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.

中文翻译：

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鲁索替尼与真性红细胞增多症最佳可用疗法的长期疗效和安全性（响应）：3 期研究的 5 年随访。

背景技术 真性红细胞增多症是一种骨髓增生性肿瘤，其特征是由于 Janus 激酶 2 (JAK2) 基因突变导致骨髓中红细胞、髓细胞和巨核细胞成分过度增殖。鲁索替尼是一种 JAK 1 和 JAK 2 抑制剂，在对羟基脲耐药或不耐受的真性红细胞增多症患者的 2 期研究中显示优于最佳可用疗法。我们旨在比较鲁索替尼与最佳可用疗法在对羟基脲耐药或不耐受的真性红细胞增多症患者中的长期安全性和有效性。方法 我们报告了一项随机、开放标签、3 期研究 (RESPONSE) 的 5 年结果，该研究在北美、南美、欧洲和亚太地区的 109 个地点招募了患者。对羟基脲耐药或不耐受的真性红细胞增多症患者（18 岁或以上）以 1:1 的比例随机分配接受鲁索替尼或最佳可用治疗。随机分配到鲁索替尼组的患者每天两次口服药物，起始剂量为 10 mg。单药最佳可用疗法包括羟基脲、干扰素或聚乙二醇化干扰素、哌泊溴曼、阿那格雷、经批准的免疫调节剂或无药物治疗的观察。先前报道了 32 周时的主要终点，复合反应（在没有放血的情况下实现了血细胞比容控制和脾脏体积从基线减少 35% 或更多的患者）。接受最佳可用治疗的患者可在第 32 周后转用鲁索替尼。我们评估了主要复合反应的持久性，5 年随访后的完全血液学缓解、总体临床血液学反应、总体生存率、患者报告的结果和安全性。该研究已在 ClinicalTrials.gov 注册，NCT01243944。结果 我们在 2010 年 10 月 27 日至 2013 年 2 月 13 日期间招募了患者，研究于 2018 年 2 月 9 日结束。在筛选合格的 342 人中，222 名患者被随机分配接受鲁索替尼（n=110, 50%）或最佳可用疗法（n=112, 50%）。鲁索替尼组自诊断为真性红细胞增多症的中位时间为 8·2 年（IQR 3·9-12·3），而最佳可用治疗组为 9·3 年（4·9-13·8）。最初被随机分配到最佳可用治疗的 112 名患者中有 98 名（88%）交叉接受鲁索替尼，并且在 80 周的研究后没有患者继续接受最佳可用治疗。在 ruxolitinib 组的 25 名主要反应者中，有 6 名在最终分析时出现了进展。5 年时，维持主要复合反应的概率为 74% (95% CI 51-88)。维持血液学完全缓解的概率为 55% (95% CI 32-73)，维持整体临床血液学反应的概率为 67% (54-77)。在不考虑交叉的意向治疗分析中，鲁索替尼治疗的 5 年生存概率为 91·9% (84·4-95·9) 和 91·0% (82·8-95·4 ) 最好的治疗。贫血是接受鲁索替尼治疗的患者最常见的不良事件（每 100 患者年暴露的发生率对于鲁索替尼为 8·9，对于交叉人群为 8·8），尽管大多数贫血事件的严重程度为轻度至中度（每 100 患者年暴露的 1 级或 2 级贫血率对于 ruxolitinib 为 8·0，对于交叉人群为 8·2）。长期鲁索替尼治疗的非血液学不良事件通常低于最佳可用治疗。鲁索替尼组的血栓栓塞事件低于可用的最佳治疗组。鲁索替尼组有两例治疗期间死亡。其中一名死亡是由于胃腺癌，研究者评估其与鲁索替尼治疗有关。解释 我们表明，对于对羟基脲耐药或不耐受的真性红细胞增多症患者，鲁索替尼是一种安全有效的长期治疗选择。综合起来，ruxolitinib 治疗为这种羟基脲后患者群体提供了第一个被广泛批准的治疗替代方案。资助诺华制药公司。