Ruxolitinib versus standard therapy for the treatment of polycythemia vera

Abstract

Background: Ruxolitinib, a Janus kinase (JAK) 1 and 2 inhibitor, was shown to have a clinical benefit in patients with polycythemia vera in a phase 2 study. We conducted a phase 3 open-label study to evaluate the efficacy and safety of ruxolitinib versus standard therapy in patients with polycythemia vera who had an inadequate response to or had unacceptable side effects from hydroxyurea.

Methods: We randomly assigned phlebotomy-dependent patients with splenomegaly, in a 1:1 ratio, to receive ruxolitinib (110 patients) or standard therapy (112 patients). The primary end point was both hematocrit control through week 32 and at least a 35% reduction in spleen volume at week 32, as assessed by means of imaging.

Results: The primary end point was achieved in 21% of the patients in the ruxolitinib group versus 1% of those in the standard-therapy group (P<0.001). Hematocrit control was achieved in 60% of patients receiving ruxolitinib and 20% of those receiving standard therapy; 38% and 1% of patients in the two groups, respectively, had at least a 35% reduction in spleen volume. A complete hematologic remission was achieved in 24% of patients in the ruxolitinib group and 9% of those in the standard-therapy group (P=0.003); 49% versus 5% had at least a 50% reduction in the total symptom score at week 32. In the ruxolitinib group, grade 3 or 4 anemia occurred in 2% of patients, and grade 3 or 4 thrombocytopenia occurred in 5%; the corresponding percentages in the standard-therapy group were 0% and 4%. Herpes zoster infection was reported in 6% of patients in the ruxolitinib group and 0% of those in the standard-therapy group (grade 1 or 2 in all cases). Thromboembolic events occurred in one patient receiving ruxolitinib and in six patients receiving standard therapy.

Conclusions: In patients who had an inadequate response to or had unacceptable side effects from hydroxyurea, ruxolitinib was superior to standard therapy in controlling the hematocrit, reducing the spleen volume, and improving symptoms associated with polycythemia vera. (Funded by Incyte and others; RESPONSE ClinicalTrials.gov number, NCT01243944.).

Figure 1. Ruxolitinib Discontinuations

Shown are Kaplan–Meier estimates of the probability of continued use of ruxolitinib therapy after randomization.

Figure 2. Primary Response and Duration of Response

Panel A shows the percentage of patients who met the composite primary end point of hematocrit control through week 32 and at least a 35% reduction in spleen volume at week 32 (primary response). Individual components of the primary end point are also shown. To have hematocrit control, patients could not be eligible for phlebotomy on the basis of protocol-defined hematocrit values (with eligibility defined as a hematocrit >45% and ≥3 percentage points higher than the baseline level or a hematocrit >48%). Patients who discontinued therapy or had missing data or assessments outside protocol-defined windows were considered not to have had a response. Panel B shows the duration of the primary response, defined as the time from the initial documented response to the loss of response (event).

Figure 3. Symptom Assessments

Panel A shows the percentage of patients who had at least a 50% reduction in the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) total symptom score (with regard to 14 symptoms; higher scores indicate greater severity of symptoms) and in total scores for the cytokine symptom cluster (tiredness, itching, muscle ache, night sweats, and sweating while awake), the hyperviscosity symptom cluster (vision problems, dizziness, concentration problems, headache, numbness or tingling in the hands or feet, ringing in the ears, and skin redness), and the splenomegaly symptom cluster (abdominal discomfort and early satiety) at week 32. Panel B shows the median percentage change from baseline to week 32 in the score for each of the 14 symptoms on the MPN-SAF. Patients with data at both baseline (value >0) and week 32 were included in the analyses for both panels. Negative values indicate a reduction in the severity of symptoms.