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Abstract：
Bruton\'s Tyrosine Kinase (BTK) inhibitors have become one of the most vital drugs in the therapy of chronic lymphocytic leukemia (CLL). Inactivation of BTK disrupts the B-cell antigen receptor (BCR) signaling pathway, which leads to the inhibition of the proliferation and survival of CLL cells. BTK inhibitors (BTKi) are established as leading drugs in the treatment of both treatment-naïve (TN) and relapsed or refractory (R/R) CLL. Furthermore, BTKi demonstrate outstanding efficacy in high-risk CLL, including patients with chromosome 17p deletion, TP53 mutations, and unmutated status of the immunoglobulin heavy-chain variable region (IGHV) gene. Ibrutinib is the first-in-class BTKi which has changed the treatment landscape of CLL. Over the last few years, novel, covalent (acalabrutinib, zanubrutinib), and non-covalent (pirtobrutinib) BTKi have been approved for the treatment of CLL. Unfortunately, continuous therapy with BTKi contributes to the acquisition of secondary resistance leading to clinical relapse. In recent years, it has been demonstrated that the predominant mechanisms of resistance to BTKi are mutations in BTK or phospholipase Cγ2 (PLCG2). Some differences in the mechanisms of resistance to covalent BTKi have been identified despite their similar mechanism of action. Moreover, novel mutations resulting in resistance to non-covalent BTKi have been recently suggested. This article summarizes the clinical efficacy and the latest data regarding resistance to all of the registered BTKi.
摘要：
Bruton的酪氨酸激酶(BTK)抑制剂已成为治疗慢性淋巴细胞白血病(CLL)的重要药物之一。BTK失活破坏B细胞抗原受体（BCR）信号通路，从而抑制CLL细胞的增殖和存活。BTK抑制剂（BTKi）被确定为治疗初治（TN）和复发或难治性（R/R）CLL的主要药物。此外，BTKi在高危CLL中表现出突出的疗效，包括染色体17p缺失的患者,TP53突变,和免疫球蛋白重链可变区（IGHV）基因的未突变状态。Ibrutinib是一流的BTKi，它改变了CLL的治疗前景。在过去的几年里，小说,共价(acalabrutinib，扎努布替尼)，和非共价（pirtobrutinib）BTKi已被批准用于治疗CLL。不幸的是,BTKi持续治疗有助于获得继发性耐药,导致临床复发.近年来,已经证明，对BTKi的抗性的主要机制是BTK或磷脂酶Cγ2（PLCG2）的突变。尽管对共价BTKi的抗性机制类似,但已经鉴定了它们的作用机制中的一些差异。此外，最近提出了导致对非共价BTKi耐药的新突变。本文总结了对所有注册的BTKi的临床疗效和最新数据。
