在ALPINE研究中进展的复发/耐药CLL患者中获得的突变
Jennifer R Brown1, Jessica Li2, Barbara F Eichhorst3
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
Blood advances
|January 24, 2025
概括
慢性淋巴细胞白血病患者接受布鲁顿氨酸激酶 (BTK) 抑制剂治疗可能会发生耐药性突变. 治疗扎努布鲁丁尼布或易布鲁丁尼布的早期进展性疾病与一些患者获得的BTK突变有关,但其他机制可能导致最早期的进展.
科学领域:
- 在瘤学瘤学.
- 遗传学 遗传学 是一个
- 药理学 药理学是指药理学的学科.
背景情况:
- 性布鲁顿氨酸激酶 (BTK) 抑制剂对慢性淋巴细胞白血病 (CLL) 有效.
- 一些患者在BTK抑制剂上由于BTK或PLCG2.2的耐药性突变而发展出进展性疾病 (PD).
- 了解耐药机制对于优化CLL治疗至关重要.
研究的目的:
- 为了研究CLL患者的基因突变概况,这些患者在采布鲁丁尼布或易布鲁丁尼布治疗中经历了早期进展性疾病 (PD).
- 为了识别BTK和其他基因中的获得性耐药性突变.
- 探索基线突变和BTK突变的发展之间的关联.
主要方法:
- 在ALPINE试验中,分析了52名接受扎努布鲁丁尼布或易布鲁丁尼布治疗的患者的对对外周围血液样本 (基线和PD).
- 下一代测序用于检测BTK,PLCG2和其他驱动基因的突变.
- 基线基因突变与PD时获得的突变之间的相关性分析.
主要成果:
- 在PD时,8名患者获得了17个BTK突变,主要在C481 (82.4%).
- 在接受扎努布鲁丁尼布治疗的患者中观察到非C481 BTK突变 (L528W,A428D).
- 在52名患者中,48名患者有≥1个基线驱动基因突变;≥2个基线突变与在PD获得BTK突变的可能性更高有关.
- 在TP53,XPO1,SETD2,SF3B1和ASXL1.1中观察到BTK/PLCG2以外的获得突变.
结论:
- 虽然BTK突变,特别是在C481中,是抵抗机制,但它们在早期PD的发生率很低.
- 多个基线驱动基因突变的存在可以预测BTK耐药性突变的发展.
- 除了BTK/PLCG2突变之外的其他机制可能会驱动大多数用共价BTK抑制剂治疗的CLL患者的早期进展性疾病.
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