背景:COMMANDS试验的预先计划的中期分析显示,luspatercept比epoetinalfa治疗红细胞生成刺激剂(ESA)初治的输血依赖性患者贫血的疗效更高,低风险骨髓增生异常综合征。在这篇文章中,我们报告了试验的主要分析结果.
方法:命令是第3阶段,开放标签,随机化,在26个国家的142个地点进行的对照试验。符合条件的患者是18岁或以上的患者,骨髓增生异常综合征的风险非常低,低风险,或中等风险(由修订的国际预后评分系统定义),谁是ESA-天真的和输血依赖,血清促红细胞生成素浓度低于500U/L患者按基线红细胞输血负荷进行分层,血清促红细胞生成素浓度,和环sideroblast状态,并随机分配(1:1)接受luspatercept(1·0-1·75mg/kg体重,皮下,每3周一次)或epoetinalfa(450-1050IU/kg体重,皮下,每周一次;最大总剂量80000IU)至少24周。主要终点是红细胞输注独立持续至少12周,同时平均血红蛋白增加至少1·5g/dL(1-24周),在意向治疗人群中进行评估。安全性人群包括接受至少一个剂量治疗的所有患者。该试验已在ClinicalTrials.gov(NCT03682536;活性,不招募)。
结果:在2019年1月2日至2022年9月29日之间,对363例患者进行了筛选并随机分配:182(50%)接受luspatercept,181(50%)接受epoetinalfa。中位年龄为74岁(IQR69-80),162名(45%)患者为女性,男性201人(55%)。289(80%)是白人,44(12%)是亚洲人,和两个(1%)是黑人或非洲裔美国人。23(6%)是西班牙裔或拉丁裔,311(86%)不是西班牙裔或拉丁裔。luspatercept组的主要终点的中位随访时间为17·2个月(10·4-27·7),epoalfa组为16·9个月(10·1-26·6)。luspatercept组达到主要终点的患者比例明显更高(110[60%]vs63[35%];缓解率的常见风险差异为25·4%[95%CI15·8-35·0];p<0·0001)。luspatercept组的安全性分析的中位随访时间为21·4个月(IQR14·2-32·4),epoetinalfa组为20·3个月(12·7-30·9)。luspatercept接受者(n=182)中常见的3-4级治疗紧急不良事件是高血压(19[10%]患者),贫血(18[10%]),肺炎(十[5%]),晕厥(十[5%]),中性粒细胞减少症(九[5%]),血小板减少症(八[4%]),呼吸困难(八[4%]),和骨髓增生异常综合征(6[3%]);在epoetinalfa接受者中(n=179)是贫血(14[8%]),肺炎(14[8%]),中性粒细胞减少症(11[6%]),骨髓增生异常综合征(十[6%]),高血压(八[4%]),铁过载(七[4%]),和COVID-19肺炎(6种[3%])。两组中最常见的因治疗引起的严重不良事件是肺炎(9例[5%]鲁帕特西普接受者和13例[7%]依泊汀α受体)和COVID-19(8例[4%]鲁帕特西普接受者和10例[6%]依泊汀αα受体)。在中期分析中报告了一例被认为与luspatercept相关的死亡(由于急性髓性白血病)。
结论:Luspatercept代表了ESA初治输血依赖患者的新护理标准,低风险骨髓增生异常综合征。luspatercept的红细胞输注独立性和血液学改善明显多于epoetinalfa的患者,观察到患者亚组的益处。
背景:Celgene和AcceleronPharma。
BACKGROUND: The preplanned interim analysis of the COMMANDS trial showed greater efficacy of luspatercept than epoetin alfa for treating anaemia in erythropoiesis-stimulating agent (ESA)-naive patients with transfusion-dependent, lower-risk myelodysplastic syndromes. In this Article, we report the results of the primary analysis of the trial.
METHODS: COMMANDS is a phase 3, open-label, randomised, controlled trial conducted at 142 sites in 26 countries. Eligible patients were those aged 18 years or older, with myelodysplastic syndromes of very low risk, low risk, or intermediate risk (as defined by the Revised International Prognostic Scoring System), who were ESA-naive and transfusion dependent, and had a serum erythropoietin concentration of less than 500 U/L. Patients were stratified by baseline red blood cell transfusion burden, serum erythropoietin concentration, and ring sideroblast status, and randomly allocated (1:1) to receive luspatercept (1·0-1·75 mg/kg body weight, subcutaneously, once every 3 weeks) or epoetin alfa (450-1050 IU/kg body weight, subcutaneously, once a week; maximum total dose 80 000 IU) for at least 24 weeks. The primary endpoint was red blood cell transfusion independence lasting at least 12 weeks with a concurrent mean haemoglobin increase of at least 1·5 g/dL (weeks 1-24), evaluated in the intention-to-treat population. The safety population included all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov (NCT03682536; active, not recruiting).
RESULTS: Between Jan 2, 2019, and Sept 29, 2022, 363 patients were screened and randomly allocated: 182 (50%) to luspatercept and 181 (50%) to epoetin alfa. Median age was 74 years (IQR 69-80), 162 (45%) patients were female, and 201 (55%) were male. 289 (80%) were White, 44 (12%) were Asian, and two (1%) were Black or African American. 23 (6%) were Hispanic or Latino and 311 (86%) were not Hispanic or Latino. Median follow-up for the primary endpoint was 17·2 months (10·4-27·7) for the luspatercept group and 16·9 months (10·1-26·6) for the epoetin alfa group. A significantly greater proportion of patients in the luspatercept group reached the primary endpoint (110 [60%] vs 63 [35%]; common risk difference on response rate 25·4% [95% CI 15·8-35·0]; p<0·0001). Median follow-up for safety analyses was 21·4 months (IQR 14·2-32·4) for the luspatercept group and 20·3 months (12·7-30·9) for the epoetin alfa group. Common grade 3-4 treatment-emergent adverse events occurring among luspatercept recipients (n=182) were hypertension (19 [10%] patients), anaemia (18 [10%]), pneumonia (ten [5%]), syncope (ten [5%]), neutropenia (nine [5%]), thrombocytopenia (eight [4%]), dyspnoea (eight [4%]), and myelodysplastic syndromes (six [3%]); and among epoetin alfa recipients (n=179) were anaemia (14 [8%]), pneumonia (14 [8%]), neutropenia (11 [6%]), myelodysplastic syndromes (ten [6%]), hypertension (eight [4%]), iron overload (seven [4%]), and COVID-19 pneumonia (six [3%]). The most common serious treatment-emergent adverse events in both groups were pneumonia (nine [5%] luspatercept recipients and 13 [7%] epoetin alfa recipients) and COVID-19 (eight [4%] luspatercept recipients and ten [6%] epoetin alfa recipients). One death (due to acute myeloid leukaemia) considered to be luspatercept-related was reported at the interim analysis.
CONCLUSIONS: Luspatercept represents a new standard of care for ESA-naive patients with transfusion-dependent, lower-risk myelodysplastic syndromes. Significantly more patients had red blood cell transfusion independence and haematological improvement with luspatercept than with epoetin alfa, with benefits observed across patient subgroups.
BACKGROUND: Celgene and Acceleron Pharma.