MILAN — Ruxolitinib (Jakafi, Incyte) led to substantial improvements in patients with polycythemia vera (PV), a chronic and incurable blood cancer, in the first pivotal phase 3 study of the agent.
The findings appear impressive, and unprecedented, according to one expert.
"No other drug has shown a comparable efficacy, and the side effects are acceptable," said Anton Hagenbeek, MD, PhD, professor of hematology at the University Medical Center of Utrecht in the Netherlands, who was not involved with the study.
"Ruxolitinib does not really interfere with the origin of PV, unlike imatinib in chronic myelogenous leukemia; however, it significantly reduces signs and symptoms, which are of the utmost importance to the individual patient," he told Medscape Medical News.
Effective treatments are currently lacking for PV, leaving patients at risk for complications, including heart attack and stroke, said investigator Alessandro M. Vannucchi, MD, from the University of Florence in Italy.
Dr. Vannucchi presented results from the RESPONSE study here at the 19th Congress of the European Hematology Association.
"Hematocrit control is a key therapeutic goal in PV; maintaining hematocrit of less than 45% has been shown to decrease the risk of cardiovascular death and major thrombotic events," Dr. Vannucchi explained.
PV is associated with the overactivation of the JAK/STAT pathway, and ruxolitinib is a potent JAK1/JAK2 inhibitor.
Ruxolitinib was approved for the treatment of intermediate or high-risk myelofibrosis by the US Food and Drug Administration in 2011. Incyte plans to file an application for approval for the PV indication, according to a company press release.
In a previous phase 2 trial, the drug was shown to be well tolerated and to effectively control hematocrit and symptoms in patients with PV.
The international, multicenter, open-label, phase 3 RESPONSE trial assessed 222 patients with splenomegaly who were resistant to or intolerant of hydroxyurea and therefore required phlebotomy.
Patients were treated with ruxolitinib 10 mg twice daily or with best available therapy (control group), which consisted of investigator-selected monotherapy or observation only.
More patients in the ruxolitinib group than in the control group met at least 1 component of the composite primary end point (77% vs 20%) — hematocrit control without the need for phlebotomy from weeks 8 to 32 and a reduction in spleen volume of at least 35% from baseline to week 32.
In addition, more patients in the ruxolitinib group than in the control group met both components of the composite end point (21% vs 1%; P < .0001), and 91% of patients in the ruxolitinib group maintained the improvement at week 48.
For the secondary end point of improvement in PV-related symptoms of at least 50%, rates were better in the ruxolitinib group than in the control group (49% vs 5%).
Complete hematologic remission — defined as maintaining hematocrit control without the need for phlebotomy, a platelet count below 400 × 10⁹/L, and a white blood cell count below 10 × 10⁹/L — was achieved by more patients in the ruxolitinib group than in the control group (24% vs 9%; P = .003).
Patients treated with ruxolitinib also experienced a significant reduction in night sweats (approximately 99%) and itchiness (approximately 95%), both common symptoms of the disease.
At week 32, patients in the control group were able to cross over to ruxolitinib. Because the early findings showed robust efficacy, most did.
More patients in the ruxolitinib group than in the control group discontinued treatment because of adverse events (3.6% vs 1.8%). And at week 32, 1 patient in the ruxolitinib group experienced a thromboembolic event, as did 6 patients in the control group.
However, when adverse events were adjusted for exposure per 100 patient-years, there were fewer exposures in the ruxolitinib group (64.7 vs 145.6). When grade 3/4 events were adjusted over the entire course of treatment, there were also fewer events in the ruxolitinib group (28.8 vs 44.0).
The adverse event that was more common at week 32 in the ruxolitinib group than in the control group was diarrhea (14.5% vs 7.2%). Adverse events that were less common in the ruxolitinib group included headache (16.4% vs 18.9%), fatigue (14.5% vs 15.3%), and pruritus (13.6% vs 22.5%). Most of the events were grade 1 or 2.
"Overall, there were no unexpected adverse events observed in PV patients treated with ruxolitinib," Dr. Vannucchi said. And rates were generally the same as those in patients with myelofibrosis, or lower, he pointed out.
At a median follow-up of 81 weeks, no patients in the ruxolitinib group had discontinued therapy, whereas 85% of patients in the control group had. At the end of the study period, 85% of patients in the ruxolitinib group were still receiving treatment.
The study was funded by Incyte. Dr. Hagenbeek has disclosed no relevant financial relationships.
19th Congress of the European Hematology Association (EHA): Abstract LB-2436. Presented June 14, 2014.
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Cite this: Ruxolitinib Provides New Benchmarks in Polycythemia Vera - Medscape - Jun 18, 2014.