Department of Hematology, Zealand University Hospital, Sygehusvej 10, 4000, Roskilde, Denmark.
Department of Hematology, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark.
Drugs. 2018 Nov;78(16):1653-1663. doi: 10.1007/s40265-018-1003-6.
Bruton's tyrosine kinase (BTK) is crucial in B-cell development and survival. The role of BTK as a downstream kinase in the B-cell receptor (BCR) signaling pathway is well described. As a key player in the pathogenesis of B-cell malignancies, targeting of dysregulated BCR signaling has been explored by development of inhibitors of downstream mediators. Discovery of the biological function of BTK and the development of covalent inhibitors for clinical use, ibrutinib as the lead agent and acalabrutinib as the second clinically approved BTK inhibitor, have revolutionized the treatment options for B-cell malignancies. Currently, ibrutinib is approved for mantle cell lymphoma, chronic lymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, small lymphocytic lymphoma, marginal zone lymphoma and chronic graft versus host disease, while acalabrutinib is approved for mantle cell lymphoma. Potential expansion of indications in other diseases is under investigation in several clinical trials, while combination of BTK inhibitors with either chemoimmunotherapy or other targeted agents is being systematically explored in B-cell malignancies.
布鲁顿酪氨酸激酶（BTK）在 B 细胞发育和存活中至关重要。BTK 作为 B 细胞受体（BCR）信号通路下游激酶的作用已得到充分描述。作为 B 细胞恶性肿瘤发病机制中的关键参与者，通过开发下游介质的抑制剂来靶向失调的 BCR 信号已被探索。BTK 的生物学功能的发现和用于临床的共价抑制剂的开发，以伊布替尼为先导药物和阿卡替尼为第二个临床批准的 BTK 抑制剂，彻底改变了 B 细胞恶性肿瘤的治疗选择。目前，伊布替尼已获批用于套细胞淋巴瘤、慢性淋巴细胞白血病、淋巴浆细胞淋巴瘤/华氏巨球蛋白血症、小淋巴细胞淋巴瘤、边缘区淋巴瘤和慢性移植物抗宿主病，而阿卡替尼已获批用于套细胞淋巴瘤。几项临床试验正在研究其他疾病适应证的扩展，而 BTK 抑制剂与化疗免疫治疗或其他靶向药物的联合正在 B 细胞恶性肿瘤中得到系统探索。
