Ruxolitinib Beats Out Best Available Therapy in Polycythemia Vera

Special ReportsHematologic Malignancies: Polycythemia Vera
Volume 3
Issue 3

Follow up at 80 weeks to the open-label phase III RESPONSE trial confirmed the benefit of ruxolitinib over best available therapy (BAT) in the treatment of patients with polycythemia vera (PV) who are resistant to or intolerant of hydroxyurea.

Alessandro M. Vannucchi, MD

Follow up at 80 weeks to the open-label phase III RESPONSE trial confirmed the benefit of ruxolitinib over best available therapy (BAT) in the treatment of patients with polycythemia vera (PV) who are resistant to or intolerant of hydroxyurea, according to a study published inHaematologica.1The extended follow-up of the study showed that ruxolitinib was better able to maintain hematocrit control and reduce spleen volume and the risk of thromboembolic events than BAT.

Ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, was approved in December 2014 by the FDA for use in the treatment of patients with PV who are intolerant to hydroxyurea. The approval was based on original data from the RESPONSE trial and represented the first treatment indicated specifically for patients with PV.

“These long-term follow-up data from the RESPONSE study confirm that ruxolitinib might be a well-tolerated and effective treatment for patients with advanced PV who are not adequately and safely managed with conventional therapy, mainly hydroxyurea. It is a new option for this previously unmet clinical need,” said Alessandro M. Vannucchi, MD, head investigator of the RESPONSE trial, in an interview withTargeted Oncology.

The study enrolled patients with PV who required a phlebotomy for hematocrit control, had a spleen volume of ≥450 cm3, and had never received treatment with a JAK inhibitor.2Overall, 222 patients were randomized 1:1 to receive either ruxolitinib (n = 110) or a single-agent therapy determined to be most appropriate by the physician, or observation (n = 112). Dosage and BAT options were adjusted throughout the trial as needed, and patients who progressed on BAT were allowed to cross over to the ruxolitinib arm after week 32.

The original primary endpoint of the study was met when 23 patients (21%) in the ruxolitinib arm maintained hematocrit control without phlebotomy and achieved &ge;35% reduction in spleen size from baseline, compared with 1 patient (0.9%) in the BAT arm (P<.001).

Follow-up to the RESPONSE trial at week 80 examined the long-term safety and efficacy of the drug for all patients that continued treatment.1

As of follow-up at week 80, 91 patients (82.7%) who had been randomized to receive ruxolitinib were continuing treatment at a median of 111 weeks. Ninety-eight patients (87.5%) had crossed over to ruxolitinib from the BAT arm as of, or soon after, week 32 when they were first allowed to switch. Eighty-one of these patients were still receiving ruxolitinib at week 80.

By week 80, 2 additional patients had achieved a primary response, amounting to an overall 22.7% of patients who had achieved a primary response to ruxolitinib.

Complete hematologic remission was a key secondary endpoint of the trial. Twenty-six patients (23.6%) originally randomized to ruxolitinib achieved a complete hematologic response by week 32 compared with an adjusted rate of 9 patients (8%) in the BAT arm, taking into account 1 patient who had a phlebotomy at week 8 (P= .0013).

Hematocrit control without phlebotomy was achieved as of week 32 by 60% of patients originally randomized to ruxolitinib compared with an adjusted 18.8% of patients in the BAT arm; analysis at week 80 revealed an additional patient who had a phlebotomy from the BAT arm. Eighty-eight of 98 patients (89.8%) who continued ruxolitinib treatment did not have a phlebotomy between weeks 32 and 80.

Forty-four patients (40%) randomized to ruxolitinib therapy achieved spleen response of &ge;35% reduction in spleen size from baseline by week 32 versus 0.9% in the BAT group. Spleen responses were maintained until week 80 by 43 of the 44 patients.

As of week 32, patients were allowed to cross over from the BAT arm to ruxolitinib treatment; 98 of 112 patients (87.5%) crossed over to ruxolitinib on or shortly after week 32. By data cutoff, 81 of these patients (82.7%) were still receiving ruxolitinib therapy. Overall, 79.2% of the cross over patients did not need a phlebotomy and 18.8% achieved a reduction in their spleen volume after 16 weeks of treatment.

Adverse events (AEs) were more common in the BAT arm, but the rate of certain infections and disease progressions was higher in the ruxolitinib arm, as well as for those who crossed over to receive ruxolitinib treatment. The BAT group experienced common nonhematologic AEs of all grades at a rate of 32.6 per 100 patient-years of exposure for pruritus, 28.5 for headache, and 23.1 for fatigue. Comparatively, the ruxolitinib arm had rates of 9.7, 10.5, and 8.3, respectively; the group of patients that crossed over to ruxolitinib showed rates of 8.8, 8.8, and 6.8, respectively.

The patients receiving ruxolitinib had fewer occurrences of thromboembolic events than the BAT group, which is of interest since these events are a common risk for patients with PV. Thromboembolic AEs occurred at a rate of 8.2 in the BAT group versus 4.1 in the cross over patients and 1.8 in the ruxolitinib group.

&ldquo;One interesting and stimulating finding was a confirmation that a reduced rate of thrombotic events occurred in patients receiving ruxolitinib as compared to the BAT group,&rdquo; said Vannucchi, who is an associate professor of hematology at the University of Florence in Italy. &ldquo;Such a difference had been already highlighted in the original report at 32 weeks of treatment, so it is really promising to have it confirmed even at a later time point with a reduction rate of thrombosis from 8.2 per 100 patient-years to 1.8. Clearly, because of the randomized design and the number of events, this could not be statistically controlled, and additional studies are needed before we can firmly conclude about this effect.&rdquo;

The rate of infections, particularly herpes zoster infection, however, was higher among patients receiving ruxolitinib, with 12 accounts of the herpes zoster infection in the ruxolitinib group, 8 in the cross over patients, and none in the BAT arm. Overall, there were 67 infections in the ruxolitinib group versus 41 in the cross over group, and 43 in the BAT arm.

Ten patients receiving ruxolitinib developed a nonmelanoma skin cancer versus 3 cross over patients and 2 patients receiving BAT. In addition, 3 cases each of polycythemia vera transformed to myelofibrosis in the ruxolitinib arm and ruxolitinib cross over group, 1 of which began before crossing over to ruxolitinib, versus 1 case in the BAT group. One patient developed acute myeloid leukemia in both the ruxolitinib group and the cross over group.

Two patients who crossed over to ruxolitinib treatment had died as of the 48-week analysis, after crossing over. One of the patients died from central nervous system hemorrhage and 1 from multiorgan failure and hypovolemic shock, although this patient had discontinued ruxolitinib because of a grade 3 anemia shortly before she died. These deaths were not considered to be treatment related.

The extended follow-up of the patients in the RESPONSE trial showed that responses to ruxolitinib therapy were durable. Longer-term follow-up to the RESPONSE trial is ongoing and results will be released in the future.


  1. Verstovsek S, Vannucchi AM, Griesshammer M, et al. Ruxolitinib versus best available therapy in patients with polycythemia vera: 80-week follow-up for the RESPONSE trial.Haematologica.2016;101(7):821-829.
  2. Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera.N Engl J Med.2015;372(5):426-435.
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