Unmet medical needs remain in patients with red blood cell transfusion-dependent (RBC-TD) lower-risk myelodysplastic syndromes (LR-MDS) who are not responding to or are ineligible for erythropoiesis-stimulating agents (ESAs). Imetelstat, a competitive telomerase inhibitor, showed promising results in a phase 2 trial. We aimed to compare the RBC transfusion independence (RBC-TI) rate with imetelstat versus placebo in patients with RBC-TD LR-MDS. In phase 3 of IMerge, a double-blind, placebo-controlled trial conducted in 118 sites including university hospitals, cancer centres, and outpatient clinics in 17 countries, patients (aged ≥18 years) with ESA-relapsed, ESA-refractory, or ESA-ineligible LR-MDS (low or intermediate-1 risk disease as per International Prognostic Scoring System [IPSS] criteria) were randomly assigned via a computer-generated schedule (2:1) to receive imetelstat 7·5 mg/kg or placebo, administered as a 2-h intravenous infusion, every 4 weeks until disease progression, unacceptable toxic effects, or withdrawal of consent. Randomisation was stratified by previous RBC transfusion burden and IPSS risk group. Patients, investigators, and those analysing the data were masked to group assignment. The primary endpoint was 8-week RBC-TI, defined as the proportion of patients without RBC transfusions for at least 8 consecutive weeks starting on the day of randomisation until subsequent anti-cancer therapy, if any. Primary efficacy analyses were performed in the intention-to-treat population, and safety analyses were conducted in patients who received at least one dose of trial medication or placebo. This trial is registered with (; substudy active and recruiting). Between Sept 11, 2019, and Oct 13, 2021, 178 patients were enrolled and randomly assigned (118 to imetelstat and 60 to placebo). 111 (62%) were male and 67 (38%) were female. 91 (77%) of 118 patients had discontinued treatment by data cutoff in the imetelstat group versus 45 (75%) in the placebo group; a further one patient in the placebo group did not receive treatment. Median follow-up was 19·5 months (IQR 12·0–23·4) in the imetelstat group and 17·5 months (12·1–22·7) in the placebo group. In the imetelstat group, 47 (40% [95% CI 30·9–49·3]) patients had an RBC-TI of at least 8 weeks versus nine (15% [7·1–26·6]) in the placebo group (rate difference 25% [9·9 to 36·9]; p=0·0008). Overall, 107 (91%) of 118 patients receiving imetelstat and 28 (47%) of 59 patients receiving placebo had grade 3–4 treatment-emergent adverse events. The most common treatment-emergent grade 3–4 adverse events in patients taking imetelstat were neutropenia (80 [68%] patients who received imetelstat two [3%] who received placebo) and thrombocytopenia (73 [62%] five [8%]). No treatment-related deaths were reported. Imetelstat offers a novel mechanism of action with durable transfusion independence (approximately 1 year) and disease-modifying activity for heavily transfused patients with LR-MDS who are not responding to or are ineligible for ESAs. Janssen Research & Development before April 18, 2019, and Geron Corporation thereafter.

中文翻译：

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伊美司他治疗复发或对红细胞生成刺激剂耐药的低危骨髓增生异常综合征患者 (IMerge)：一项多国、随机、双盲、安慰剂对照 3 期试验

对于红细胞输注依赖型 (RBC-TD) 低危骨髓增生异常综合征 (LR-MDS) 患者，他们对红细胞生成刺激剂 (ESA) 无反应或不适合使用，但医疗需求仍未得到满足。 Imetelstat 是一种竞争性端粒酶抑制剂，在 2 期试验中显示出有希望的结果。我们的目的是比较 imetelstat 与安慰剂治疗 RBC-TD LR-MDS 患者的红细胞输血独立性 (RBC-TI) 率。 IMerge 是一项双盲、安慰剂对照试验，在 17 个国家的 118 个地点（包括大学医院、癌症中心和门诊诊所）进行了第 3 期试验，受试者为 ESA 复发、ESA 难治性或 ESA 难治性患者（年龄≥18 岁）。通过计算机生成的时间表 (2:1) 将不符合 ESA 资格的 LR-MDS（根据国际预后评分系统 [IPSS] 标准的低或中 1 风险疾病）随机分配至接受 imetelstat 7·5 mg/kg 或安慰剂治疗，每 4 周进行 2 小时静脉输注，直至疾病进展、出现不可接受的毒性作用或撤回同意。根据既往红细胞输血负担和 IPSS 风险组对随机分组进行分层。患者、研究人员和数据分析人员对分组情况不知情。主要终点是 8 周 RBC-TI，定义为从随机分组之日开始直至后续抗癌治疗（如果有）至少连续 8 周未输注 RBC 的患者比例。主要疗效分析是在意向治疗人群中进行的，安全性分析是在接受至少一剂试验药物或安慰剂的患者中进行的。该试验已在（；子研究活跃和招募）中注册。 2019年9月11日至2021年10月13日期间，共有178名患者入组并随机分配（118名患者接受imetelstat治疗，60名患者接受安慰剂治疗）。 111 名（62%）为男性，67 名（38%）为女性。 118 名患者中，伊美司他组中有 91 名患者 (77%) 在数据截止时停止治疗，而安慰剂组有 45 名患者 (75%) 停止治疗；安慰剂组的另外一名患者没有接受治疗。 imetelstat 组的中位随访时间为 19·5 个月 (IQR 12·0–23·4)，安慰剂组的中位随访时间为 17·5 个月 (12·1–22·7)。在 imetelstat 组中，47 名（40% [95% CI 30·9–49·3]）患者的 RBC-TI 至少为 8 周，而对照组为 9 名（15% [7·1–26·6]）。安慰剂组（比率差异 25% [9·9 至 36·9]；p=0·0008）。总体而言，接受 imetelstat 的 118 名患者中有 107 名 (91%) 以及接受安慰剂的 59 名患者中有 28 名 (47%) 出现了 3-4 级治疗引起的不良事件。服用 imetelstat 的患者中最常见的治疗中出现的 3-4 级不良事件是中性粒细胞减少症（80 [68%] 患者接受 imetelstat 2 [3%] 接受安慰剂）和血小板减少症（73 [62%] 5 [8%] ）。没有报告与治疗相关的死亡。Imetelstat 为对 ESA 无反应或不适合接受 ESA 治疗的大量输血 LR-MDS 患者提供了一种新颖的作用机制，具有持久的输血独立性（约 1 年）和疾病缓解活性。 Janssen Research & Development 在 2019 年 4 月 18 日之前为 Janssen Research & Development，此后为 Geron Corporation。