Gisslinger Heinz, Klade Christoph, Georgiev Pencho, Krochmalczyk Dorota, Gercheva-Kyuchukova Liana, Egyed Miklos, Rossiev Viktor, Dulicek Petr, Illes Arpad, Pylypenko Halyna, Sivcheva Lylia, Mayer Jiri, Yablokova Vera, Krejcy Kurt, Grohmann-Izay Barbara, Hasselbalch Hans C, Kralovics Robert, Kiladjian Jean-Jacques
Department of Internal Medicine I, Division of Haematology and Blood Coagulation, Medical University Vienna, Vienna, Austria.
AOP Orphan Pharmaceuticals AG, Vienna, Austria.
Lancet Haematol. 2020 Mar;7(3):e196-e208. doi: 10.1016/S2352-3026(19)30236-4. Epub 2020 Jan 31.
The PROUD-PV and CONTINUATION-PV trials aimed to compare the novel monopegylated interferon ropeginterferon alfa-2b with hydroxyurea, the standard therapy for patients with polycythaemia vera, over 3 years of treatment.
PROUD-PV and its extension study, CONTINUATION-PV, were phase 3, randomised, controlled, open-label, trials done in 48 clinics in Europe. Patients were eligible if 18 years or older with early stage polycythaemia vera (no history of cytoreductive treatment or less than 3 years of previous hydroxyurea treatment) diagnosed by WHO's 2008 criteria. Patients were randomly assigned 1:1 to ropeginterferon alfa-2b (subcutaneously every 2 weeks, starting at 100 μg) or hydroxyurea (orally starting at 500 mg/day). After 1 year, patients could opt to enter the extension part of the trial, CONTINUATION-PV. The primary endpoint in PROUD-PV was non-inferiority of ropeginterferon alfa-2b versus hydroxyurea regarding complete haematological response with normal spleen size (longitudinal diameter of ≤12 cm for women and ≤13 cm for men) at 12 months; in CONTINUATION-PV, the coprimary endpoints were complete haematological response with normalisation of spleen size and with improved disease burden (ie, splenomegaly, microvascular disturbances, pruritus, and headache). We present the final results of PROUD-PV and an interim analysis at 36 months of the CONTINUATION-PV study (per statistical analysis plan). Analyses for safety and efficacy were per-protocol. The trials were registered on EudraCT, 2012-005259-18 (PROUD-PV) and 2014-001357-17 (CONTINUATION-PV, which is ongoing).
Patients were recruited from Sept 17, 2013 to March 13, 2015 with 306 enrolled. 257 patients were randomly assigned, 127 were treated in each group (three patients withdrew consent in the hydroxyurea group), and 171 rolled over to the CONTINUATION-PV trial. Median follow-up was 182·1 weeks (IQR 166·3-201·7) in the ropeginterferon alfa-2b and 164·5 weeks (144·4-169·3) in the standard therapy group. In PROUD-PV, 26 (21%) of 122 patients in the ropeginterferon alfa-2b group and 34 (28%) of 123 patients in the standard therapy group met the composite primary endpoint of complete haematological response with normal spleen size. In CONTINUATION-PV, complete haematological response with improved disease burden was met in 50 (53%) of 95 patients in the ropeginterferon alfa-2b group versus 28 (38%) of 74 patients in the hydroxyurea group, p=0·044 at 36 months. Complete haematological response without the spleen criterion in the ropeginterferon alfa-2b group versus standard therapy group were: 53 (43%) of 123 patients versus 57 (46%) of 125 patients, p=0·63 at 12 months (PROUD-PV), and 67 (71%) of 95 patients versus 38 (51%) of 74 patients, p=0·012 at 36 months (CONTINUATION-PV). The most frequently reported grade 3 and grade 4 treatment-related adverse events were increased γ-glutamyltransferase (seven [6%] of 127 patients) and increased alanine aminotransferase (four [3%] of 127 patients) in the ropeginterferon alfa-2b group, and leucopenia (six [5%] of 127 patients) and thrombocytopenia (five [4%] of 127 patients) in the standard therapy group. Treatment-related serious adverse events occurred in three (2%) of 127 patients in the ropeginterferon alfa-2b group and five (4%) of 127 patients in the hydroxyurea group. One treatment-related death was reported in the standard therapy group (acute leukaemia).
