Background

Aplastic anaemia is a rare, life-threatening condition, characterised by pancytopenia with hypocellular bone marrow. Haematopoietic stem cells and most progenitor cells express thrombopoietin receptor (c-MPL). Romiplostim is a peptibody with c-MPL agonist activity that stimulates endogenous thrombopoietin production and leads to promoting the proliferation and differentiation of megakaryocytes in the bone marrow. In this phase 2 trial we aimed to assess the activity and safety of romiplostim in patients with aplastic anaemia who were previously treated with immunosuppressive therapy.

Methods

We did an open-label, phase 2 study including a randomised, parallel, dose-finding part followed by an extension part to evaluate long-term treatment at two clinical centres in Seoul, South Korea. Eligible patients were aged 19 years or older, and had aplastic anaemia confirmed by bone marrow and cytogenetic studies and thrombocytopenia (platelet count ≤30 × 10⁹/L), an Eastern Cooperative Oncology Group performance status score of 2 or lower, and were previously treated with immunosuppressive therapy, including at least one course of antithymocyte globulin plus cyclosporin. In the dose-finding part, patients were randomly assigned to fixed dose cohorts (1, 3, 6, or 10 μg/kg) of subcutaneous romiplostim once weekly for 8 weeks, according to a static allocation procedure after stratification by platelet count. In the extension part of the study, patients continued romiplostim titrated every 4 weeks in single steps (1, 3, 6, 10, 13, 16, and 20 μg/kg once weekly), depending on platelet response and safety up to 1 year (weeks 9–52). Patients who had a platelet response during weeks 46–53 continued dose titration in single steps (3, 6, 10, 13, 16, and 20 μg/kg once weekly) for an additional 2 years (weeks 53–156). The primary endpoint was the proportion of patients achieving a platelet response at week 9 (after completion of the dose-finding part). Activity was assessed per-protocol in all patients evaluable for response at week 9 and safety was assessed in all patients who received at least one dose of romiplostim. This trial is registered with ClinicalTrials.gov, NCT02094417.

Findings

Between April 14 and Nov 24, 2014, 35 patients were enrolled and randomly assigned to one of four dose cohorts: romiplostim 1 μg/kg (n=7), 3 μg/kg (n=9), 6 μg/kg (n=9), and 10 μg/kg (n=10). Data cutoff for this final analysis was on April 14, 2018. The median duration of treatment for all patients was 53 weeks (IQR 35–155). Ten (30%) of 33 evaluable patients achieved a platelet response at week 9, including seven (70%) of ten patients in the 10 μg/kg cohort, three (33%) of nine patients in the 6 μg/kg cohort, and no patients in both the 3 μg/kg and 1 μg/kg cohorts. During the extension study, 18 (55%) of 33 evaluable patients had a platelet response during weeks 46–53 and were eligible for continued treatment. Ten (30%) patients maintained a platelet response at 2 and 3 years, of whom nine had an erythroid response and five a neutrophil response, and completed protocol treatment. Treatment-related adverse events occurred in three (9%) of 35 patients, including grade 1 or 2 myalgia, fatigue, and dizziness. 17 (49%) of 35 patients had adverse events of grade 3 or higher; seven (20%) had serious adverse events (one event of febrile neutropenia, cataract, retinal detachment, macular fibrosis, inguinal hernia, appendicitis, cellulitis, tendon injury, and transfusion reaction); and one patient died from sepsis during treatment; none of these events were related to treatment. No patients developed clonal evolution.

Interpretation

Romiplostim seems to be active and has a favourable safety profile in patients with refractory aplastic anaemia. 10 μg/kg once weekly might be used as a recommended starting dose in future studies. These findings warrant further investigation.

Funding

Kyowa Hakko Kirin Korea.

