Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; and.
Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH.
Blood. 2021 Sep 30;138(13):1099-1109. doi: 10.1182/blood.2020006783.
Bruton tyrosine kinase inhibitors (BTKi) have significantly changed the treatment landscape for patients with B-cell malignancies, including chronic lymphocytic leukemia, Waldenstrom macroglobulinemia, mantle cell lymphoma, and marginal zone lymphoma. Unfortunately, patients with BTKi-resistant disease have shortened survival. Clinical and molecular risk factors, such as number of prior therapies and presence of TP53 mutations, can be used to predict patients at the highest risk of developing BTKi resistance. Many mechanisms of BTKi resistance have been reported with mutations in BTK and phospholipase C γ2 supported with the most data. The introduction of venetoclax has lengthened the survival of patients with BTKi-resistant disease. Ongoing clinical trials with promising treatment modalities, such as next-generation BTKi and chimeric antigen receptor T-cell therapy, have reported promising efficacy in patients with BTKi-resistant disease. Continued research focusing on resistance mechanisms and methods of how to circumvent resistance is needed to further prolong the survival of patients with BTKi-resistant B-cell malignancies.
布鲁顿酪氨酸激酶抑制剂 (BTKi) 显著改变了 B 细胞恶性肿瘤患者的治疗格局，包括慢性淋巴细胞白血病、华氏巨球蛋白血症、套细胞淋巴瘤和边缘区淋巴瘤。不幸的是，BTKi 耐药的患者生存期缩短。临床和分子危险因素，如先前治疗的次数和 TP53 突变的存在，可以用于预测发生 BTKi 耐药风险最高的患者。已有许多 BTKi 耐药机制被报道，其中 BTK 和磷脂酶 Cγ2 的突变得到了最多的数据支持。维奈托克的引入延长了 BTKi 耐药疾病患者的生存期。正在进行的临床试验采用了有前途的治疗方法，如下一代 BTKi 和嵌合抗原受体 T 细胞疗法，在 BTKi 耐药疾病患者中报告了有希望的疗效。需要继续研究耐药机制以及如何规避耐药的方法，以进一步延长 BTKi 耐药 B 细胞恶性肿瘤患者的生存期。
