Long-term efficacy and safety of ruxolitinib versus best available therapy in polycythaemia vera (RESPONSE): 5-year follow up of a phase 3 study

Abstract

Background: Polycythaemia vera is a myeloproliferative neoplasm characterised by excessive proliferation of erythroid, myeloid, and megakaryocytic components in the bone marrow due to mutations in the Janus kinase 2 (JAK2) gene. Ruxolitinib, a JAK 1 and JAK 2 inhibitor, showed superiority over best available therapy in a phase 2 study in patients with polycythaemia vera who were resistant to or intolerant of hydroxyurea. We aimed to compare the long-term safety and efficacy of ruxolitinib with best available therapy in patients with polycythaemia vera who were resistant to or intolerant of hydroxyurea.

Methods: We report the 5-year results for a randomised, open-label, phase 3 study (RESPONSE) that enrolled patients at 109 sites across North America, South America, Europe, and the Asia-Pacific region. Patients (18 years or older) with polycythaemia vera who were resistant to or intolerant of hydroxyurea were randomly assigned 1:1 to receive either ruxolitinib or best available therapy. Patients randomly assigned to the ruxolitinib group received the drug orally at a starting dose of 10 mg twice a day. Single-agent best available therapy comprised hydroxyurea, interferon or pegylated interferon, pipobroman, anagrelide, approved immunomodulators, or observation without pharmacological treatment. The primary endpoint, composite response (patients who achieved both haematocrit control without phlebotomy and 35% or more reduction from baseline in spleen volume) at 32 weeeks was previously reported. Patients receiving best available therapy could cross over to ruxolitinib after week 32. We assessed the durability of primary composite response, complete haematological remission, overall clinicohaematological response, overall survival, patient-reported outcomes, and safety after 5-years of follow-up. This study is registered with ClinicalTrials.gov, NCT01243944.

Findings: We enrolled patients between Oct 27, 2010, and Feb 13, 2013, and the study concluded on Feb 9, 2018. Of 342 individuals screened for eligibility, 222 patients were randomly assigned to receive ruxolitinib (n=110, 50%) or best available therapy (n=112, 50%). The median time since polycythaemia vera diagnosis was 8·2 years (IQR 3·9-12·3) in the ruxolitinib group and 9·3 years (4·9-13·8) in the best available therapy group. 98 (88%) of 112 patients initially randomly assigned to best available therapy crossed over to receive ruxolitinib and no patient remained on best available therapy after 80 weeks of study. Among 25 primary responders in the ruxolitinib group, six had progressed at the time of final analysis. At 5 years, the probability of maintaining primary composite response was 74% (95% CI 51-88). The probability of maintaining complete haematological remission was 55% (95% CI 32-73) and the probability of maintaining overall clinicohaematological responses was 67% (54-77). In the intention-to-treat analysis not accounting for crossover, the probability of survival at 5 years was 91·9% (84·4-95·9) with ruxolitinib therapy and 91·0% (82·8-95·4) with best available therapy. Anaemia was the most common adverse event in patients receiving ruxolitinib (rates per 100 patient-years of exposure were 8·9 for ruxolitinib and 8·8 for the crossover population), though most anaemia events were mild to moderate in severity (grade 1 or 2 anaemia rates per 100 patient-years of exposure were 8·0 for ruxolitinib and 8·2 for the crossover population). Non-haematological adverse events were generally lower with long-term ruxolitinib treatment than with best available therapy. Thromboembolic events were lower in the ruxolitinib group than the best available therapy group. There were two on-treatment deaths in the ruxolitinib group. One of these deaths was due to gastric adenocarcinoma, which was assessed by the investigator as related to ruxolitinib treatment.

Interpretation: We showed that ruxolitinib is a safe and effective long-term treatment option for patients with polycythaemia vera who are resistant to or intolerant of hydroxyurea. Taken together, ruxolitinib treatment offers the first widely approved therapeutic alternative for this post-hydroxyurea patient population.

Funding: Novartis Pharmaceuticals Corporation.

Conflict of interest statement

Declaration of interests

JJK reports membership on an entity’s board of directors or advisory committees and research funding for Novartis, AOP Orphan, and Celgene. MH reports honoraria and research funding from Otsuka Pharmaceutical, Kyowa-Kirin, Chugai, Astellas, Takeda, MSD, Sumitomo Dainippon, Pfizer, and Daiichisankyo: research funding from Taiho, Teijin, Eisai, Japan Blood Products Organization, and Nihon Pharmaceutical; honoraria from BMS, Jansenn, Celgene, Mochida, Ono, Sanofi, Nippon Shinyaku, Mundi Pharma, and Alexion. FP reports research funding and speakers bureau from Novartis and personal fees from Celgene. TM reports consultancy for AbbVie, BMS, Janssen-Cilag, Novartis, Pfizer, and Takeda. CNH reports consultancy, honoraria, research funding, and speakers bureau from Novartis; consultancy, honoraria, and speakers bureau from Celgene; consultancy and honoraria from Roche and CTI BioPharma; personal fees from AOP, Jannsen, Sierra Oncology, Promedior. RM reports consultancy for Novartis, Sierra Oncology, and LaJolla; and research funding from Incyte, Abbvie, Genentech, and Celgene. CBM reports honoraria and speakers bureau from Novartis; and consultancy, honoraria, research funding, and speakers bureau from Incyte. FP reports consultancy and speakers bureau for Novartis, Celgene, Roche, and Janssen. MG reports membership on an entity’s board of directors or advisory committees and speakers bureau for Novartis. KK reports honoraria for Novartis. ER reports a speakers bureau for Novartis. NF, TD, and MW report employment and equity ownership for Novartis. AMV reports speakers bureau, and membership on an entity’s board of directors or advisory committees for Novartis and CTI BioPharma; and membership on an entity’s board of directors or advisory committees for Celgene and Incyte. SV reports consultancy for Novartis, Constellation, Pragmatist, Sierra, Incyte, and Celegene; and honoraria and research funding for Incyte, Roche, NS Pharma, Celgene, Gilead, Promedior, CTI Biopharma, Genentech, and Blueprint Medicines. CB, PZ, BM, VR, SD, and IWB declare no competing interests.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Figures

Figure 1:. Trial profile

*Reasons for ineligibility are described in detail in the appendix (p 1); patients might have more than one reason for ineligibility. †One patient was randomly assigned to best available therapy but did not receive study treatment. Initial best available therapy comprised hydroxyurea (n=66), interferon or pegylated interferon (n=13), anagrelide (n=8), immunomodulators (n=5), pipobroman (n=2), and observation (n=17). ‡98 of 112 patients were eligible for cross over to ruxolitinib. §One patient in the ruxolitinib group, determined by the investigator to have discontinued the study treatment because of adverse events, died afterwards.

Figure 2:. Response in patients treated with ruxolitinib

(A) Primary response (patients who achieved both haematocrit control without phlebotomy and 35% or more reduction from baseline in spleen volume). There were 25 responders, six events, and 19 censored. (B) Complete haematological remission. There were 26 responders, ten events, and 16 censored. (C) Overall clinicohaematological response. There were 70 responders, 21 events, and 49 censored. Crosses indicate censored patients.

Figure 3:. Overall survival by intention-to-treat analysis

HR=hazard ratio. Crosses indicate censored patients.