Ruxolitinib can ease the symptoms of myelofibrosis and improve patient survival, according to results of the COMFORT-I study.
Detailed data from this phase 3 trial, which led to the US approval of ruxolitinib in November, appear in the March 1 edition of The New England Journal of Medicine. Some of these data were also presented at the recent ASH meeting.
“The phase 1/2 clinical trial showed that ruxolitinib improves quality of life for many patients with myelofibrosis, and now this phase 3 study indicates that the drug extends survival in a patient population that has lacked effective treatments,” said principal investigator Srdan Verstovsek, MD, PhD, of The University of Texas MD Anderson Cancer Center.
The trial, which was funded by the maker of ruxolitinib, enrolled 309 patients from 89 US centers. The researchers randomized patients to receive ruxolitinib (n=155) or placebo (n=154) orally twice daily.
Patients recorded their symptoms over the course of the 24-week study using an electronic diary. And the investigators monitored patients’ spleen volumes via MRI. The primary endpoint of the study was a 35% reduction in spleen volume.
Most patients on placebo experienced progressive splenomegaly and a worsening of myelofibrosis-related symptoms. For this reason, 38 patients in the placebo arm withdrew from the study, and 111 patients crossed over to the ruxolitinib arm.
The median time to cross over was 41 weeks. Only 2 patients remained on placebo at the time of analysis.
Reduction in splenomegaly
“It quickly became apparent who was getting the placebo and who was getting the drug,” said study author Jason Gotlib, MD, of Stanford University Medical Center.
Dr Gotlib noted that the spleen volume in patients receiving the drug began to decrease within 1 to 2 weeks. In fact, 41.9% of treated patients experienced at least 35% shrinkage in their spleen volume. And the spleen remained smaller in 67% of those responders for 48 weeks or longer.
In comparison, 0.7% of patients in the placebo group experienced spleen reduction by 35%. At week 24, the ruxolitinib group had an average reduction in spleen volume of 31.6%, while the placebo group experienced an average increase in spleen volume of 8.1%.
Symptom improvement
Every night, patients completed the Myelofibrosis Symptom Assessment Form, an electronic diary. They evaluated the intensity of night sweats, itching, abdominal discomfort, pain under the ribs on the left side, a feeling of fullness, muscle and bone pain, and inactivity.
In the treated group, 45.9% of patients reported a reduction of 50% or more in their total symptom score over 24 weeks, compared to 5.3% in the placebo group. In addition, treated patients gained weight, while patients in the placebo group lost weight.
Improvements usually occurred within the first 4 weeks of treatment and were not limited to patients who also experienced reduction in spleen size, Dr Verstovsek said.
Adverse events and other drawbacks
Nonhematologic adverse events occurred at similar rates in both treatment arms. And roughly 11% of patients in each arm withdrew from the study due to adverse events.
However, anemia and thrombocytopenia were more common among patients who received ruxolitinib. One patient discontinued the drug due to anemia and one due to thrombocytopenia.
Other shortcomings of the drug are that it failed to reverse bone marrow damage and did not have a lasting effect on splenomegaly. Although many patients maintained a smaller spleen volume for at least 48 weeks while on ruxolitinib, their spleens began to enlarge again if they stopped taking the drug.
“Ruxolitinib doesn’t cure the disease,” Dr Gotlib said. “But the degree of benefit is clinically meaningful and substantial and allows many patients to re-engage in their daily activities.”
Mysteries of survival and mechanism
At a median follow-up of 51 weeks, there had been 13 deaths (8.4%) in the ruxolitinib group, compared with 24 (15.7%) in the placebo group. This represents a nearly 50% reduction in mortality, but Dr Gotlib indicated that the long-term implications of these data are not clear.
Another puzzler is how, exactly, ruxolitinib works. The drug is an inhibitor of JAK1 and JAK2, but patients responded to the drug whether or not they had the JAK2V617F mutation.
“Ruxolitinib is inhibiting overactive JAK/STAT intracellular signaling pathway no matter what,” Dr Verstovsek said.
