Polycythaemia vera is a myeloproliferative neoplasm characterised by clonal stem-cell proliferation of erythroid, myeloid, and megakaryocytic cell lines.1, 2 Most patients have an activating Janus kinase 2 (JAK2) mutation (JAK2 Val617Phe or exon 12 mutation), leading to an overactive JAK–STAT signalling pathway, unregulated myeloid cell proliferation, and imbalances in cytokine production.1, 3 Polycythaemia vera is characterised by erythrocytosis, with an associated increase in white blood cell and platelet counts in about 40% of patients.4 Patients with polycythaemia vera are at high risk of vascular complications, which are associated with advanced age, history of thrombosis, and leukocytosis,5 and these patients also have a shortened life expectancy.6 Genetic instability predisposes to clonal evolution, and patients might progress to postpolycythaemia vera myelofibrosis or acute myeloid leukaemia.7, 8 Patients with polycythaemia vera also have a substantial symptom burden, including pruritus, fatigue, and night sweats.9 Additionally, splenomegaly can be observed in about 30% of patients during the course of the disease.9
Research in context
Evidence before this study
We searched PubMed for articles published in the past 10 years (July 1, 2006–July 1, 2016) that reported findings from phase 3 studies assessing commercially available therapies in patients with polycythaemia vera who were resistant to or intolerant of hydroxyurea. The search terms used were “polycythemia vera AND hydroxyurea AND resistance”, “polycythemia vera AND second-line”, and “polycythemia vera AND phase 3”. Before our study, the only phase 3 study assessing treatment in this setting was the RESPONSE study, which investigated the Janus kinase (JAK)1 and JAK2 inhibitor ruxolitinib in patients with polycythaemia vera who had an inadequate response to or unacceptable side-effects from hydroxyurea and presented with splenomegaly. Other studies assessed the use of anagrelide or busulfan in patients with polycythaemia vera who were resistant to or intolerant of hydroxyurea. Both agents showed efficacy, but the studies were small (≤15 patients with polycythaemia vera). Busulfan, in particular, was associated with a high rate of transformation. Interferon was considered a second-line therapy for patients with polycythaemia vera and was assessed in two phase 2 studies, with positive results. However, patients in these two studies were not resistant to or intolerant of hydroxyurea. Of interest, the use of interferon was reported in the prospective RESPONSE study; however, response rates were inferior to those of ruxolitinib in patients with polycythaemia vera who had an inadequate response to or intolerable side-effects from hydroxyurea. Our search also identified reviews of the current treatment landscape for patients with polycythaemia vera. In general, these reviews highlighted the few treatment options for those who are resistant to or intolerant of hydroxyurea, with JAK inhibitors representing a new therapeutic option for patients with polycythaemia vera in need of second-line therapy.
Added value of this study
Findings from our randomised phase 3b study showed that ruxolitinib is superior to best available therapy at providing control of haematocrit, inducing complete haematological remission, and improving disease-associated symptoms in patients with polycythaemia vera who have an inadequate response to or have unacceptable side-effects from hydroxyurea therapy, regardless of spleen size.
Implications of all the available evidence
Our findings, taken together with other studies in patients with polycythaemia vera who are resistant to or intolerant of hydroxyurea, show that ruxolitinib is safe and effective in these patients and could be considered a standard of care for second-line therapy in this patient population.
Therapeutic options aim to reduce thrombotic risk and include phlebotomy and low-dose aspirin; cytoreductive drugs, usually hydroxyurea, are given to patients with high-risk disease.10 A prospective randomised trial unequivocally showed that maintenance of haematocrit level at less than 45% resulted in a four-times lower incidence of death from cardiovascular causes or major thrombosis than did maintaining haematocrit at 45–50%.11 A subsequent multivariable analysis found that a white blood cell count of greater than 11 × 109 cells per L was an independent risk factor for thrombosis.12 Improvement of polycythaemia vera-related symptoms during follow-up has already been shown to improve quality of life.13
In some patients, conventional therapies can lose effectiveness over time.14, 15 Although hydroxyurea is well tolerated in most patients, about 15–20% of patients become resistant or intolerant,14, 15 with hydroxyurea resistance affecting survival and increasing the risk of progression to myelofibrosis.4, 14 Additionally, patients who are intolerant of hydroxyurea can have adverse side-effects, such as drug-induced fever, mouth ulcers, leg ulcers, and skin malignancies, which necessitate discontinuation of first-line therapy.16
Patients who are resistant to or intolerant of hydroxyurea have few therapeutic options.5 Ruxolitinib, a JAK1 and JAK2 inhibitor, was approved in the European Union17 on Jan 22, 2015, for patients with polycythaemia vera who are resistant to or intolerant of hydroxyurea and in the USA18 on Dec 4, 2014, for patients who have had an inadequate response to or are intolerant of the treatment. These approvals were based on findings from the phase 3 RESPONSE study, which showed ruxolitinib to be superior to the best available therapy at controlling haematocrit, improving splenomegaly, and improving symptoms in patients with polycythaemia vera and disease-associated splenomegaly who had an inadequate response to or unacceptable side-effects from hydroxyurea.13 This benefit occurred regardless of the degree of splenomegaly at baseline.19
Although splenomegaly is an important indicator of advanced disease20 and has been associated with decreased survival,21 only 18% of patients who are resistant to or intolerant of hydroxyurea by European LeukemiaNet (ELN) criteria have splenomegaly.15 We present findings from the primary analysis of the RESPONSE-2 study, a phase 3b study in patients without palpable splenomegaly who had an inadequate response to or unacceptable side-effects from hydroxyurea.