Ruxolitinib offers relief for symptoms of myelofibrosis
Ruxolitinib is now being evaluated in clinical trials of other myeloproliferative neoplasms
- Date : 02 Mar 2012
- Topic : Anticancer agents & Biologic therapy
Patients with myelofibrosis can benefit from ruxolitinib, according to a randomised, double-blind, placebo-controlled clinical trial with more than 300 participating patients at 89 clinical sites. The results of this multi-site phase III trial are published in the March 1 issue of the New England Journal of Medicine. They led the USA Food and Drug Administration (FDA) to approve the drug in November as treatment for patients with intermediate or advanced disease.
Ruxolitinib is marketed as Jakafi by Incyte Corp., which funded the trial, known as COMFORT-1. Investigators at the MD Anderson Cancer Center and the Mayo Clinic led the study. The Stanford arm of the trial was managed by Dr Jason Gotlib, associate professor of medicine. Fifteen of his patients participated in the study, making Stanford the single largest recruiting site. Dr Hagop Kantarjian, chair of the department of leukemia in the division of cancer medicine at MD Anderson Cancer Center, is the senior author of the paper. The first author is Dr Srdan Verstovsek, an associate professor in the same department at MD Anderson.
Ruxolitinib clearly better at relieving symptoms and quality of life
Patients with advanced forms of myelofibrosis develop worsening blood counts, spleen enlargement and other symptoms including fever, night sweats and pain in their bones and muscles. Due to splenomegaly, patients develop abdominal discomfort, early satiety and weight loss. In the study, many patients who received the drug experienced a significant reduction in spleen volume and a lessening of symptoms.
According to Dr Gotlib ruxolitinib is clearly better at relieving patients' symptoms and quality of life than anything doctors could offer before. A parallel phase III randomised trial named COMFORT-2, which was conducted in Europe, demonstrated that ruxolitinib was also superior to the best available therapy in reducing spleen size and disease-related symptoms.
Myelofibrosis belongs to a class of diseases known as myeloproliferative neoplasms. Patients with myeloproliferative neoplasms can develop life-threatening blood clots and bleeding, and in some cases their condition progresses to acute leukemia. Some patients with myeloproliferative neoplasms respond well to current treatments, but those with myelofibrosis do not.
Although myelofibrosis typically progresses slowly, patients often exhibit an inexorable course resulting in premature death. The overall survival ranges from 11 years in low-risk patients to a little more than two years in patients with high-risk disease. Stem cell transplantation can cure some patients, but it is available to only a small proportion of patients and can carry substantial treatment-related morbidity and mortality.
Ruxolitinib is a first in the class of compounds called JAK2 inhibitors
Ruxolitinib is the first FDA-approved therapy for the disorder, and the first of a class of compounds belonging to JAK2 inhibitors. This targeted therapy was developed to block the action of the JAK2 tyrosine kinase protein, which is mutated and abnormally active in 50-60% of myelofibrosis cases. However, for reasons that are not entirely understood, the drug works in patients regardless of whether they have the mutant protein.
In the trial, patients were randomly assigned to receive either ruxolitinib (155 patients) or a placebo (154 patients) orally twice a day. Their spleen volumes were monitored over the course of the 24-week study by magnetic resonance imaging, and patients reported their symptoms using an electronic diary. The primary endpoint in the study was a 35% reduction in spleen volume.
Study investigators observed that the spleen volume in patients receiving the drug began to decrease within one to two weeks. Among patients on the drug 41.9% met the study endpoint of at least a 35% reduction in spleen volume, while only 0.7% of those on the placebo did so. Patients receiving placebo were allowed to crossover to active, unblinded treatment with ruxolitinib after a designated period of time.
Nearly 46% of patients on ruxolitinib reported an improvement of 50% or more in their disease-associated symptoms, versus about 5% of those on placebo. The drug did have some side effects, however, including anaemia. And although the majority patients maintained a smaller spleen volume for at least 48 weeks while on the drug, their spleens began to enlarge again if they stopped taking the drug.
According to the study investigators ruxolitinib doesn't cure the disease, but the degree of benefit is clinically meaningful and substantial, and allows many patients to re-engage in their daily activities.
Compared with placebo, ruxolitinib therapy was associated with a 50% reduction in mortality after nearly one year of follow-up, but the long-term implications of these data are not clear. The study researchers believe that the FDA approval of ruxolitinib and the ongoing evaluation of other JAK inhibitors in clinical trials will continue to spur drug development for myelofibrosis and similar orphan diseases for which there is a large unmet need. Ruxolitinib is now being evaluated in clinical trials of other myeloproliferative neoplasms.
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