Refractoriness to eltrombopag in adult primary immune thrombocytopenia: utility of next-generation sequencing techniques

Blood Vessels, Thrombosis & Hemostasis Pub Date : 2025-02-17 DOI:10.1016/j.bvth.2025.100061

Tomás José González-López , Ricardo Sanchez , Carmen Pastoriza , Pavel Olivera , Silvia Bernat , Fernando Fernandez-Fuertes , Isabel Socorro Caparrós-Miranda , Gloria Pérez-Rus , Isidro Jarque , Maria Esperanza Moreno-Beltrán , Emma López-Abadía , Erik De Cabo , Shally Marcellini , Gloria Pérez-Segura , Carmen Fernández-Miñano , María Jesús Peñarrubia , Sergio Matarraz , María Pérez-Caro , Alberto Orfao , Drew Provan , Joaquín Martínez-López

{"title":"Refractoriness to eltrombopag in adult primary immune thrombocytopenia: utility of next-generation sequencing techniques","authors":"Tomás José González-López , Ricardo Sanchez , Carmen Pastoriza , Pavel Olivera , Silvia Bernat , Fernando Fernandez-Fuertes , Isabel Socorro Caparrós-Miranda , Gloria Pérez-Rus , Isidro Jarque , Maria Esperanza Moreno-Beltrán , Emma López-Abadía , Erik De Cabo , Shally Marcellini , Gloria Pérez-Segura , Carmen Fernández-Miñano , María Jesús Peñarrubia , Sergio Matarraz , María Pérez-Caro , Alberto Orfao , Drew Provan , Joaquín Martínez-López","doi":"10.1016/j.bvth.2025.100061","DOIUrl":null,"url":null,"abstract":"<div><h3>Abstract</h3><div>Thrombopoietin receptor agonists, for example eltrombopag, are standard second-line treatment for immune thrombocytopenia (ITP). Eltrombopag has demonstrated high response rates, both in clinical trials and in routine practice studies. However, some patients with ITP are refractory to this drug. Next-generation sequencing (NGS) may help us identify underlying molecular biology variants that may be involved in eltrombopag refractoriness. Our multicenter national NGS study investigated 110 genes of the most important cell-signaling pathways involved in the mechanism of action of eltrombopag in 35 refractory cases and 35 eltrombopag-responsive controls. Our refractory population comprised 51.4% men with a median age at diagnosis of 48 (range, 38-69) years and a median platelet count of 7 × 10<sup>9</sup>/μL (range, 4 × 10<sup>9</sup>/μL to 16 × 10<sup>9</sup>/μL). At eltrombopag initiation, 78.3% had chronic ITP with a median platelet count of 8 × 10<sup>9</sup>/μL (range, 5× 10<sup>9</sup>/μL to 30 × 10<sup>9</sup>/μL). Treatment with eltrombopag was maintained for a median of 3 (range, 1-9) months before discontinuation. No major grade 3-4 side effects were observed. Several statistical differences were observed in relation to the control responders. Of the total sum of the NGS variants found, 13 variants with statistical significance (<em>P</em> ≤ .05) between case and controls were observed. Two of these have been shown to be associated with cancer. Seven variants are considered benign. Four variants are not previously described, and their significance is unknown. To our knowledge, none of the 13 variants described here has ever been correlated with ITP or eltrombopag refractoriness. Further studies are required to establish their role in this setting.</div></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"2 3","pages":"Article 100061"},"PeriodicalIF":0.0000,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Blood Vessels, Thrombosis & Hemostasis","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S295032722500018X","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}

引用次数: 0

Abstract

Thrombopoietin receptor agonists, for example eltrombopag, are standard second-line treatment for immune thrombocytopenia (ITP). Eltrombopag has demonstrated high response rates, both in clinical trials and in routine practice studies. However, some patients with ITP are refractory to this drug. Next-generation sequencing (NGS) may help us identify underlying molecular biology variants that may be involved in eltrombopag refractoriness. Our multicenter national NGS study investigated 110 genes of the most important cell-signaling pathways involved in the mechanism of action of eltrombopag in 35 refractory cases and 35 eltrombopag-responsive controls. Our refractory population comprised 51.4% men with a median age at diagnosis of 48 (range, 38-69) years and a median platelet count of 7 × 10⁹/μL (range, 4 × 10⁹/μL to 16 × 10⁹/μL). At eltrombopag initiation, 78.3% had chronic ITP with a median platelet count of 8 × 10⁹/μL (range, 5× 10⁹/μL to 30 × 10⁹/μL). Treatment with eltrombopag was maintained for a median of 3 (range, 1-9) months before discontinuation. No major grade 3-4 side effects were observed. Several statistical differences were observed in relation to the control responders. Of the total sum of the NGS variants found, 13 variants with statistical significance (P ≤ .05) between case and controls were observed. Two of these have been shown to be associated with cancer. Seven variants are considered benign. Four variants are not previously described, and their significance is unknown. To our knowledge, none of the 13 variants described here has ever been correlated with ITP or eltrombopag refractoriness. Further studies are required to establish their role in this setting.

查看原文本刊更多论文

成人原发性免疫性血小板减少症患者对铂的难治性：新一代测序技术的应用

【摘要】血小板生成素受体激动剂，如eltrombopag，是治疗免疫性血小板减少症（ITP）的标准二线药物。在临床试验和常规实践研究中，Eltrombopag都显示出很高的反应率。然而，一些ITP患者对该药难治。下一代测序（NGS）可以帮助我们识别潜在的分子生物学变异，这些变异可能与电曲巴耐药有关。我们的多中心国家NGS研究调查了110个最重要的细胞信号通路基因，这些基因参与了35例难治病例和35例eltrombopag反应性对照的作用机制。我们的难治性人群包括51.4%的男性，诊断时的中位年龄为48岁（范围38-69岁），中位血小板计数为7 × 109/μL（范围4 × 109/μL至16 × 109/μL）。在开始治疗时，78.3%的患者患有慢性ITP，血小板中位数为8 × 109/μL（范围为5× 109/μL至30 × 109/μL）。在停药前，伊曲巴格的治疗中位维持时间为3个月（范围1-9个月）。未观察到主要的3-4级副作用。与对照应答者相比，观察到一些统计差异。在发现的NGS变异总数中，有13个变异在病例和对照组之间具有统计学意义（P≤0.05）。其中两种已被证明与癌症有关。有七种变体被认为是良性的。四种变体以前没有描述过，它们的意义是未知的。据我们所知，本文所描述的13种变异中，没有一种与ITP或铂难熔性相关。需要进一步研究以确定它们在这种情况下的作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Blood Vessels, Thrombosis & Hemostasis

自引率

0.00%

发文量