Ruxolitinib：a selective JAK1 and JAK2 inhibitor

Ruxolitinib(INCB-018424) (Incyte) looks set to become the first drug for the treatment of myelofibrosis, a potentially life-threatening disorder characterized by the scarring of tissue in the bone marrow. It affects about 3500 people annually in the United States, and tends to develop in older patients.

Results from 2 recently completed phase 3 clinical trials show that the drug has a significant effect on symptoms, including a significant reduction in the enlarged spleen of these patients. These data have just been submitted to the US Food and Drug Administration with a request for priority review, and they were presented here at the American Society of Clinical Oncology 2011 Annual Meeting.

"Patients responded very quickly to ruxolitinib — within 2 to 4 weeks," said Alessandro Vannucchi, MD, associate professor of hematology at the University of Florence, Italy, who was principal investigator on one of the trials.

"This therapy has the potential to change the treatment landscape," he said at a press briefing. "We've urgently needed new treatments for this condition."

Risk for Premature Death

There are currently no approved therapies for myelofibrosis, Richard Stone, MD, from the Dana-Farber Cancer Institute in Boston, Massachusetts, told Medscape Medical News.

The main defect is scar tissue in the bone marrow, which leads to the disruption of blood cell formation, causing anemia and thrombocytopenia, Dr. Stone explained in an interview. There is a risk for transformation to leukemia in about 10% of patients, he noted.

The defect in the bone marrow might also lead to systemic symptoms, because it leads to scarred bone marrow tissue forming and accumulating in other organs, notably in the spleen and the liver. This results in the distention of the spleen (which causes discomfort), early satiety because the spleen is crushing the stomach (which leads to weight loss), and dyspnea. In addition, the spleen is pushing on the liver. That, together with the accumulation of bone marrow in the liver, can lead to hepatic failure.

The combined impact is an abrupt shortening of life expectancy. The course of the disease is variable, but patients with high-risk myelofibrosis have a median survival of 5 to 8 years, Dr. Stone said, but he added that "some patients do far worse."

Current management is based on supportive care, Dr. Stone explained. Blood transfusions treat the anemia, drugs such as thalidomide and lenalinomide are used to change the cytokine environment in the bone marrow, which might reduce the need for blood transfusions, and corticosteroids are often used to dampen the cytokine release and "to make the patients feel better," he said.

The enlargement of the spleen is tackled with splenic irradiation and with hydroxyurea, both of which can lead to some shrinkage, but splenectomy is not really an option. The spleen is engorged and becomes attached to other organs, so surgery is problematic and carries a mortality risk of 10% to 15%. There is also a concern that splenectomy increases the risk for conversion to leukemia, Dr. Stone explained.

Against this background, ruxolitinib is "the first drug to make an impact on this disease," Dr. Stone noted, although he added that it is also "the first to have been studied extensively in this disease."

The results from all the clinical trials "consistently show the same thing," he said; they demonstrate that ruxolitinib significantly reduces spleen size, reduces pruritis, and improves constitutional symptoms such as fatigue and malaise. The drug does not appear to a have an impact on the underlying disorder, but it does offer symptomatic relief. "This looks to be sufficient for approval and, as a doctor treating these patients, I think it is beneficial for this drug to be available," Dr. Stone said.

Adverse Effect of Anemia

One adverse effect of ruxolitinib is anemia, which could be problematic because these patients already have anemia as a result of the disease, Dr. Stone explained. He is concerned that in some instances this adverse effect could increase the anemia, so that the patient might require blood transfusions.

"This can happen," acknowledged Dr. Vannucchi, "but I think that this problem has been overemphasized," he toldMedscape Medical News.

In the trial that he presented (known as COMFORT-2), there were more blood transfusions in the ruxolitinib group than in the control group receiving best available therapy (51% vs 38%), but the number of units transfused was similar, Dr. Vannucchi noted.

"As a practicing clinician seeing these patients, giving one more blood transfusion is not that big a problem when you see the significant effect on the spleen size and other symptoms," he explained.

Anemia and thrombocytopenia as adverse effects of ruxolitinib are seen at the beginning of treatment; they then subside, probably as a result of the drug having an impact on the bone marrow, he said.

Spleen Shrinkage Documented on MRI

The reduction in spleen volume was documented with magnetic resonance imaging (MRI), and the primary end point was a reduction in spleen size of 35% or more. In the COMFORT-2 study, ruxolitinib achieved this reduction in 31.9% of patients at 24 weeks, and in 28.5% at 48 weeks. In the control group receiving the best available therapy, no patients showed this magnitude of reduction in spleen size.

Because spleen enlargement is the major symptom in this disease, and because ruxolitinib offers a nonsurgical option to reduce spleen size — in a patient population where surgery is a risky option — "I would argue that ruxolitinib is a very significant agent for our patients," said Ross Levine, MD, from Memorial Sloan-Kettering Cancer Center in New York City, who was a discussant at the meeting.

More Drugs Under Development

Ruxolitinib is a JAK inhibitor, and is the first of several such agents for which development was prompted by the discovery that the JAK signaling pathway is activated in myelofibrosis and related diseases.

A number of other JAK inhibitors are now being tested in clinical trials; they vary in their impact on the JAK signaling pathways. There have been hints that some of these might be free of the adverse effect of anemia, and that some might have an effect on the underlying disease, but these are early data, explained Dr. Stone.

Ruxolitinib does not appear to have a disease-modifying effect. "The percentage of mutation cells is not changed," Dr. Vannucchi told Medscape Medical News.

However, it might be that significantly improving the symptoms in itself improves survival, he speculated. There are no data as yet on overall survival; the trials were not long enough (they were 48 weeks), he said. These patients will be followed-up over the long-term, but any attempts to evaluate survival data will be complicated by a crossover effect — patients who were in the control groups (placebo in COMFORT-1 and best available therapy in COMFORT-2) were offered ruxolitinib when the studies concluded.

The trials were funded by Incyte. Dr. Vannucchi reports acting as a consultant or advisor for Novartis. Dr. Levine reports relationships with AstraZeneca, Incyte, and TageGen.

American Society of Clinical Oncology (ASCO^®) 2011 Annual Meeting: Abstract LBA6501. Presented June 6, 2011.