Universitätsklinikum "Carl Gustav Carus" der Technischen Universität Dresden, Dresden, Germany.
Klinik für Hämatologie, Onkologie und klinische Immunologie, Universitätsklinikum Düsseldorf, Düsseldorf, Germany.
Lancet Oncol. 2017 Oct;18(10):1338-1347. doi: 10.1016/S1470-2045(17)30615-0. Epub 2017 Sep 1.
Myelodysplastic syndromes are characterised by ineffective erythropoiesis. Luspatercept (ACE-536) is a novel fusion protein that blocks transforming growth factor beta (TGF β) superfamily inhibitors of erythropoiesis, giving rise to a promising new investigative therapy. We aimed to assess the safety and efficacy of luspatercept in patients with anaemia due to lower-risk myelodysplastic syndromes.
In this phase 2, multicentre, open-label, dose-finding study (PACE-MDS), with long-term extension, eligible patients were aged 18 years or older, had International Prognostic Scoring System-defined low or intermediate 1 risk myelodysplastic syndromes or non-proliferative chronic myelomonocytic leukaemia (white blood cell count <13 000/μL), and had anaemia with or without red blood cell transfusion support. Enrolled patients were classified as having low transfusion burden, defined as requiring less than 4 red blood cell units in the 8 weeks before treatment (and baseline haemoglobin <10 g/dL), or high transfusion burden, defined as requiring 4 or more red blood cell units in the 8 weeks before treatment. Patients received luspatercept subcutaneously once every 21 days at dose concentrations ranging from 0·125 mg/kg to 1·75 mg/kg bodyweight for five doses (over a maximum of 12 weeks). Patients in the expansion cohort were treated with 1·0 mg/kg luspatercept; dose titration up to 1·75 mg/kg was allowed, and patients could be treated with luspatercept for a maximum of 5 years. Patients in the base study were assessed for response and safety after 12 weeks in order to be considered for enrolment into the extension study. The primary endpoint was the proportion of patients achieving modified International Working Group-defined haematological improvement-erythroid (HI-E), defined as a haemoglobin concentration increase of 1·5 g/dL or higher from baseline for 14 days or longer in low transfusion burden patients, and a reduction in red blood cell transfusion of 4 or more red blood cell units or a 50% or higher reduction in red blood cell units over 8 weeks versus pre-treatment transfusion burden in high transfusion burden patients. Patient data were subcategorised by: luspatercept dose concentrations (0·125-0·5 mg/kg vs 0·75-1·75 mg/kg); pre-study transfusion burden (high transfusion burden vs low transfusion burden, defined as ≥4 vs <4 red blood cell units per 8 weeks); pre-study serum erythropoietin concentration (<200 IU/L, 200-500 IU/L, and >500 IU/L); presence of 15% or more ring sideroblasts; and presence of SF3B1 mutations. Efficacy analyses were carried out on the efficacy evaluable and intention-to-treat populations. This trial is currently ongoing. This study is registered with ClinicalTrials.gov, numbers NCT01749514 and NCT02268383.
Between Jan 21, 2013, and Feb 12, 2015, 58 patients with myelodysplastic syndromes were enrolled in the 12 week base study at nine treatment centres in Germany; 27 patients were enrolled in the dose-escalation cohorts (0·125-1·75 mg/kg) and 31 patients in the expansion cohort (1·0-1·75 mg/kg). 32 (63% [95% CI 48-76]) of 51 patients receiving higher dose luspatercept concentrations (0·75-1·75 mg/kg) achieved HI-E versus two (22% [95% CI 3-60]) of nine receiving lower dose concentrations (0·125-0·5 mg/kg). Three treatment-related grade 3 adverse events occurred in one patient each: myalgia (one [2%]), increased blast cell count (one [2%]), and general physical health deterioration (one [2%]). Two of these treatment-related grade 3 adverse events were reversible serious grade 3 adverse events: one patient (2%) had myalgia and one patient (2%) had general physical health deterioration.
