Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital Leipzig, Leipzig, Germany.
German MDS Study Group (D-MDS), Leipzig, Germany.
Blood Adv. 2021 Mar 9;5(5):1565-1575. doi: 10.1182/bloodadvances.2020002177.
Luspatercept (Reblozyl) was recently approved for treating patients with transfusion-dependent lower-risk myelodysplastic syndrome (MDS) with ring sideroblasts (RS) and/or SF3B1 mutation who were not eligible for erythropoiesis-stimulating agents (ESAs) or patients for whom those agents failed. Luspatercept acts as an activin receptor type IIB fusion protein ligand trap that targets the altered transforming growth factor beta pathway in MDS, which is associated with impaired terminal erythroid maturation. Treatment with luspatercept results in decreased SMAD signaling, which enables erythroid maturation by means of late-stage erythroblast differentiation and thus improves anemia. ESAs, the current standard first-line therapeutic option for anemic lower-risk patients with MDS, also improve red cell parameters mainly by expanding proliferation of early erythroid progenitor cells. However, erythropoietin (EPO) and its receptor (EPO-R) are also required for survival of late-stage definitive erythroid cells, and they play an essential role in promoting proliferation, survival, and appropriate timing of terminal maturation of primitive erythroid precursors. Thus, luspatercept joins the mechanism of ESAs in promoting erythroid maturation. Especially in the subgroup of MDS patients with RS, luspatercept showed high clinical activity for the treatment of anemia in the phase 2 (PACE-MDS) trial and subsequently in the phase 3 (MEDALIST) trial, which resulted in approval by both the US Food and Drug Administration and the European Medicines Agency in April 2020. Additional studies are needed to better understand the mechanism of action and pharmacodynamics of this novel agent in MDS.
芦昔帕肽（Reblozyl）最近被批准用于治疗不符合红细胞生成刺激剂（ESA）治疗条件或ESA 治疗失败的伴有环形铁幼粒细胞（RS）和/或 SF3B1 突变的输血依赖性低危骨髓增生异常综合征（MDS）患者。芦昔帕肽作为一种激活素受体 IIB 融合蛋白配体陷阱，作用于 MDS 中改变的转化生长因子-β途径，该途径与晚期红细胞成熟受损有关。芦昔帕肽治疗可减少 SMAD 信号转导，通过晚期红系母细胞分化促进红细胞成熟，从而改善贫血。ESA 是目前治疗低危 MDS 贫血患者的一线标准治疗选择，主要通过扩大早期红细胞祖细胞的增殖来改善红细胞参数。然而，红细胞生成素（EPO）及其受体（EPO-R）也是晚期定型红细胞存活所必需的，它们在促进原始红细胞前体的增殖、存活和适当的终末成熟时机方面发挥着重要作用。因此，芦昔帕肽加入了 ESA 促进红细胞成熟的机制。特别是在伴有 RS 的 MDS 患者亚组中，芦昔帕肽在 2 期（PACE-MDS）试验和随后的 3 期（MEDALIST）试验中显示出治疗贫血的高临床活性，这导致美国食品和药物管理局和欧洲药品管理局于 2020 年 4 月批准该药用于临床。需要进一步研究以更好地了解这种新型药物在 MDS 中的作用机制和药效动力学。
