicity, in patients with relapsed or refractory hairy-cell leukemia, according to a report from two phase II studies published in The New England Journal of Medicine.

Though purine analogues (such as cladribine and pentostatin) induce durable complete responses in approximately 80 percent of patients with this cancer, the authors, led by Enrico Tiacci, MD, from the University of Perugia in Italy, explained that 30 to 50 percent of patients eventually relapse and experience a progressively worse response to these drugs.

Previous research has shown that the V600E mutation of BRAF is a key genetic lesion of hairy-cell leukemia leading, in part, to the development of the BRAF inhibitor vemurafenib. To test the safety and efficacy of this oral medication, Dr. Tiacci and colleagues conducted two phase II, multicenter clinical trials (one in Italy, the other in the United States) in patients with relapsed or refractory hairy-cell leukemia.

Patients received oral vemurafenib (960 mg twice-daily) for a minimum of eight weeks and up to 16 weeks (in the Italian trial) or 12 weeks (in the U.S. trial).

The Italian trial enrolled 28 patients; 26 patients completed the planned treatment course, with a median treatment duration of 16 weeks (range = 8-20 weeks). Twenty-six patients had been enrolled in the U.S. trial (out of a planned enrollment of 36 patients) at the time the paper was published; though enrollment was ongoing, the primary endpoint of overall response rate (ORR; including complete and partial responses) had already been met, the authors noted.

After a median follow-up of 23 months in the Italian trial and 11.7 months in the U.S. trial, the ORRs were 96 percent and 100 percent, respectively.

“The rates of complete response [CR] were similar in the two trials, as were the rates of partial response [PR],” Dr. Tiacci and colleagues wrote. “In the Italian study, after a median of eight weeks, 35 percent of the patients (9 of 26) had a CR and 62 percent (16 of 26) had a PR. In the U.S. trial, after 12 weeks of vemurafenib treatment, 42 percent of the patients (10 of 24 patients) had a CR and 58 percent (14 of 24) had a PR.”

These responses were rapid, with a median time to response of 8 weeks in the Italian trial and 12 weeks in the U.S. trial, the authors added.

The median treatment-free survival was 21.5 months in the evaluable 26 patients in the Italian trial, while the median relapse-free survival was nine months. Patients who had a CR had significantly longer relapse-free survival than patients who had a PR (19 months vs. 6 months; hazard ratio [HR] for relapse = 0.26; 95% CI 0.10-0.68; p=0.006).

At one year, the rate of progression-free survival among patients in the U.S. trial was 73 percent (95% CI 55-97), and the rate of overall survival was 91 percent (95% CI 79-99). Seven of the 24 patients had progressive disease, including three patients who had a CR and four who had a PR.

The most common vemurafenib-related adverse events (AEs) were mostly mild (grade 1 or 2) and were all reversible; these included rash, photosensitivity, arthralgias or arthritis, pyrexia, and an elevated bilirubin level.

However, multiple patients developed carcinomas, including three cases of cutaneous basal-cell carcinomas (2 Italian, 1 U.S.), one case of cutaneous superficial melanoma, and three cases of cutaneous squamous-cell carcinoma. “All these tumors were managed by simple excision,” the authors wrote.

In the Italian trial, toxicities led to vemurafenib-dose reductions for at least three weeks in 17 instances. Rates of dose reductions were similar in the U.S. trial, with 50 percent of patients requiring dose reductions. Most of these reductions were related to rash or arthralgia.

Despite the high ORRs, “residual disease (hairy cells in bone marrow with their associated BRAF V600E allele burden) was consistently present at the end of treatment, even after a complete response [in the U.S. trial],” the authors observed. Also, in the Italian trial, in approximately half of the patients who could be evaluated, hairy cells showed persistent expression of phosphorylated ERK despite prolonged ongoing exposure to vemurafenib. Persistent disease appeared to correlate with a higher burden of residual leukemia and shorter progression-free survival. “This finding suggests that, in at least some patients, leukemic cells develop alternative mechanisms for reactivating MEK and ERK to bypass BRAF blockade.”

“Prospective clinical trials are needed to formally evaluate toxicity, response rate, and survival with lower vemurafenib doses or longer treatment durations than those we used in these trials,” Dr. Tiacci and co-authors concluded.


Tiacci E, Park JH, De Carolis L, et al. Targeting mutant BRAF in relapsed or refractory hairy-cell leukemia. N Engl J Med. 2015;373:1733-47.