Two studies, one in Italy and one in the United States, have found that the BRAF inhibitor vemurafenib (Zelboraf, Roche/Plexxikon) produced high response rates in patients with relapsed or refractory hairy-cell leukemia (HCL).
Results from both studies of vemurafenib, which is approved for use in advanced melanoma, were published online September 19 in the New England Journal of Medicine.
"[Vemurafenib is a] new, non-myelotoxic and very active targeted drug that can be given orally to patients with HCL who do not respond or relapse after standard chemotherapy with the purine analogs cladribine and pentostatin, and who may have scarce bone marrow reserve due to multiple previous courses of purine analogs," commented lead author Brunangelo Falini, MD, director of the Institute of Hematology at the University of Perugia, Italy.
"More than 95% of HCL patients responded to vemurafenib, but only 30-40% reached a complete response," he added. "In 10-15% of HCL patients, vemurafenib induced secondary skin tumors, although they were of low malignant potential and required just a simple excision," he said.
Even though about 90% of patients with HCL respond to a first round of standard therapy, about 20% to 30% of patients eventually relapse beyond two rounds of treatment.
"It's amazing how well BRAF inhibitors work. Even though HCL is a relatively rare disease, for the people who do relapse this is a big deal because they have few other treatment options," coauthor Jae Park, MD, told Medscape Medical News. He is a hematologist/oncologist at Memorial Sloan Kettering Cancer Center in New York City.
The new studies are the first published reports of molecularly targeted therapy in HCL. Results were initially presented at the 2014 annual meeting of the European Hematology Association and at the 2014 annual meeting of the American Society of Hematology.
Not a Cure Yet
In the phase 2 studies, patients with relapsed or refractory HCL received oral vemurafenib at the standard dose used in melanoma (960 mg twice daily). In the Italian study, patients received vemurafenib for a median of 16 weeks, while the median duration of therapy was 18 weeks in the US study. The Italian study enrolled 28 patients, and had a median follow-up of nearly two years. The US study remains open, and has enrolled 26 of 36 planned patients.
Results showed overall response rates of 96% (25/26) after a median of 8 weeks in the Italian study, and 100% (24/24) after a median of 12 weeks in the US study. Complete response rates were 35% (9/26) in the Italian study, and 42% (10/24) in the US study.
After a median follow-up of 23 months, patients in the Italian study who had complete response had a median relapse-free survival of 19 months. Patients with partial response had a median relapse-free survival of 6 months. (hazard ratio for relapse, 0.26; 95% confidence interval, 0.10 to 0.68; P = .006).
After 1 year of follow-up, patients in the US trial had a progression-free survival of 73%, with an overall survival of 91%. Patients had a cumulative incidence of relapse of 27% 1 year after initial response.
Most drug-related adverse events were reversible grade 1 or grade 2 reactions. Dose reductions were most commonly necessary for arthralgias, rash, or arthritis. Six of 50 patients developed skin tumors, treated with simple excision without requiring dose reductions.
About half the patients available for evaluation in the Italian study had persistent HCL cells in the bone marrow after the end of treatment. These patients had more residual disease and shorter progression-free survival than those without persistent cells, suggesting a resistance mechanism.
Vemurafenib doesn't appear to be a cure yet, Dr Park pointed out, because some HCL cells were still detectable after the end of the treatment period. Studies also showed that the MAP-kinase pathway in which BRAF lies is still active. That could explain why vemurafenib does not completely eradicate all possible hairy cells, he explained.
The persistence of HCL cells points to the need for additional therapy to enhance response rates. One way to do this, according to Dr Park, is by more completely inhibiting the BRAF pathway through use of more extended treatment. A more rational method may be to combine a BRAF inhibitor with another drug that targets the pathway, like an MEK inhibitor. A monoclonal antibody targeting CD20, which HCL cells strongly express, might also be used.
"Because of side effects, sometimes it's difficult to get the total duration of treatment, so we believe that the combination approach will be better with less toxicity," Dr Park said.
Other question marks include the proper dose of the drug, although it appears that patients with HCL may be more sensitive to lower-than-standard doses of vemurafenib. Optimal duration of the treatment will also need to be addressed.
Several important discoveries motivated the studies.
In 2011, Dr Falini and coauthor Enrico Tiacci, MD, found that almost all HCL patients have BRAF V600E mutations, implicating it as the key mutation underlying HCL pathogenesis (New Engl J Med. 2011;364:2305-2315).
Dr Tiacci and colleagues also found that the BRAF V600E mutation activates the mitogen-activated protein kinase (MAPK) pathway in HCL. Further in vitro studies suggested that BRAF inhibitors like vemurafenib could potentially kill HCL cells.
A number of study authors have financial relationships with Roche.
Roche sponsored both trials.
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