Treatment with ruxolitinib, an oral inhibitor of Janus kinase 1 and 2, was associated with significantly better responses and improvement in symptoms in patients with polycythemia vera who had not responded to or had experienced unacceptable side effects with hydroxyurea, compared with those who received standard therapy, in a phase III, open-label study, Dr. Alessandro Vannucchi of the University of Florence (Italy) and his associates reported.

In the RESPONSE study, patients with splenomegaly who required phlebotomy for control of hematocrit and had an inadequate response or had experienced unacceptable side effects with hydroxyurea were randomized to treatment with the kinase inhibitor (110 patients) or to interferon and other standard treatments (112). After 32 weeks, 21% of those treated with ruxolitinib had met the primary endpoint, which was control of hematocrit and at least a 35% reduction in spleen volume (measured by MRI or CT), compared with 1% of those on standard treatment, a statistically significant difference with a P value less than .001. A significantly greater proportion of those in the ruxolitinib-treated group also met the two individual components of the primary endpoint.

“Response rates with ruxolitinib were similar among patients who had unacceptable side effects from hydroxyurea and those who had an inadequate response to hydroxyurea. … and there was no relationship between response and age, sex, or baseline spleen volume,” the authors wrote. The study is the basis of the recent Food and Drug Administration approval of ruxolitinib for this indication (N. Engl. J. Med. 2015 Jan. 28. [ doi:10.1056/NEJMoa1409002 ])Other endpoints included complete hematologic remission, achieved by 24% of those treated with ruxolitinib vs. 9% on standard therapy. At week 32, almost half of those on ruxolitinib had at least a 50% reduction in the total symptom score that assessed disease-related symptoms vs. 5% of those on standard therapy.

Some hematologic adverse events were more common among those on ruxolitinib: 2% developed grade 3 or 4 anemia, and 5% developed grade 3 or 4 thrombocytopenia, compared with 0% and 4% of those on standard treatment. In addition, 6% of those on ruxolitinib developed herpes zoster infections, compared with none of those on standard therapy. One patient on ruxolitinib and six patients on standard therapy had thromboembolic events. Three patients treated with ruxolitinib developed myelofibrosis 120-469 days after being randomized to treatment (about 5-9 years after they had been diagnosed with polycythemia vera) and one patient was diagnosed with acute myeloid leukemia after 56 days of treatment. Among those on standard therapy, one patient developed myelofibrosis after 101 days of treatment and two were diagnosed with myelofibrosis more than 300 days after they crossed over to treatment with ruxolitinib, including one patient who progressed to acute myelogenous leukemia.

While many patients with polycythemia vera respond adequately to hydroxyurea, the most commonly used cytoreductive agent used to treat polycythemia vera, about 25% do not have a satisfactory response or experience unacceptable side effects, “and alternative treatment options are needed for these patients,” the authors said.

The mean age of the patients in the study was 60-62 years, and they had been diagnosed with polycythemia vera a median of 8-9 years previously; 60% of those in the ruxolitinib group and 71% in the standard therapy group were men. The investigators chose the standard therapy, which included hydroxyurea at a dose that did not result in unacceptable side effects (59%), interferon (12%), anagrelide (7%), immunomodulators (4.5%), and pipobroman (2%); and in about 15% of patients, no medication was given.

Ruxolitinib was approved by the Food and Drug Administration in December 2014 for the treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea. It was initially approved by the FDA in 2011, for the treatment of patients with intermediate- or high-risk myelofibrosis, including primary myelofibrosis, post polycythemia vera myelofibrosis, and post essential thrombocythemia myelofibrosis.

Ruxolitinib inhibits Janus kinase (JAK) 1 and JAK2, which “mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function,” according to the prescribing information . It is marketed as Jakafi by Incyte.

Most of the patients on ruxolitinib are continuing treatment in the RESPONSE study, which is ongoing but is not recruiting any more patients, according to the authors.

The study was sponsored by Incyte and Novartis, which has licensed ruxolitinib from Incyte for development and commercialization outside the United States. Dr. Vannucchi disclosed having received grant support and serving as an adviser for Novartis; three authors are employees of Incyte; three are employees of Novartis in the United States or Switzerland, six authors had no disclosures, and one author received grants from Incyte during the study. The remaining three authors reported serving on the advisory board, serving as speakers or lecturers, and/or receiving grant support from Novartis.


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