Aw Andrew, Brown Jennifer R
Division of Hematology, Department of Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada.
CLL Center and Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA, 02215, USA.
Drugs Aging. 2017 Jul;34(7):509-527. doi: 10.1007/s40266-017-0468-4.
The B-cell receptor (BCR) pathway plays an important role in the survival, proliferation and trafficking of cancer cells in a variety of B-cell malignancies. Recently, a number of agents have been developed to target various components of the BCR pathway. One such target is Bruton's tyrosine kinase (BTK), a Tec family kinase member found near the cell membrane that is involved in upstream BCR signaling. The biological function of BTK in several B-cell lymphoid malignancies has led to the development of the oral BTK inhibitor ibrutinib. In chronic lymphocytic leukemia (CLL), ibrutinib has demonstrated durable clinical responses in relapsed/refractory (R/R) patients, including those with the high-risk del(17p) cytogenetic abnormality. These findings have paved the way for trials evaluating ibrutinib in previously untreated CLL patients, and also in combination with chemoimmunotherapy or other novel agents. Durable clinical responses have also been demonstrated in mantle cell lymphoma (MCL) and Waldenström's macroglobulinemia (WM) patients treated with ibrutinib. Ibrutinib is generally well tolerated, although current follow-up remains short and patients of advanced age are more likely to discontinue treatment for toxicity. Treatment-specific side effects such as bleeding and atrial fibrillation may, at least partly, be related to off-target inhibition of non-BTK kinases. Studies evaluating other potential indications for BTK inhibition are ongoing, including in post-allogeneic hematopoietic stem cell transplant patients for whom ibrutinib may be effective in modulating graft-versus-host disease. Combination trials of ibrutinib with venetoclax, a Bcl-2 inhibitor, are underway and are supported by sound preclinical rationale. Several next-generation BTK inhibitors are under development with the goal of decreasing treatment-related toxicity and resistance.
B细胞受体（BCR）通路在多种B细胞恶性肿瘤中，对癌细胞的存活、增殖和迁移起着重要作用。最近，人们开发了许多药物来靶向BCR通路的各个组成部分。其中一个靶点是布鲁顿酪氨酸激酶（BTK），它是一种Tec家族激酶成员，位于细胞膜附近，参与BCR上游信号传导。BTK在几种B细胞淋巴瘤中的生物学功能促使了口服BTK抑制剂伊布替尼的研发。在慢性淋巴细胞白血病（CLL）中，伊布替尼在复发/难治性（R/R）患者中显示出持久的临床反应，包括那些具有高危del(17p)细胞遗传学异常的患者。这些发现为评估伊布替尼在初治CLL患者中的疗效以及与化疗免疫疗法或其他新型药物联合使用的试验铺平了道路。在接受伊布替尼治疗的套细胞淋巴瘤（MCL）和华氏巨球蛋白血症（WM）患者中也证实了持久的临床反应。伊布替尼一般耐受性良好，尽管目前的随访时间较短，且老年患者更有可能因毒性而停药。出血和心房颤动等特定治疗副作用可能至少部分与非BTK激酶的脱靶抑制有关。评估BTK抑制其他潜在适应症的研究正在进行中，包括在异基因造血干细胞移植后患者中，伊布替尼可能对调节移植物抗宿主病有效。伊布替尼与Bcl-2抑制剂维奈克拉的联合试验正在进行中，并有可靠的临床前理论依据支持。几种下一代BTK抑制剂正在研发中，目标是降低治疗相关毒性和耐药性。
