Shah Pratik V, Gladstone Douglas E
Department of Hematology Oncology, Zuckerberg Cancer Center, Northwell Health Cancer Institute, New Hyde Park, NY, USA.
Curr Treat Options Oncol. 2025 Jul 18. doi: 10.1007/s11864-025-01339-z.
Bruton's tyrosine kinase (BTK) inhibitors are transforming chronic lymphocytic leukemia (CLL) treatment. Given the availability of both covalent and non-covalent BTK inhibitors (BTKis) CLL treatment has become more nuanced. Here the mechanisms of action, efficacy, and resistance patterns associated with both inhibitor classes are reviewed to help create a framework for integrating covalent and non-covalent BTKis into CLL treatment algorithms. Our treatment algorithm based on the available data is as follows, in the frontline setting when oral therapy is preferred/chosen and indefinite therapy is not a deterrent, irrespective of DNA and IGVH mutational status, a second-generation covalent BTK inhibitor (cBTKi) is recommended. In the relapsed/refractory setting when oral therapy is preferred a second-generation cBTKi is preferred. For those suffering disease progression during second generation cBTK, it is recommended to change to an alternative cBTKi and for those exposed to greater than two lines of therapy, challenging to a non-covalent BTKi (ncBTKi) in the form of pirtobrutinib. At the time of disease progression on a BTKi, we recommend testing for resistance mutations. Data on combination therapy's role and time-limited BTKi use remain under active investigation.
布鲁顿酪氨酸激酶（BTK）抑制剂正在改变慢性淋巴细胞白血病（CLL）的治疗方式。鉴于共价和非共价BTK抑制剂（BTKi）均可获得，CLL治疗变得更加细致入微。在此，对与这两类抑制剂相关的作用机制、疗效和耐药模式进行综述，以帮助建立一个将共价和非共价BTKi纳入CLL治疗方案的框架。基于现有数据，我们的治疗方案如下：在一线治疗中，当首选/选择口服治疗且非限期治疗不是阻碍因素时，无论DNA和免疫球蛋白重链可变区（IGVH）突变状态如何，推荐使用第二代共价BTK抑制剂（cBTKi）。在复发/难治性情况下，当首选口服治疗时，首选第二代cBTKi。对于在第二代cBTK治疗期间病情进展的患者，建议换用另一种cBTKi；对于接受过两种以上治疗方案的患者，可选用pirtobrutinib形式的非共价BTKi（ncBTKi）进行挑战。在BTKi治疗期间病情进展时，我们建议检测耐药突变。联合治疗的作用和限时使用BTKi的数据仍在积极研究中。
