González-López Tomás José, Sanchez Ricardo, Pastoriza Carmen, Olivera Pavel, Bernat Silvia, Fernandez-Fuertes Fernando, Caparrós-Miranda Isabel Socorro, Pérez-Rus Gloria, Jarque Isidro, Moreno-Beltrán Maria Esperanza, López-Abadía Emma, De Cabo Erik, Marcellini Shally, Pérez-Segura Gloria, Fernández-Miñano Carmen, Peñarrubia María Jesús, Matarraz Sergio, Pérez-Caro María, Orfao Alberto, Provan Drew, Martínez-López Joaquín
Department of Hematology, Hospital Universitario de Burgos, Burgos, Spain.
Department of Hematology, Hospital Universitario 12 de Octubre, Madrid, Spain.
Blood Vessel Thromb Hemost. 2025 Feb 17;2(3):100061. doi: 10.1016/j.bvth.2025.100061. eCollection 2025 Aug.
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/μL (range, 4 × 10/μL to 16 × 10/μL). At eltrombopag initiation, 78.3% had chronic ITP with a median platelet count of 8 × 10/μL (range, 5× 10/μL to 30 × 10/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 ( ≤ .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.
血小板生成素受体激动剂，例如艾曲泊帕，是免疫性血小板减少症（ITP）的标准二线治疗药物。在临床试验和常规实践研究中，艾曲泊帕均显示出高缓解率。然而，一些ITP患者对该药物难治。下一代测序（NGS）可能有助于我们识别可能与艾曲泊帕难治性有关的潜在分子生物学变异。我们的全国多中心NGS研究在35例难治性病例和35例艾曲泊帕反应性对照中，对参与艾曲泊帕作用机制的最重要细胞信号通路的110个基因进行了研究。我们的难治性人群中男性占51.4%，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）。在开始使用艾曲泊帕时，78.3%的患者患有慢性ITP，中位血小板计数为8×10⁹/μL（范围5×10⁹/μL至30×10⁹/μL）。在停药前，使用艾曲泊帕治疗的中位时间为3个月（范围1 - 9个月）。未观察到3 - 4级严重副作用。与对照反应者相比，观察到了一些统计学差异。在发现的NGS变异总数中，病例组和对照组之间观察到13个具有统计学意义（P≤0.05）的变异。其中两个已被证明与癌症有关。七个变异被认为是良性的。四个变异以前未被描述，其意义未知。据我们所知，此处描述的13个变异中没有一个曾与ITP或艾曲泊帕难治性相关。需要进一步研究以确定它们在这种情况下的作用。
