Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD20892-1202, USA.
Hematology Am Soc Hematol Educ Program. 2012;2012:88-96. doi: 10.1182/asheducation-2012.1.88.
Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells that depend on host factors in the tissue microenvironment for survival and proliferation. In vitro, CLL cells rapidly undergo apoptosis unless microenvironmental factors are provided that support their survival. Signaling pathways activated in the microenvironment in vivo include the B-cell receptor (BCR) and NF-κB pathways. Thus, CLL is a disease "addicted to the host" and is dependent on pathways that promote normal B-cell development, expansion, and survival; this is particularly true in the case of the BCR signaling cascade. Small-molecule inhibitors of kinases that are essential for BCR signal transduction abrogate the stimulating effects of the microenvironment on CLL cells. The orally administered tyrosine kinase inhibitors fostamatinib and ibrutinib and the phosphatidylinositol 3-kinase inhibitor GS-1101 have induced impressive responses in relapsed and refractory CLL patients, mostly with moderate side effects. Reductions in lymphadenopathy and splenomegaly are seen within weeks and are frequently accompanied by a transient rise in absolute lymphocyte count that is asymptomatic and probably the result of changes in CLL cell trafficking. This review discusses the biologic basis for kinase inhibitors as targeted therapy of CLL and summarizes the exciting early clinical experience with these agents.
慢性淋巴细胞白血病（CLL）是一种成熟 B 细胞的恶性肿瘤，其生存和增殖依赖于组织微环境中的宿主因素。在体外，CLL 细胞会迅速凋亡，除非提供支持其生存的微环境因素。体内微环境中激活的信号通路包括 B 细胞受体（BCR）和 NF-κB 通路。因此，CLL 是一种“依赖宿主”的疾病，依赖于促进正常 B 细胞发育、扩增和生存的通路；在 BCR 信号级联中尤其如此。对 BCR 信号转导至关重要的激酶的小分子抑制剂可消除微环境对 CLL 细胞的刺激作用。口服酪氨酸激酶抑制剂 fostamatinib 和 ibrutinib 以及磷脂酰肌醇 3-激酶抑制剂 GS-1101 在复发和难治性 CLL 患者中引起了令人印象深刻的反应，大多数患者的副作用较轻。在数周内可观察到淋巴结病和脾肿大减轻，并且经常伴随着绝对淋巴细胞计数的短暂升高，这是无症状的，可能是 CLL 细胞迁移变化的结果。这篇综述讨论了激酶抑制剂作为 CLL 靶向治疗的生物学基础，并总结了这些药物令人兴奋的早期临床经验。
