Nancy A. Melville

June 16, 2014

MILAN — The BRAF-inhibiting drug vemurafenib (Zelboraf, Roche) is safe and effective for patients with hairy cell leukemia who have failed to respond to conventional therapies, new research shows.

This study "suggests that vemurafenib is a good therapeutic option for hairy cell leukemia patients not responding anymore to purine analogs," said first author Enrico Tiacci, MD, from the Institute of Hematology at the University of Perugia, Italy.

Approximately 40% of patients with hairy cell leukemia become less responsive to purine analogues. Even when the drugs are effective, they have the disadvantage of being myelotoxic and immunosuppressive.

Dr. Tiacci's team discovered that BRAF-V600E was the mutation underlying hairy cell leukemia, as previously reported in by Medscape Medical News.

Vemurafenib has shown success in the treatment of BRAF-mutated metastatic melanoma, and has been approved by the US Food and Drug Administration for use in late-stage melanoma.

Therefore, Dr. Tiacci and his colleagues took the next logical step and evaluated vemurafenib in patients with hairy cell leukemia.

Dr. Tiacci presented the results here at the 19th Congress of the European Hematology Association.

The study involved carriers of the BRAF-V600E mutation with hairy cell leukemia who were refractory to or who relapsed after purine analogs and who required therapy for cytopenia. Patients received the standard dose of vemurafenib (960 mg) twice a day for a median of 16 weeks.

The patients had received a median of 4 previous therapies.

After 16 weeks, 25 of the 26 patients responded to therapy; 16 achieved a partial response and 9 achieved a complete response.

All of the complete responders had minimal residual disease (≤10%) at the end of treatment.

Median time to response was 8 weeks for the complete responders and 9 weeks for the partial responders.

At a median of 9 months after treatment, 7 of the 9 complete responders maintained normal blood counts. The other 2 developed mild neutropenia (one at 5 months and the other at 12 months); one of these patients required therapy for worsening neutropenia 9 months after treatment.

Follow-up data were available for 15 of the 16 partial responders. For 8, normal blood counts were maintained at a median of 6 months after treatment. For the other 7, cytopenia developed a median of 5 months after treatment.

The drug was well tolerated. The most common drug-related adverse events were arthralgias, various skin toxicities, and pancreatitis, but they were always reversible and most were low grade.

Only 6 patients had grade 3 events and there were no grade 4 events. None of the patients experienced myelosuppression, which is important and desirable for a drug used to treat a hairy cell leukemia, Dr. Tiacci explained.

"Hairy cell leukemia causes blood cytopenias due to marrow infiltration and/or splenomegaly. Cytopenias are initially worsened by the treatment with purine analogs (i.e., cladribine and pentostatin), which are significantly myelotoxic and immunosuppressive," he said.

Unlike patients with melanoma, none of the patients with hairy cell leukemia developed keratoacanthomas or cutaneous squamous cell carcinomas. Two cases of basalioma and 1 case of superficial melanoma did develop, but all were treated with simple excision.

Small studies and case reports conducted after the discovery of BRAF showed improvements in patients with hairy cell leukemia treated with vemurafenib. However, "our study is the first clinical trial of a sizable number of patients with a meaningful follow-up," Dr. Tiacci reported.

One intriguing preclinical study suggested that after eventual relapse occurs, the tumor growth appears dependent on the presence of the vemurafenib (Nature. 2013:494:251-255). Feasibly, withdrawal of the drug would result in further regression of the cancer.

Dr. Tiacci said his team evaluated that theory.

"We tried to take it into account in our trial by introducing 2 weeks off-drug between the first 8 weeks of treatment and the subsequent 4 weeks," he said.

"However, to formally explore the potential clinical benefit of such a strategy in humans, other trials should be specifically designed and performed in melanoma and in hairy cell leukemia patients to address this question," he explained.

One challenge to conducting larger trials in patients with hairy cell leukemia is simply obtaining the necessary number of patients because the disease is uncommon, Dr. Tiacci pointed out.

"Considering that purine analogs are very effective in the front-line setting, we think the next step is to increase the complete remission rate and duration in the refractory/relapsed setting, for example by combining a BRAF inhibitor with a MEK inhibitor, a strategy already shown to work in BRAF-mutated melanoma patients, or with immunotherapy using an anti-CD20 monoclonal antibody," he said.

The findings add to the recent discovery of the role of the BRAF mutation in hairy cell leukemia patients, said George A. Follows, MD, from Cambridge University Hospitals in the United Kingdom.

"The results were striking, with 25 of the 26 patients responding with either a partial or complete remission. And the side effects were tolerable," he told Medscape Medical News.

"Unfortunately, many patients relapsed when therapy was stopped, which is perhaps to be expected, given the nature of the therapy," he pointed out.

Still to be determined are the correct dosing strategy, whether patients are likely to be better served by continuing on therapy after remission induction, and when patients derive the maximal benefit from vemurafenib.

"These questions and many others can only really be addressed through prospective trials, which will be challenging considering the rarity of the condition," Dr. Follows added.

However, the team deserves "warm congratulations for this ground-breaking piece of clinical research," he said.

Dr. Tiacci and lead investigator Brunangelo Falini, MD, from the University of Perugia, have filed a patent on the clinical use of the BRAF mutation in hairy cell leukemia. Dr. Follows has disclosed no relevant financial relationships.

19th Congress of the European Hematology Association (EHA): Abstract S696. Presented June 14, 2014.


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