Vemurafenib Produces Rapid Responses in Hairy Cell Leukemia
Preliminary results of an ongoing clinical trial suggest that the BRAF inhibitor vemurafenib (Zelboraf)—indicated for the treatment of metastatic melanoma with BRAF V600E mutation—may have an important role in the treatment of hairy cell leukemia.
The cornerstone of therapy for this rare chronic B-cell proliferative cancer has been purine analogs, but 30% to 40% of patients will relapse. Patients with refractory disease or early relapse have limited treatment options, explained Jae Park, MD, of Memorial Sloan-Kettering Cancer Center, New York, at the Chemotherapy Foundation Symposium XXXI.
BRAF V600E Mutations in Hairy Cell Leukemia
A major breakthrough occurred with the discovery of BRAF V600E mutations in hairy cell leukemia. “Although these mutations occur in close to 100% of patients with hairy cell leukemia, they are absent in other B-cell mutations,” Dr. Park noted.
On the heels of that discovery, genomic sequencing of more than 400 patients with hairy cell leukemia revealed that more than 95% had BRAF V600E mutations.
“The mutation is also present when the disease relapses, implying that it is important in the pathogenesis of hairy cell leukemia,” Dr. Park said.
Experimental studies have shown that the BRAF pathway is consistently activated in hairy cell leukemia, providing a rationale for use of a BRAF inhibitor in this malignancy. A preliminary case report showed that vemurafenib reduced splenomegaly, returned platelet counts to normal, and achieved complete remission within 6 weeks in a patient with refractory hairy cell leukemia.
Phase II Study
Based on encouraging preliminary data, Dr. Park and a team of investigators from six other institutions have mounted a multicenter, open-label, single-arm phase II study of vemurafenib in patients with refractory hairy cell leukemia. All patients were relapsed and in need of therapy, he said.
The primary objective of the study is overall response rate, and secondary objectives include safety and tolerability as well as progression-free survival and overall survival.
Patients are treated with oral vemurafenib at 960 mg twice daily, the approved dose for melanoma. A biopsy is obtained at 1 month to assess to early response. Then a second biopsy is obtained at 3 months for official overall response rate.
Patients who achieve a minimal residual disease–positive complete remission or partial response at 3 months are treated for 6 additional months then followed for 6 months. Those who are in minimal residual disease–negative complete remission are followed for 12 months. Those with no response at 3 months are taken off study.
Thus far, the study has enrolled 12 patients previously treated with two to four cycles of cladribine. Some of the patients also received pentostatin, interferon, and/or rituximab (Rituxan).
Rapid Responses Observed
Adverse events are similar to those reported in melanoma patients, mostly grades 1 and 2 arthralgia, rash, and photosensitivity. One patient had tumor lysis syndrome, one had squamous cell carcinoma, and one had grade 3 hand-foot syndrome.
“Most adverse events can be managed with low-dose prednisone , but some patients require dose reductions,” Dr. Park noted.
Responses are rapid, he continued. At 3 months, 7 of 12 patients achieved complete remission, 2 achieved partial response, and 3 were not evaluable. Vemurafenib has a strong effect on serum inflammatory cytokines, Dr. Park said.
Issues that need to be resolved include the optimal duration of treatment (1 month vs 3–4 months or longer), optimal dose of vemurafenib (twice daily 240 mg vs 480 mg vs 960 mg), and the best time to assess disease response. The study is ongoing.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
