Wiestner Adrian
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
Haematologica. 2015 Dec;100(12):1495-507. doi: 10.3324/haematol.2014.119123.
Chronic lymphocytic leukemia is a malignancy of mature auto-reactive B cells. Genetic and functional studies implicate B-cell receptor signaling as a pivotal pathway in its pathogenesis. Full B-cell receptor activation requires tumor-microenvironment interactions in lymphoid tissues. Spleen tyrosine kinase, Bruton's tyrosine kinase, and the phosphatidylinositol 3-kinase (PI3K) δ isoform are essential for B-cell receptor signal transduction but also mediate the effect of other pathways engaged in chronic lymphocytic leukemia cells in the tissue-microenvironment. Orally bioavailable inhibitors of spleen tyrosine kinase, Bruton's tyrosine kinase, or PI3Kδ, induce high rates of durable responses. Ibrutinib, a covalent inhibitor of Bruton's tyrosine kinase, and idelalisib, a selective inhibitor of PI3Kδ, have obtained regulatory approval in chronic lymphocytic leukemia. Ibrutinib and idelalisib are active in patients with high-risk features, achieving superior disease control in difficult-to-treat patients than prior best therapy, making them the preferred agents for chronic lymphocytic leukemia with TP53 aberrations and for patients resistant to chemoimmunotherapy. In randomized trials, both ibrutinib, versus ofatumumab, and idelalisib in combination with rituximab, versus placebo with rituximab improved survival in relapsed/refractory chronic lymphocytic leukemia. Responses to B-cell receptor inhibitors are mostly partial, and within clinical trials treatment is continued until progression or occurrence of intolerable side effects. Ibrutinib and idelalisib are, overall, well tolerated; notable adverse events include increased bruising and incidence of atrial fibrillation on ibrutinib and colitis, pneumonitis and transaminase elevations on idelalisib. Randomized trials investigate the role of B-cell receptor inhibitors in first-line therapy and the benefit of combinations. This review discusses the biological basis for targeted therapy of chronic lymphocytic leukemia with B-cell receptor inhibitors, and summarizes the clinical experience with these agents.
慢性淋巴细胞白血病是一种成熟的自身反应性B细胞恶性肿瘤。遗传学和功能研究表明，B细胞受体信号传导是其发病机制中的关键途径。完整的B细胞受体激活需要淋巴组织中的肿瘤微环境相互作用。脾酪氨酸激酶、布鲁顿酪氨酸激酶和磷脂酰肌醇3激酶（PI3K）δ亚型对于B细胞受体信号转导至关重要，但也介导了慢性淋巴细胞白血病细胞在组织微环境中其他途径的作用。脾酪氨酸激酶、布鲁顿酪氨酸激酶或PI3Kδ的口服生物可利用抑制剂可诱导高比例的持久反应。伊布替尼是布鲁顿酪氨酸激酶的共价抑制剂，idelalisib是PI3Kδ的选择性抑制剂，已在慢性淋巴细胞白血病中获得监管批准。伊布替尼和idelalisib在具有高危特征的患者中具有活性，在难治性患者中实现了比先前最佳治疗更好的疾病控制，使其成为具有TP53畸变的慢性淋巴细胞白血病和对化疗免疫治疗耐药患者的首选药物。在随机试验中，伊布替尼与奥法木单抗相比，以及idelalisib与利妥昔单抗联合使用与利妥昔单抗安慰剂相比，均改善了复发/难治性慢性淋巴细胞白血病患者的生存率。对B细胞受体抑制剂的反应大多是部分反应，在临床试验中，治疗会持续到疾病进展或出现无法耐受的副作用。总体而言，伊布替尼和idelalisib耐受性良好；显著的不良事件包括伊布替尼导致的瘀伤增加和房颤发生率增加，以及idelalisib导致的结肠炎、肺炎和转氨酶升高。随机试验正在研究B细胞受体抑制剂在一线治疗中的作用以及联合治疗的益处。本综述讨论了用B细胞受体抑制剂靶向治疗慢性淋巴细胞白血病的生物学基础，并总结了这些药物的临床经验。
