Sedlarikova Lenka, Petrackova Anna, Papajik Tomas, Turcsanyi Peter, Kriegova Eva
Department of Immunology, Faculty of Medicine and Dentistry, Palacky University and University Hospital, Olomouc, Czechia.
Department of Hemato-Oncology, Faculty of Medicine and Dentistry, Palacky University and University Hospital, Olomouc, Czechia.
Front Oncol. 2020 Jun 25;10:894. doi: 10.3389/fonc.2020.00894. eCollection 2020.
Inhibitors of B-cell receptor signaling, ibrutinib and idelalisib, and BCL-2 antagonist, venetoclax, have become the mainstay of treatment for chronic lymphocytic leukemia (CLL). Despite significant efficacy in most CLL patients, some patients develop resistance to these agents and progress on these drugs. We provide a state-of-the-art overview of the acquired resistance to novel agents. In 80% of patients with ibrutinib failure, acquired mutations in and genes were detected. No distinct unifying resistance-associated mutations or deregulated signaling pathways have been reported in idelalisib failure. Acquired mutations in the gene were detected in patients who had failed on venetoclax. In most cases, patients who have progressed on ibrutinib and venetoclax experience resistance-associated mutations, often present at low allelic frequencies. Resistance-associated mutations tend to occur between the second and fourth years of treatment and may already be detected several months before clinical relapse. We also discuss the development of next-generation agents for CLL patients who have acquired resistant mutations to current inhibitors.
B细胞受体信号通路抑制剂伊布替尼和艾代拉里斯，以及BCL-2拮抗剂维奈托克，已成为慢性淋巴细胞白血病（CLL）治疗的主要手段。尽管这些药物对大多数CLL患者具有显著疗效，但仍有一些患者会对其产生耐药性并在用药过程中病情进展。我们提供了关于新型药物获得性耐药的最新综述。在80%伊布替尼治疗失败的患者中，检测到了 和 基因的获得性突变。在艾代拉里斯治疗失败的患者中，尚未报告有明显的统一的耐药相关突变或信号通路失调。在维奈托克治疗失败的患者中检测到了 基因的获得性突变。在大多数情况下，伊布替尼和维奈托克治疗进展的患者会出现耐药相关突变，这些突变通常以低等位基因频率存在。耐药相关突变往往发生在治疗的第二至第四年，甚至在临床复发前几个月就可能被检测到。我们还讨论了针对对当前抑制剂已产生耐药突变的CLL患者的下一代药物的研发情况。
