Myelofibrosis, a lethal bone marrow malignancy, comes with especially debilitating symptoms that sap a patient's quality of life.
Jeanie Fuelberg, of Dripping Springs, Texas, had them all.
"I was having trouble breathing. My liver was enlarged. I couldn't eat because my spleen was so huge. I lost lots and lots of weight. There was an intense itching - if you can imagine an itching sensation inside your body. I had night sweats, abdominal pain and was extremely tired all of the time," she says.
"I had been told by my hematologist that I did not have much time to live."
When she enrolled in a phase III clinical trial at MD Anderson in October 2009, she was told the study drug was likely to ease her symptoms and improve her quality of life if she received it in the randomized, blinded placebo study. It would not cure the illness.
Fuelberg began to feel better within two weeks. "My health has improved tremendously and most symptoms have stopped. And there've been no bad side effects. They told me that it would not prolong my life, but I think it has because I'm doing so much better."
Her impression has been confirmed by data from the study, which shows that the drug ruxolitinib, known commercially as Jakafi ®, improves survival of myelofibrosis patients. Clinical trial results for the drug made by Incyte Corporation were published recently in The New England Journal of Medicine.
Principal investigator of the COMFORT1 study, which enrolled 309 patients in 89 centers across the United States, Canada and Australia, was Srdan Verstovsek, M.D., Ph.D., associate professor in MD Anderson's Department of Leukemia.
"COMFORT1 shows that with very good control of signs and symptoms of the disease, including spleen shrinkage, liver reduction, improving the patients' ability to walk, eat, and gain weight, we actually have prolongation of survival as the ultimate result," Verstovsek says.
"I can't say enough wonderful things about what this drug has done for me or about Dr. Verstovsek and his team at MD Anderson," Fuelberg says.
The U.S. Food and Drug Administration approved ruxolitinib for treatment of myelofibrosis in November, making it the first drug ever approved for the disease, which strikes about 3,000 patients annually in the United States.
FDA approval was based on results of COMFORT1 and COMFORT2, a sister trial in Europe that compared ruxolitinib to best available treatment, and focused on spleen shrinkage and symptom relief. Updated survival data from COMFORT1 were not available at the time.
No effective options
With no proven therapies for the disease before then, physicians tried drugs used for other malignancies of the blood and bone marrow. These help few patients and when they do, the effect only lasts for six to 12 months, Verstovsek noted. Fewer than 10 percent of patients are eligible for blood stem cell transplants.
Most care is supportive, mainly in the form of blood transfusions to treat anemia caused by the disease.
Patients enrolled in COMFORT1 had intermediate or high-risk myelofibrosis. Their disease was resistant to available treatments or those treatments had been discontinued due to side effects.
Patients randomized to the ruxolitinib and placebo arms of the trial had similar demographic and disease characteristics. They were eligible for transfusions as needed.
Survival improvement with crossover option
The study had a crossover provision that allowed patients with disease progression at prespecified points to have their treatment unblinded and, if they had been on placebo, to receive the study drug. Of 154 patients who started the trial on placebo, 111 crossed over to treatment.
Even with so many of the original placebo patients receiving the study drug, those in the ruxolitinib arm still showed improved survival over a relatively short period of time.
The trial called for an analysis at prespecified time point and then a second safety analysis four months later required by the FDA as part of Incyte's new drug application. The second analysis, with median patient follow-up of 51 weeks, found 13 deaths (8.4 percent) in the ruxolitinib group compared with 24 (15.7 percent) in the placebo group.
Minimal side effects
Those who took the study drug were more likely to have lowered red blood cell counts or reduced platelets. These were manageable by dose adjustment or temporary discontinuation. Only one patient had to quit taking ruxolitinib because of anemia and one for low platelets. Red blood cell counts, after an initial dip, improved over time.
Non-hematological side effects were statistically the same for the drug as for placebo.
In the European study, those on ruxolitinib also experienced spleen shrinkage and symptom relief, while those on best available treatment received no benefit. The study was not statistically powered to evaluate survival.
Verstovsek noted that those in the best available treatment arm in COMFORT2 had results that were similar to the placebo arm in COMFORT1
Ruxolitinib does not reverse myelofibrosis, as originally hoped. It does inhibit the JAK1 and JAK2 enzymes, which are involved in myelofibrosis, and is thought to ease inflammation caused by the disease.
Clinical trials are under way combining ruxolitinib with other drugs and testing a variety of new single agents, including other JAK inhibitors.
The American Society of Clinical Oncology selected the advancement of ruxolitinib as one of only two developments for hematological cancers for its list of Clinical Cancer Advances 2011.
MD Anderson news release