Elsevier

The Lancet Oncology

Volume 18, Issue 1, January 2017, Pages 88-99
The Lancet Oncology

Articles
Ruxolitinib for the treatment of inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): a randomised, open-label, phase 3b study

https://doi.org/10.1016/S1470-2045(16)30558-7Get rights and content

Summary

Background

In the pivotal RESPONSE study, ruxolitinib, a Janus kinase (JAK)1 and JAK2 inhibitor, was superior to best available therapy at controlling haematocrit and improving splenomegaly and symptoms in patients with polycythaemia vera with splenomegaly who were inadequately controlled with hydroxyurea. In this study, we assessed the efficacy and safety of ruxolitinib in controlling disease in patients with polycythaemia vera without splenomegaly who need second-line therapy.

Methods

RESPONSE-2 is a randomised, open-label, phase 3b study assessing ruxolitinib versus best available therapy in patients with polycythaemia vera done in 48 hospitals or clinics across 12 countries in Asia, Australia, Europe, and North America. Eligible patients (aged ≥18 years) with polycythaemia vera, no palpable splenomegaly, and hydroxyurea resistance or intolerance were stratified by their hydroxyurea therapy status (resistance vs intolerance) and randomly assigned (1:1) by an interactive response technology provider using a validated system to receive either oral ruxolitinib 10 mg twice daily or investigator-selected best available therapy (hydroxyurea [at the maximum tolerated dose], interferon or pegylated interferon, pipobroman, anagrelide, approved immunomodulators, or no cytoreductive treatment). Investigators and patients were not masked to treatment assignment; however, the study sponsor was masked to treatment assignment until database lock. The primary endpoint was the proportion of patients achieving haematocrit control at week 28. Analyses were done according to an intention-to-treat principle, including data from all patients randomly assigned to treatment. This study is registered with ClinicalTrials.gov (NCT02038036) and is ongoing but not recruiting patients.

Findings

Between March 25, 2014, and Feb 11, 2015, of 173 patients assessed for eligibility, 74 patients were randomly assigned to receive ruxolitinib and 75 to receive best available therapy. At randomisation, best available therapy included hydroxyurea (37 [49%] of 75 in the best available therapy group), interferon or pegylated interferon (ten [13%] of 75), pipobroman (five [7%] of 75), lenalidomide (one [1%] of 75), no treatment (21 [28%] of 75), and other (one [1%] of 75). Haematocrit control was achieved in 46 (62%) of 74 ruxolitinib-treated patients versus 14 (19%) of 75 patients who received best available therapy (odds ratio 7·28 [95% CI 3·43–15·45]; p<0·0001). The most frequent haematological adverse events of any grade were anaemia (ten [14%] of 74 in the ruxolitinib group vs two [3%] of 75 in the best available therapy group) and thrombocytopenia (two [3%] vs six [8%]). No cases of grade 3–4 anaemia or thrombocytopenia occurred with ruxolitinib; one patient (1%) reported grade 3–4 anaemia and three patients (4%) reported grade 3–4 thrombocytopenia in the group receiving best available therapy. Frequent grade 3–4 non-haematological adverse events were hypertension (five [7%] of 74 vs three [4%] of 75) and pruritus (0 of 74 vs two [3%] of 75). Serious adverse events occurring in more than 2% of patients in either group, irrespective of cause, included thrombocytopenia (none in the ruxolitinib group vs two [3%] of 75 in the best available therapy group) and angina pectoris (two [3%] of 74 in the ruxolitinib group vs none in the best available therapy group). Two deaths occurred, both in the best available therapy group.

Interpretation

RESPONSE-2 met its primary endpoint. The findings of this study indicate that ruxolitinib could be considered a standard of care for second-line therapy in this post-hydroxyurea patient population.

Funding

Novartis.

Introduction

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.

Section snippets

Study design and participants

RESPONSE-2 is a prospective, randomised, open-label, multicentre, phase 3b study assessing the efficacy and safety of ruxolitinib versus best available therapy in patients with polycythaemia vera without splenomegaly who need second-line therapy. The study was done in 48 hospitals or clinics across 12 countries (Australia, Belgium, Canada, France, Germany, Hungary, India, Israel, Italy, Korea, Spain, and Turkey; appendix pp 6–7). The study was approved by the institutional review board or

Results

Between March 25, 2014, and Feb 11, 2015, a total of 173 patients were screened for eligibility; 149 eligible patients were enrolled and randomly assigned to receive either ruxolitinib (n=74) or best available therapy (n=75; figure 1). In general, baseline characteristics were similar between treatment groups; however, there were slight differences in median age and sex between the groups (table 1). Overall, 105 (70%) of 149 patients across both treatment groups had received only one previous

Discussion

The results of this study showed that ruxolitinib was superior to best available therapy at controlling haematocrit level in patients with polycythaemia vera who had an inadequate response to or unacceptable side-effects from previous hydroxyurea therapy. Additionally, more than 80% of patients treated with ruxolitinib were phlebotomy-free compared with 40% of patients treated with best available therapy, further highlighting the benefit provided by ruxolitinib treatment. Ruxolitinib also led

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