Zosia Chustecka

December 18, 2013

NEW ORLEANS — Patients with myelofibrosis treated with ruxolitinib (Jakafi, Novartis) lived longer than those treated with placebo or standard therapy, according to the analysis of long-term data from 2 pivotal trials.

The studies, known as COMFORT-1 and COMFORT-2 (Controlled Myelofibrosis Study With Oral JAK Inhibitor Therapy), were conducted by the manufacturer and used in the approval application of the drug.

A pooled survival analysis of both of these studies, presented here at the American Society of Hematology  55th Annual Meeting (abstract 2820), shows that the risk for death at 3 years after randomization was significantly reduced by 35% in patients initially randomized to ruxolitinib, compared with patients in the control groups (hazard ratio, 0.65; P = .01).

"The COMFORT studies provide evidence that we've been able to extend the lives of patients with myelofibrosis with ruxolitinib," commented Alessandro Vannucchi, MD, from the Department of Hematology at the University of Florence, Italy. A principal investigator on COMFORT, he was presenting the pooled survival analysis at the meeting.

"It's promising to start seeing the long-term effects of this therapy, which has changed the treatment paradigm for most patients with this life-threatening disease," he said in a press statement.

Overall, 301 patients were randomized to ruxolitinib (COMFORT-1, n = 155; COMFORT-2, n = 146), and 227 patients were randomized to placebo (n = 154) in the COMFORT-1 study or to best available therapy (n = 73) in the COMFORT-2 study. Patients in the control group were allowed to crossover to ruxolitinib on disease progression, and at this 3-year analysis, all of the control patients had done so.

At the 3-year update, 71 patients (24%) died in the ruxolitinib group, compared with 76 patients (33%) in the control group. Survival was consistent across both studies and represented an overall survival benefit in favor of ruxolitinib, Dr. Vannucchi reported.

However, myelofibrosis experts approached for comment cautioned against describing the results as showing an overall survival benefit.

"You have to be very careful about saying that it affects overall survival.... This means it is having an effect on the disease," commented Richard Silver, MD, professor of medicine and director of the Leukemia and Myeloproliferative Center at New York Presbyterian-Weill Cornell Medical Center in New York City. "But I don't think this is like Hodgkin's disease, where you give chemotherapy and it improves overall survival by curing the disease."

"I don't think here we are curing the disease," he commented to Medscape Medical News, and to talk about overall survival here is "confounding." Ruxolitinib has many secondary effects, and it may be helping people to survive longer because they are feeling better and eating better "and this is important too...but this is a secondary effect," he said. It is generally accepted that ruxolitinib does offer relief of symptoms. "It may improve some symptoms in some patients, to a greater or lesser degree," he said, "but it does not affect the disease itself in the majority of patients."

There is also a high discontinuation rate, of around 60%, Dr. Silver said, because many patients cannot tolerate the drug because of adverse effects such as thrombocytopenia and anemia.

Eyal Attar, MD, assistant professor of medicine at Massachusetts General Hospital in Boston, said: "Patients with myelofibrosis have very limited treatment options."

In the past, they have been managed by very general chemotherapeutic agents, typically hydroxyurea, which can reduce spleen size and some of the constitutional symptoms, such as lack of appetite, night sweats, and fevers. More recently, ruxolitinib has been approved for use in myelofibrosis, and this drug is particularly useful for patients who don't respond to hydroxyurea, he said.

Dr. Attar said ruxolitinib has not had much of an impact on his clinical practice. "I certainly don't want to take away anything from the rational development of a targeted agent for patients with  myeloproliferative neoplasms; however, there are several limitations to the use of ruxolitinib in these disease."

Ruxolitinib and other agents in this class that inhibit JAK2 have many off-targets effects and various toxicities, especially neurotoxicity, which limit their usefulness. In addition, clinically, they have many of the same effects on symptoms that are seen with hydroxyurea, and hydroxyurea is much cheaper, he said.

Dr. Attar said that most clinicians would use hydroxyurea first, and patients could stay on this for months or years, and they may also consider using 6-mercaptopurine. Ruxolitinib would be used second-line or even third-line in the late stages of myelofibrosis, he said.

Ruxolitinib is "definitely useful" in the treatment of myelofibrosis, but is not beneficial to the same magnitude that a drug like imatinib (Gleevec) is for patients with chronic myeloid leukemia.

"It does represent a very tangible advance for patients with myeloproliferative neoplasma, there is no doubt about that; however, it is not a home run in that patients continue to have evidence of disease," he commented to Medscape Medical News. "It is another arrow in the quiver for MPN, and especially myelofibrosis, but it is not curative," he added.

Dr. Vannucchi reports receiving honoraria from and serving on the advisory board of Novartis, the manufacturer of ruxolitinib.

American Society of Hematology (ASH) 55th Annual Meeting: Abstract 2820. Presented December 8, 2013.

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