中文翻译：

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先前接受过免疫抑制治疗的难治性再生障碍性贫血患者中的Romiplostim：一项剂量确定和长期治疗2期试验

背景

再生障碍性贫血是一种罕见的危及生命的疾病，其特征是全血细胞减少症伴有低细胞性骨髓。造血干细胞和大多数祖细胞表达血小板生成素受体（c-MPL）。Romiplostim是一种具有c-MPL激动剂活性的肽体，可刺激内源性血小板生成素的产生并促进骨髓中巨核细胞的增殖和分化。在这项2期试验中，我们旨在评估romiplostim在再生障碍性贫血患者中的活性和安全性，这些患者先前曾接受过免疫抑制治疗。

方法

我们进行了一项开放标签的2期研究，包括随机，平行，剂量寻找部分，然后是扩展部分，以评估在韩国首尔的两个临床中心的长期治疗。符合条件的患者年龄在19岁或以上，并通过骨髓和细胞遗传学研究以及血小板减少症（血小板计数≤30×10 ^9）证实患有再生障碍性贫血。/ L），东部合作肿瘤小组的工作状态评分为2或更低，并且之前接受过免疫抑制治疗，包括至少一个疗程的抗胸腺细胞球蛋白加环孢菌素。在剂量确定部分，根据血小板计数分层后的静态分配程序，每周一次将患者随机分配至固定剂量组（1、3、6、10μg/ kg）皮下注射罗莫司汀，持续8周。在研究的扩展部分，根据血小板反应和长达1年的安全性，患者每4周连续逐步滴加罗莫司汀滴定（每周一次1、3、6、10、13、16和20μg/ kg），具体取决于血小板反应和安全性（第9–52周）。在46-53周内有血小板反应的患者可以单步继续进行剂量滴定（3、6、10、13、16，每周一次，每次20μg/ kg），另外两年（第53-156周）。主要终点指标是在第9周（完成剂量确定部分后）达到血小板反应的患者比例。在第9周评估所有可评估疗效的患者，均按方案评估活性，并在所有接受至少一剂romiplostim的患者中评估安全性。该试验已在ClinicalTrials.gov上注册，NCT02094417。

发现

在2014年4月14日至11月24日之间，共有35名患者入选，并随机分为以下四个剂量组之一：romiplostim 1μg/ kg（n = 7），3μg/ kg（n = 9），6μg/ kg（n = 9）和10μg/ kg（n = 10）。该最终分析的数据截止日期为2018年4月14日。所有患者的中位治疗时间为53周（IQR 35-155）。33名可评估患者中的10名（30％）在第9周时达到了血小板反应，包括10μg/ kg组中的10名患者中的7名（70％），6μg/ kg组中的9名患者中的3名（33％），在3μg/ kg和1μg/ kg的队列中均没有患者。在扩展研究期间，33位可评估患者中有18位（55％）在46-53周内有血小板反应，并且有资格继续治疗。10名（30％）患者在2年和3年时维持血小板反应，其中9例有红系反应，5例有中性粒细胞反应，并完成了方案治疗。与治疗相关的不良事件发生在35例患者中的3例（9％）中，包括1级或2级肌痛，疲劳和头晕。35名患者中有17名（49％）发生3级或更高的不良事件；7例（20％）有严重不良事件（高热性中性粒细胞减少，白内障，视网膜脱离，黄斑纤维化，腹股沟疝，阑尾炎，蜂窝织炎，肌腱损伤和输血反应1例）；一名患者在治疗期间死于败血症；这些事件均与治疗无关。没有患者发生克隆进化。7例（20％）有严重不良事件（高热性中性粒细胞减少，白内障，视网膜脱离，黄斑纤维化，腹股沟疝，阑尾炎，蜂窝织炎，肌腱损伤和输血反应1例）；一名患者在治疗期间死于败血症；这些事件均与治疗无关。没有患者发生克隆进化。7例（20％）有严重不良事件（高热中性粒细胞减少，白内障，视网膜脱离，黄斑纤维化，腹股沟疝，阑尾炎，蜂窝织炎，肌腱损伤和输血反应1例）；一名患者在治疗期间死于败血症；这些事件均与治疗无关。没有患者发生克隆进化。

解释

对于难治性再生障碍性贫血患者，Romiplostim似乎很活跃，并且具有良好的安全性。每周一次10μg/ kg可用作未来研究的推荐起始剂量。这些发现值得进一步调查。

资金

Kyowa Hakko Kirin韩国。