PDF(Pubmed)
Abstract：
Diamond-Blackfan anaemia (DBA) is a rare, inherited bone marrow failure syndrome with a ribosomal defect causing slowed globin chain production with normal haem synthesis, causing an overabundance of reactive iron/haem and erythroid-specific cellular toxicity. Eltrombopag, a non-peptide thrombopoietin receptor agonist, is a potent intracellular iron chelator and induced a robust durable response in an RPS19-mutated DBA patient on another trial. We hypothesized eltrombopag would improve RBC production in DBA patients. We conducted a single-centre, single-arm pilot study (NCT04269889) assessing safety and erythroid response of 6 months of daily, fixed-dose eltrombopag for DBA patients. Fifteen transfusion-dependent (every 3-5 weeks) patients (median age 18 [range 2-56]) were treated. One responder had sustained haemoglobin improvement and >50% reduction in RBC transfusion frequency. Of note, 7/15 (41%) patients required dose reductions or sustained discontinuation of eltrombopag due to asymptomatic thrombocytosis. Despite the low response rate, eltrombopag has now improved erythropoiesis in several patients with DBA with a favourable safety profile. Dosing restrictions due to thrombocytosis may cause insufficient iron chelation to decrease haem production and improve anaemia in most patients. Future work will focus on erythropoiesis dynamics in patients and use of haem synthesis inhibitors without an impact on other haematopoietic lineages.
摘要：
Diamond-Blackfan贫血(DBA)是一种罕见的,遗传性骨髓衰竭综合征伴有核糖体缺陷，导致正常血红素合成的珠蛋白链产生减慢，导致过量的反应性铁/血红素和红细胞特异性细胞毒性。Eltrombopag,非肽类血小板生成素受体激动剂,是一种有效的细胞内铁螯合剂，在另一项试验中，在RPS19突变的DBA患者中诱导了强大的持久反应。我们假设eltrombopag可以改善DBA患者的RBC产生。我们进行了一个单中心，单臂试点研究（NCT04269889）评估每天6个月的安全性和红细胞反应，DBA患者的固定剂量艾曲波帕。15例依赖输血（每3-5周）的患者（中位年龄18[范围2-56]）接受治疗。一名反应者血红蛋白持续改善，红细胞输血频率减少>50%。值得注意的是，7/15（41％）患者由于无症状的血小板增多而需要减少剂量或持续停药eltrombopag。尽管回复率低，艾曲波帕现在已经改善了一些DBA患者的红细胞生成，具有良好的安全性。在大多数患者中，由于血小板增多导致的剂量限制可能会导致铁螯合不足，从而减少血红素产生并改善贫血。未来的工作将集中在患者的红细胞生成动力学和血红素合成抑制剂的使用上，而不会影响其他造血谱系。
