NEW YORK—The targeted therapy vemurafenib has transformed the treatment of melanoma and now shows potential to surpass standard therapy for the treatment of hairy cell leukemia (HCL).
“Although purine analogues induce high response rates in HCL, the rates and duration of complete response decline with each subsequent line of therapy, and they are not curative—30 to 40 percent of patients relapse over the long-term in follow-up studies,” noted Jae Park, MD, Attending Physician in the Leukemia Service of Memorial Sloan-Kettering Cancer Center, speaking in a presentation here at the Chemotherapy Foundation Symposium.
“Currently, there are limited treatment options for HCL patients who are refractory to purine analogues or who relapse early.”
Vemurafenib is the first molecularly targeted therapy to be licensed for the treatment of advanced melanoma. Its mechanism of action, Park explained, involves selective inhibition of the mutated BRAF V600E kinase that leads to reduced signaling through the aberrant mitogen-activated protein kinase (MAPK) pathway.
HCL, which is a rare, chronic B-cell lymphoproliferative disorder that includes an accumulation of cells with prominent irregular cytoplasmic extrusions, is commonly treated with purine analogues. Virtually all patients with HCL carry the BRAF V600E mutation, which constitutively activates the MEK-ERK pathway. The key clinical features include splenomegaly, anemia, thrombocytopenia, and neutropenia, and bone marrow fibrosis, Park continued.
There is a strong rationale for targeting the BRAF gene in HCL, he said. “The mutation is present in more than 90 percent of HCL patients. The RAF-MEK-ERK pathway is constantly activated in HCL. Treatment of primary HCL cells with the BRAF inhibitor leads to a decrease in pMEK and pERK at a clinically relevant concentration. And vemurafenib is an effective, selective BRAF inhibitor that is administered orally,” Park said.
Last year German researchers at University Hospital Heidelberg published a correspondence in the New England Journal of Medicine (2013;366:2038-2040) noting that they had used vemurafenib in a patient with refractory HCL who had a BRAF V600E mutation and 70 percent bone marrow infiltration, massive splenomegaly, and severe cytopenia.
Treatment began at a dose of 240 mg vemurafenib twice daily, followed by a slow escalation of the dose. Within days, the patient's spleen softened and decreased in size, and platelet, hemoglobin, and granulocyte counts rose. The patient achieved complete response in about one and a half months.
Since then, other studies have validated BRAF V600E in HCL, and determined that the mutation reappears at disease relapse, said Park.
Phase II Vemurafenib Study
Park and colleagues have now begun a Phase II study of vemurafenib in patients with relapsed/refractory hairy cell leukemia. This multicenter, open-label, single-arm Phase II trial plans to include 19 patients in the first stage. These patients have classical HCL with intolerance to purine analogues, failure to achieve any response to initial purine analogue-based therapy, or have relapsed within two years of standard therapy, or have had two or more relapses.
The primary objective of the study is to determine the efficacy of the drug, as assessed by overall response rate.
Patients receive a starting dose of 960 mg of vemurafenib twice daily for three months from the date their disease was assessed. Those who respond continue for another three months of treatment, and then are followed for another 12 months after vemurafenib is stopped.
A complete response is defined as morphological absence of hairy cells in the blood and bone marrow and normalization of any organomegaly and cytopenias.
At the symposium, Park presented the preliminary results of the 12 patients who have been enrolled in the trial so far. All of the patients are highly pretreated with short remission duration,” he said. Four patients have splenomegaly, and some have neutropenia.
Approximately 40 percent of patients have required dose reductions of vemurafenib, but all have completed therapy, he said. The most common adverse events are arthralgia and rash.
Seven of nine evaluable patients have achieved a complete response. “Responses have been rapid, within two weeks for normalization. We see an absence of circulating leukemic cells in peripheral blood and bone marrow,” Park said. “We also see reductions in tumor markers as well.”
Among the remaining questions, he said are:
- “What is the optimal duration of vemurafenib—Should it be one month, three to four months, or longer?
- “What are the optimal doses? They could range from 240 mg twice daily up to 960 mg twice daily.
- “Is gradual dose escalation better than dose modification based on adverse events?
- “What is the best time to assess disease response?”
An appropriate dosing schedule will be developed in clinical trials, Park said, adding that HCL is quite sensitive to BRAF inhibition.
The moderator of the session at which Park spoke, Janice Gabrilove, MD, Professor of Medicine and Director of the Clinical Education Research Program at the Icahn School of Medicine at Mount Sinai in New York, commented in an interview, “Mutation targeted therapy gets at the underlying disease. But I worry about the addition of mutations that may emerge.
“This could be a complementary strategy to target CD25 neoplasms. It will go beyond the purine analogue pentostatin and lead to moving pentostatin to the background to recover patients who no longer respond to mutation-derived therapy.”
Park explained that the mechanisms of resistance to vemurafenib do not involve development of secondary mutations in the BRAF kinase domain, but may be related to BRAF V600E over-amplification, bypassing mechanisms via upregulation and overexpression of other components in the MAPK-signaling cascade or activation of alternative pathways with potential to enhance cell growth, proliferation, and survival.
The presence of BRAF V600E in most patients with HCL suggests that it represents a key driver mutation in the disease, he said. The letter by the German researchers provides evidence to substantiate this concept and validate mutant BRAF as a therapeutic target in HCL, Park said.
The letter in the New England Journal likened targeted therapy with vemurafenib to that of targeted therapy with imatinib in patients with chronic myeloid leukemia (CML): “The findings are reminiscent of successes with targeted inhibition of BCR-ABL in CML. The fact that heavily pretreated, refractory disease responded to very low doses of vemurafenib suggests that HCL represents a single-kinase–dependent cancer that can be treated with targeted monotherapy.”
Vemurafenib is now being further explored as a treatment in several cancers, Park said, noting that clinical trials to test the efficacy of vemurafenib in combination with immunomodulatory agents, such as ipilimumab, and MAPK kinase (MEK) inhibitors in the treatment of advanced melanoma are currently underway. Also under investigation is the use of vemurafenib in other solid tumors with BRAF mutations, such as papillary thyroid cancer.
“Combination treatment with vemurafenib and epidermal growth factor receptor inhibitors might improve outcomes for BRAF V600E mutant colon cancers for which there are currently no targeted treatment options available,” Park concluded.