A phase 2 study of ruxolitinib, an oral JAK1 and JAK2 Inhibitor, in patients with advanced polycythemia vera who are refractory or intolerant to hydroxyurea

Abstract

Background: Polycythemia vera (PV) is a myeloproliferative neoplasm associated with somatic gain-of-function mutations of Janus kinase-2 (JAK2). Therapeutic options are limited in patients with advanced disease. Ruxolitinib, an oral JAK1/JAK2 inhibitor, is active in preclinical models of PV. The long-term efficacy and safety of ruxolitinib in patients with advanced PV who are refractory or intolerant to hydroxyurea were studied in a phase 2 trial.

Methods: Response was assessed using modified European LeukemiaNet criteria, which included a reduction in hematocrit to <45% without phlebotomy, resolution of palpable splenomegaly, normalization of white blood cell and platelet counts, and reduction in PV-associated symptoms.

Results: Thirty-four patients received ruxolitinib for a median of 152 weeks (range, 31 weeks-177 weeks) or 35.0 months (range, 7.1 months-40.7 months). Hematocrit <45% without phlebotomy was achieved in 97% of patients by week 24.Only 1 patient required a phlebotomy after week 4. Among patients with palpable splenomegaly at baseline, 44% and 63%, respectively, achieved nonpalpable spleen measurements at weeks 24 and 144. Clinically meaningful improvements in pruritus, night sweats, and bone pain were observed within 4 weeks of the initiation of therapy and maintained with continued treatment. Ruxolitinib treatment also reduced elevated levels of inflammatory cytokines and granulocyte activation. Thrombocytopenia and anemia were the most common adverse events.Thrombocytopenia of grade 3 or anemia of grade 3 (according to National Cancer Institute Common Terminology Criteria for Adverse Events,version 3.0) occurred in 3 patients each (9%) (1 patient had both) and were managed with dose modification.

Conclusions: Ruxolitinib was generally well tolerated and provided rapid and durable clinical benefits in patients with advanced PV who were refractory or intolerant to hydroxyurea.

Figure 1

Response to ruxolitinib is shown as measured by modified 2009 European LeukemiaNet criteria. (a) Kaplan-Meier plot of the cumulative probability over time of achieving either a complete response (CR) or a partial response (PR) as the observed first response is shown. (b) Kaplan-Meier plot of the cumulative probability over time of achieving a best response of a CR or PR is shown. Note that the cumulative probability of CR and PR does not add up to 1 because patients with a CR as their best response were censored at the time of CR for analysis of PR. (c) Kaplan-Meier plot of time to first hematocrit ≥ 45% is shown.

Figure 2

Laboratory and clinical responses to treatment with ruxolitinib are shown. (a) The median hemoglobin levels with their interquartile ranges (IQRs) are shown. (b) The median white blood cell count with the IQR is shown. (c) The median platelet count with the IQR is shown. (d) The percentage of patients with a palpable spleen at baseline who achieved a ≥ 50% reduction in palpable spleen length and those who reduced their spleen size to nonpalpable at each visit are shown. Twenty-five patients had a palpable spleen at baseline; therefore, for the analysis of palpable to nonpalpable spleen length, the number was 25 at all visits except for week 144, when there were 24 evaluable patients (1 patient was missing data). Two patients had a palpable spleen at baseline but no specific measurement was recorded. Thus, for analysis of the ≥ 50% reduction in palpable spleen length, the number was 23 at all visits except for week 144, when there were 22 evaluable patients (1 patient had missing data).

Figure 3

Reduction in polycythemia vera-associated symptoms with ruxolitinib therapy is shown. The percentages of patients who were treated with ruxolitinib and who achieved a ≥ 50% reduction and a 100% reduction in pruritus, night sweats, and bone pain over the previous week among patients with symptom scores > 2 at baseline are shown. A 100% reduction corresponds to a score of 0 for individual symptoms.