德国莱比锡大学医院Uwe Platzbecker团队研究了罗特西普与促红细胞生成素治疗低风险骨髓增生异常综合征的疗效与安全性。这一研究成果于2023年6月10日发表在《柳叶刀》杂志上。

红细胞生成刺激剂（ESA）是大多数低风险骨髓增生异常综合征患者贫血的标准治疗方法，但反应有限且短暂。罗特西普促进晚期红系成熟，并在低风险骨髓增生异常综合征患者中显示出持久的临床疗效。在这项研究中，研究组报告了一项预先指定的中期分析结果，即在3期COMMANDS试验中，罗特西普与阿法依泊汀治疗因低风险骨髓增生异常综合征引起的贫血。

COMMAND的3期开放标签随机对照试验正在26个国家的142个地点进行。符合条件的患者年龄在18岁及以上，诊断为极低风险、低风险或中等风险的骨髓增生异常综合征（根据修订的国际预后评分系统），未接受ESA治疗，需要输注红细胞（随机分组前每8周输注2-6个红细胞单位，持续≥8周）。综合反应技术用于将患者（1:1，块大小4）随机分配给罗特西普或阿法依泊汀治疗，根据基线红细胞输注负荷（每8周<4单位vs每8周≥4单位）、内源性血清红细胞生成素浓度（≤200 U/L vs200至500 U/L）和环状成铁细胞状态（阳性vs阴性）进行分层。

每3周皮下给药一次，从1.0 mg/kg体重开始，可能的滴定量高达1.75 mg/kg。阿法依泊汀每周皮下给药一次，起始剂量为450 IU/kg体重，可能滴定至1050 IU/kg（最大允许总剂量为80?000IU）。主要终点是至少12周的红细胞输注独立性，同时平均血红蛋白增加至少1.5 g/dL（第1-24周），在意向治疗人群中进行评估。对至少接受一剂研究治疗的患者进行了安全性评估。

2019年1月2日至2022年8月31日，356名患者被随机分配接受罗特西普（178名患者）或阿法依泊汀（178名病人）治疗，其中包括198名（56%）男性和158名（44%）女性（中位年龄74岁）。对301名完成24周治疗或提前停药的患者（罗特西普组147名，阿法依泊汀组154名）进行了中期疗效分析。罗特西普组147名患者中有86名（59%）达到主要终点，阿法依泊汀组154名患者中48名（31%）（有效率方面的共同风险差异为26.6；p<0.0001）。接受罗特西普治疗的患者中位治疗暴露时间更长（42周），而接受阿法依泊汀治疗的患者为27周。

罗特西普最常见的3级或4级治疗紧急不良事件（≥3%患者）为高血压、贫血、呼吸困难、中性粒细胞减少、血小板减少、肺炎、新冠肺炎、骨髓增生异常综合征和晕厥；与阿法依泊汀相关的还有贫血、肺炎、中性粒细胞减少症、高血压、铁过量、新冠肺炎和骨髓增生异常综合征。在罗特西普组中，最常见的疑似治疗相关不良事件（≥3%的患者，最常见事件发生在5%的患者）是疲劳、乏力、恶心、呼吸困难、高血压和头痛；阿法依泊汀组无一例（≥3%）。诊断为急性髓细胞白血病后的一例死亡被认为与罗特西普治疗有关（治疗44天）。

研究结果表明，在这项中期分析中，在低风险骨髓增生异常综合征的ESA初始患者中，与阿法依泊汀相比，罗特西普提高了红细胞输注独立性和血红蛋白增加的比率。需要长期随访和额外数据来证实这些结果，并进一步完善低风险骨髓增生异常综合征患者的其他亚组的发现，包括非突变的SF3B1或环状成铁细胞阴性亚组。

附：英文原文

Title: Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): interim analysis of a phase 3, open-label, randomised controlled trial

Author: Uwe Platzbecker, Matteo Giovanni Della Porta, Valeria Santini, Amer M Zeidan, Rami S Komrokji, Jake Shortt, David Valcarcel, Anna Jonasova, Sophie Dimicoli-Salazar, Ing Soo Tiong, Chien-Chin Lin, Jiahui Li, Jennie Zhang, Ana Carolina Giuseppi, Sandra Kreitz, Veronika Pozharskaya, Karen L Keeperman, Shelonitda Rose, Jeevan K Shetty, Sheida Hayati, Sadanand Vodala, Thomas Prebet, Andrius Degulys, Stefania Paolini, Thomas Cluzeau, Pierre Fenaux, Guillermo Garcia-Manero