Luspatercept was well tolerated and effective for the treatment of anaemia in lower-risk myelodysplastic syndromes and so could therefore provide a novel therapeutic approach for the treatment of anaemia associated with lower-risk myelodysplastic syndromes; further studies are ongoing.
Acceleron Pharma.
骨髓增生异常综合征的特征是无效的红细胞生成。Luspatercept（ACE-536）是一种新型融合蛋白，可阻断转化生长因子β（TGFβ）超家族对红细胞生成的抑制剂，从而带来一种很有前途的新的研究性治疗方法。我们旨在评估 luspatercept 治疗因低危骨髓增生异常综合征导致贫血的患者的安全性和有效性。
在这项 2 期、多中心、开放性、剂量发现研究（PACE-MDS）中，我们进行了长期扩展，符合条件的患者年龄为 18 岁或以上，患有国际预后评分系统定义的低危或中危 1 级骨髓增生异常综合征或非增殖性慢性髓单核细胞白血病（白细胞计数<13000/μL），且有贫血伴或不伴红细胞输血支持。纳入的患者分为低输血负担组和高输血负担组，低输血负担组定义为在治疗前 8 周内需要输注少于 4 单位的红细胞（且基线血红蛋白<10g/dL），高输血负担组定义为在治疗前 8 周内需要输注 4 个或更多单位的红细胞。患者接受皮下注射 luspatercept，剂量浓度范围为 0.125mg/kg 至 1.75mg/kg 体重，共 5 个剂量（最长 12 周），每 21 天一次。扩展队列中的患者接受 1.0mg/kg luspatercept 治疗；允许剂量滴定至 1.75mg/kg，患者最多可接受 luspatercept 治疗 5 年。在治疗 12 周后，根据反应和安全性对基础研究中的患者进行评估，以考虑将其纳入扩展研究。主要终点是改良国际工作组定义的血液学改善-红细胞（HI-E）的患者比例，定义为低输血负担患者的血红蛋白浓度增加 1.5g/dL 或更高，且持续 14 天或更长时间，或与治疗前的输血负担相比，高输血负担患者的红细胞输注减少 4 个或更多单位，或在 8 周内减少 50%或更多单位。患者的数据根据 luspatercept 剂量浓度（0.125-0.5mg/kg 与 0.75-1.75mg/kg）、研究前输血负担（高输血负担与低输血负担，定义为≥4 与<4 个单位/8 周）、研究前血清促红细胞生成素浓度（<200IU/L、200-500IU/L 和>500IU/L）、存在 15%或更多环状铁幼粒细胞和存在 SF3B1 突变进行了分类。疗效分析在疗效可评估和意向治疗人群中进行。该试验目前正在进行中。这项研究在 ClinicalTrials.gov 上注册，编号为 NCT01749514 和 NCT02268383。
2013 年 1 月 21 日至 2015 年 2 月 12 日，在德国的 9 个治疗中心，58 名患有骨髓增生异常综合征的患者参加了为期 12 周的基础研究，其中 27 名患者入组剂量递增队列（0.125-1.75mg/kg），31 名患者入组扩展队列（1.0-1.75mg/kg）。接受较高剂量 luspatercept 浓度（0.75-1.75mg/kg）的 51 名患者中有 32 名（63%[95%CI 48-76%]）达到 HI-E，而接受较低剂量浓度（0.125-0.5mg/kg）的 9 名患者中只有 2 名（22%[95%CI 3-60%]）达到 HI-E。1 名患者（2%）发生 3 级与治疗相关的不良事件，分别为肌痛（1 例[2%]）、blast 细胞计数增加（1 例[2%]）和一般身体健康恶化（1 例[2%]）。其中 2 例 3 级与治疗相关的不良事件为可逆的严重 3 级不良事件：1 例患者（2%）出现肌痛，1 例患者（2%）出现一般身体健康恶化。
Luspatercept 耐受性良好，对低危骨髓增生异常综合征相关贫血的治疗有效，因此可能为低危骨髓增生异常综合征相关贫血的治疗提供一种新的治疗方法；进一步的研究正在进行中。
Acceleron Pharma。
