Lee Jong Wook, Lee Sung-Eun, Jung Chul Won, Park Silvia, Keta Hiroyuki, Park Soo Kyeong, Kim Jin-A, Oh Il-Hoan, Jang Jun Ho
Division of Hematology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, Catholic University of Korea, Seoul, South Korea.
Division of Hematology-Oncology, Samsung Medical Center, Sunghyunkwan University School of Medicine, Seoul, South Korea.
Lancet Haematol. 2019 Nov;6(11):e562-e572. doi: 10.1016/S2352-3026(19)30153-X. Epub 2019 Aug 29.
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.
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 × 10/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.
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.
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.
Kyowa Hakko Kirin Korea.
再生障碍性贫血是一种罕见的、危及生命的疾病，其特征为全血细胞减少伴骨髓细胞减少。造血干细胞和大多数祖细胞表达血小板生成素受体（c-MPL）。罗米司亭是一种具有c-MPL激动剂活性的肽抗体，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，我们旨在评估罗米司亭在先前接受过免疫抑制治疗的再生障碍性贫血患者中的活性和安全性。
我们进行了一项开放标签的2期研究，包括一个随机、平行、剂量探索部分，随后是一个扩展部分，以在韩国首尔的两个临床中心评估长期治疗效果。符合条件的患者年龄在19岁及以上，经骨髓和细胞遗传学研究确诊为再生障碍性贫血且有血小板减少症（血小板计数≤30×10⁹/L），东部肿瘤协作组体能状态评分为2或更低，并且先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素。在剂量探索部分，根据血小板计数分层后的静态分配程序，患者被随机分配到皮下注射罗米司亭的固定剂量队列（1、3、6或10μg/kg），每周一次，共8周。在研究的扩展部分，患者根据血小板反应和安全性，每4周逐步滴定罗米司亭剂量（每周一次，剂量为1、3、6、10、13、16和20μg/kg），持续1年（第9周至第52周）。在第46 - 53周有血小板反应的患者继续逐步滴定剂量（每周一次，剂量为3、6、10、13、16和20μg/kg），再持续2年（第53周至第156周）。主要终点是在第9周（剂量探索部分结束后）达到血小板反应的患者比例。在所有第9周可评估反应的患者中按方案评估活性，在所有接受至少一剂罗米司亭的患者中评估安全性。本试验已在ClinicalTrials.gov注册，注册号为NCT02094417。
在2014年4月14日至11月24日期间，35例患者入组并被随机分配到四个剂量队列之一：罗米司亭1μg/kg（n = 7）、3μg/kg（n = 9）、6μg/kg（n = 9）和10μg/kg（n = 10）。本次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持续时间为53周（四分位间距35 - 155周）。33例可评估患者中有10例（30%）在第9周达到血小板反应，其中10μg/kg队列中的10例患者中有7例（70%）、6μg/kg队列中的9例患者中有3例（33%），而3μg/kg和1μg/kg队列中均无患者达到血小板反应。在扩展研究期间，33例可评估患者中有18例（55%）在第46 - 53周有血小板反应并符合继续治疗条件。10例（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。35例患者中有3例（9%）发生了与治疗相关的不良事件，包括1级或2级肌痛、疲劳和头晕。35例患者中有17例（49%）发生了3级或更高等级的不良事件；7例（20%）发生了严重不良事件（1例发热性中性粒细胞减少症、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。没有患者发生克隆演变。
罗米司亭似乎对难治性再生障碍性贫血患者有活性且安全性良好。每周一次10μg/kg可能作为未来研究的推荐起始剂量。这些发现值得进一步研究。
协和麒麟韩国公司。