Issue&Volume: 2023-06-10

Abstract:

Background

Erythropoiesis-stimulating agents (ESAs) are the standard-of-care treatment for anaemia in most patients with lower-risk myelodysplastic syndromes but responses are limited and transient. Luspatercept promotes late-stage erythroid maturation and has shown durable clinical efficacy in patients with lower-risk myelodysplastic syndromes. In this study, we report the results of a prespecified interim analysis of luspatercept versus epoetin alfa for the treatment of anaemia due to lower-risk myelodysplastic syndromes in the phase 3 COMMANDS trial.

Methods

The phase 3, open-label, randomised controlled COMMANDS trial is being conducted at 142 sites in 26 countries. Eligible patients were aged 18 years or older, had a diagnosis of myelodysplastic syndromes of very low risk, low risk, or intermediate risk (per the Revised International Prognostic Scoring System), were ESA-naive, and required red blood cell transfusions (2–6 packed red blood cell units per 8 weeks for ≥8 weeks immediately before randomisation). Integrated response technology was used to randomly assign patients (1:1, block size 4) to luspatercept or epoetin alfa, stratified by baseline red blood cell transfusion burden (<4 units per 8 weeks vs ≥4 units per 8 weeks), endogenous serum erythropoietin concentration (≤200 U/L vs >200 to <500 U/L), and ring sideroblast status (positive vs negative). Luspatercept was administered subcutaneously once every 3 weeks starting at 1·0 mg/kg body weight with possible titration up to 1·75 mg/kg. Epoetin alfa was administered subcutaneously once a week starting at 450 IU/kg body weight with possible titration up to 1050 IU/kg (maximum permitted total dose of 80000 IU). The primary endpoint was red blood cell transfusion independence for at least 12 weeks with a concurrent mean haemoglobin increase of at least 1·5 g/dL (weeks 1–24), assessed in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. The COMMANDS trial was registered with ClinicalTrials.gov, NCT03682536 (active, not recruiting).

Findings

Between Jan 2, 2019 and Aug 31, 2022, 356 patients were randomly assigned to receive luspatercept (178 patients) or epoetin alfa (178 patients), comprising 198 (56%) men and 158 (44%) women (median age 74 years [IQR 69–80]). The interim efficacy analysis was done for 301 patients (147 in the luspatercept group and 154 in the epoetin alfa group) who completed 24 weeks of treatment or discontinued earlier. 86 (59%) of 147 patients in the luspatercept group and 48 (31%) of 154 patients in the epoetin alfa group reached the primary endpoint (common risk difference on response rate 26·6; 95% CI 15·8–37·4; p<0·0001). Median treatment exposure was longer for patients receiving luspatercept (42 weeks [IQR 20–73]) versus epoetin alfa (27 weeks [19–55]). The most frequently reported grade 3 or 4 treatment-emergent adverse events with luspatercept (≥3% patients) were hypertension, anaemia, dyspnoea, neutropenia, thrombocytopenia, pneumonia, COVID-19, myelodysplastic syndromes, and syncope; and with epoetin alfa were anaemia, pneumonia, neutropenia, hypertension, iron overload, COVID-19 pneumonia, and myelodysplastic syndromes. The most common suspected treatment-related adverse events in the luspatercept group (≥3% patients, with the most common event occurring in 5% patients) were fatigue, asthenia, nausea, dyspnoea, hypertension, and headache; and none (≥3% patients) in the epoetin alfa group. One death after diagnosis of acute myeloid leukaemia was considered to be related to luspatercept treatment (44 days on treatment).

Interpretation

In this interim analysis, luspatercept improved the rate at which red blood cell transfusion independence and increased haemoglobin were achieved compared with epoetin alfa in ESA-naive patients with lower-risk myelodysplastic syndromes. Long-term follow-up and additional data will be needed to confirm these results and further refine findings in other subgroups of patients with lower-risk myelodysplastic syndromes, including non-mutated SF3B1 or ring sideroblast-negative subgroups.

DOI: 10.1016/S0140-6736(23)00874-7

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)00874-7/fulltext