BRAF Inhibition Successful in Relapsed/Refractory Hairy Cell Leukemia

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Vemurafenib in Hairy Cell Leukemia

A short oral course of vemurafenib was highly effective in patients with relapsed or refractory hairy cell leukemia.

—Enrico Tiacci, MD, and colleagues

In two phase II studies reported in The New England Journal of Medicine, ­Enrico Tiacci, MD, of the University of Perugia, Italy, and colleagues found that the BRAF inhibitor vemurafenib (Zelboraf) produced responses in nearly all patients with BRAF V600E–positive hairy cell leukemia that relapsed after treatment with a purine analog or who had disease refractory to purine analogs. It has been found that the BRAF V600E mutation, commonly found in solid tumors, is the key genetic lesion in hairy cell leukemia.

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. The presence of the BRAF mutation was confirmed in all patients. Patents in both studies had received a median of three prior therapies, and 56% and 41% had been disease refractory to their most recent therapy; 29% and 19% had undergone splenectomy.

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.

Responses in Italian Study

In the Italian study, the overall response rate was 96%, including complete hematologic response in 35%, after a median of 8 weeks. Median times to blood count recovery were 2 weeks for platelet count, 4 weeks for neutrophil count, and 8 weeks for hemoglobin level. Reversion of symptomatic splenomegaly and clearance of leukemia cells from the blood usually occurred within 2 weeks after start of treatment. A marked reduction in bone marrow leukemic-cell infiltration was observed at 4 weeks, the earliest evaluation. However, in all patients with complete hematologic response, immunohistochemical testing showed minimal residual disease (≤ 10% of leukemic cells) at the end of treatment.

After a median follow-up of 23 months, median relapse-free survival was 9 months, including 19 months in patients with complete hematologic response and 6 months in those with partial response (hazard ratio [HR] = 0.26, P = .006). Median treatment-free survival was 21.5 months, including 25 months in patients with complete hematologic response and 18 months in those with partial response (P = .21).

Of 20 patients with relapse (5 after complete response and 15 after partial response), 7 did not require therapy at a median of 15 months (range = 4–18 months) after relapse, since cytopenias were mild and stable. Worsening cytopenia in the remaining 13 required antileukemic treatment. An exploratory analysis indicated no difference in relapse-free or treatment-free survival between 18 patients who received additional treatment after best response and 7 who received no additional treatment.

Responses in U.S. Study

In the U.S. study, the overall response rate was 100%, including complete hematologic response in 42%, after a median of 12 weeks. Most patients had recovery of neutrophil count, hemoglobin level, and platelet count by 28 days. Among survivors at the time of data cutoff, the median follow-up was 11.7 months.

At 1 year, progression-free survival was 73% and overall survival was 91%. Progression occurred in 7 (29%) of 24 patients, including 3 who had complete hematologic response and 4 who had partial response. At 1 year after response, the cumulative incidence of relapse was 27%. In both trials, vemurafenib retreatment at the time of relapse produced responses in some patients.

Residual ERK Phosphorylation

Among 13 patients in the Italian study who could be evaluated for phosphorylated ERK in marrow biopsy specimens from the day after completion of therapy, 6 (all with partial response) had residual hairy cells still expressing phosphorylated ERK and 7 (2 with complete hematologic response and 5 with partial response) did not. In an exploratory analysis, the median progression-free survival was 8 months (range = 5–13 months) in those with vs 13 months (range = 8–24 months) in those without residual phosphorylated ERK-positive leukemic cells (HR = 10.33, P = .004).

Residual disease, measured by the Hairy Cell Index, was higher in patients with persistent phosphorylated ERK in leukemic cells (P = .03). As noted by the investigators, “[P]ersistent ERK phosphorylation in residual hairy cells at the end of treatment may indicate a greater burden of residual disease and shorter progression-free survival, which suggests that reactivation of MEK and ERK is a resistance mechanism to vemurafenib.”

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.” ■

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


1. Tiacci E, Park JH, De Carolis L, et al: Targeting mutant BRAF in relapsed or refractory hairy-cell leukemia. N Engl J Med 373:1733-1747, 2015.

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