In patients with early polycythaemia vera, who predominantly presented without splenomegaly, ropeginterferon alfa-2b was effective in inducing haematological responses; non-inferiority to hydroxyurea regarding haematological response and normal spleen size was not shown at 12 months. However, response to ropeginterferon alfa-2b continued to increase over time with improved responses compared with hydroxyurea at 36 months. Considering the high and durable haematological and molecular responses and its good tolerability, ropeginterferon alfa-2b offers a valuable and safe long-term treatment option with features distinct from hydroxyurea.
AOP Orphan Pharmaceuticals AG.
PROUD-PV试验和CONTINUATION-PV试验旨在比较新型单聚乙二醇化干扰素罗培干扰素α-2b与羟基脲（真性红细胞增多症患者的标准疗法）在3年治疗期内的疗效。
PROUD-PV试验及其扩展研究CONTINUATION-PV试验是在欧洲48家诊所开展的3期随机对照开放标签试验。符合入选标准的患者年龄在18岁及以上，根据世界卫生组织2008年标准诊断为早期真性红细胞增多症（无细胞减灭治疗史或既往羟基脲治疗少于3年）。患者按1:1随机分配接受罗培干扰素α-2b（每2周皮下注射一次，起始剂量为100μg）或羟基脲（口服，起始剂量为500mg/天）治疗。1年后，患者可选择进入试验的扩展部分CONTINUATION-PV试验。PROUD-PV试验的主要终点是在12个月时，罗培干扰素α-2b在使脾脏大小正常化（女性脾脏纵径≤12cm，男性脾脏纵径≤13cm）的情况下，与羟基脲相比在完全血液学缓解方面的非劣效性；在CONTINUATION-PV试验中，并同主要终点是脾脏大小正常化且疾病负担改善（即脾肿大、微血管病变、瘙痒和头痛）的完全血液学缓解。我们展示了PROUD-PV试验的最终结果以及CONTINUATION-PV试验36个月时的中期分析结果（根据统计分析计划）。安全性和疗效分析均按照方案进行。这些试验已在欧洲药品管理局临床试验数据库（EudraCT）注册，注册号分别为2012-005259-18（PROUD-PV）和2014-001357-17（CONTINUATION-PV，该试验正在进行）。
患者于2013年9月17日至2015年3月日入组，共纳入306例。257例患者被随机分组，每组127例（羟基脲组有3例患者撤回同意书），171例患者进入CONTINUATION-PV试验。罗培干扰素α-2b组的中位随访时间为182.1周（四分位间距166.3 - 201.7周），标准治疗组为164.5周（144.4 - 169.3周）。在PROUD-PV试验中，罗培干扰素α-2b组122例患者中有26例（21%）、标准治疗组123例患者中有34例（28%）达到了脾脏大小正常化的完全血液学缓解这一复合主要终点。在CONTINUATION-PV试验中，36个月时，罗培干扰素α-2b组95例患者中有50例（53%）达到了疾病负担改善的完全血液学缓解，而羟基脲组74例患者中有28例（%）达到该标准，p = 0.044。罗培干扰素α-2b组与标准治疗组在不考虑脾脏标准的完全血液学缓解情况如下：12个月时（PROUD-PV试验），123例患者中有53例（43%），125例患者中有57例（46%），p = 0.63；36个月时（CONTINUATION-PV试验），95例患者中有67例（71%），74例患者中有38例（51%），p = 0.012。罗培干扰素α-2b组最常报告的3级和4级治疗相关不良事件是γ-谷氨酰转移酶升高（127例患者中有7例[6%]）和丙氨酸氨基转移酶升高（127例患者中有4例[3%]），标准治疗组是白细胞减少（127例患者中有6例[5%]）和血小板减少（127例患者中有5例[4%]）。罗培干扰素α-2b组127例患者中有3例（2%）、羟基脲组127例患者中有5例（4%）发生了治疗相关严重不良事件。标准治疗组报告了1例治疗相关死亡（急性白血病）。
在主要无脾肿大表现的早期真性红细胞增多症患者中，罗培干扰素α-2b在诱导血液学缓解方面有效；在12个月时，未显示其在血液学缓解和脾脏大小正常化方面不劣于羟基脲。然而，随着时间推移，罗培干扰素α-2b的缓解率持续上升，在36个月时与羟基脲相比缓解情况有所改善。鉴于其高度持久的血液学和分子学缓解以及良好的耐受性，罗培干扰素α-2b提供了一种有价值且安全的长期治疗选择，其特点与羟基脲不同。
AOP孤儿药制药公司。
