Division of Hematology, University of Colorado School of Medicine, 1665 Aurora Court, Mail Stop F754, Aurora, CO, 80045, USA.
Curr Hematol Malig Rep. 2018 Aug;13(4):256-264. doi: 10.1007/s11899-018-0464-8.
Apoptosis results from the interaction between pro- and anti-apoptotic proteins, mediated by BCL-2 homology 3 (BH3) proteins. B cell lymphoma-2 (BCL-2) is an inhibitor of apoptosis which stabilizes the mitochondria, resulting in the prevention of activation of the pro-apoptotic proteins. In addition, BCL-2 is overexpressed in the leukemic stem cell (LSC) population, and its inhibition may lead to selective LSC eradication. Herein, we will discuss the mechanism and rationale of BCL-2 inhibition in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) with an overview of the selective BCL-2 inhibitor venetoclax.
Venetoclax has activity against AML and has displayed synergistic activity with hypomethylating agents in the preclinical setting. In the clinical setting, although it has only modest activity as a single agent in relapsed and refractory AML, in the older, treatment-naïve population, in combination with either a hypomethylator or low-dose cytarabine, it is well tolerated with impressive efficacy. In addition, BCL-2 inhibition may also have activity in MDS, and although clinical trials are in their early phases, this may be an effective strategy in both the up-front and relapsed setting. BCL-2 inhibition with venetoclax is well tolerated and active in older patients with newly diagnosed AML and in the relapsed setting has activity that may be improved in combination with other therapies. It may prove to be effective in MDS and is an exciting treatment strategy for myeloid malignancies.
细胞凋亡是由促凋亡蛋白和抗凋亡蛋白相互作用引起的，由 BCL-2 同源结构域 3（BH3）蛋白介导。B 细胞淋巴瘤-2（BCL-2）是一种凋亡抑制剂，它稳定线粒体，从而阻止促凋亡蛋白的激活。此外，BCL-2 在白血病干细胞（LSC）群体中过度表达，抑制其表达可能导致 LSC 的选择性清除。在此，我们将讨论 BCL-2 抑制剂在急性髓细胞白血病（AML）和骨髓增生异常综合征（MDS）中的作用机制和原理，并概述选择性 BCL-2 抑制剂 venetoclax。
venetoclax 对 AML 具有活性，并在临床前研究中与低甲基化剂表现出协同作用。在临床环境中，尽管它作为单一药物在复发和难治性 AML 中的活性仅适度，但在年龄较大、未经治疗的人群中，与低剂量阿糖胞苷或低剂量阿糖胞苷联合使用时，其耐受性良好，疗效显著。此外，BCL-2 抑制在 MDS 中也可能具有活性，尽管临床试验处于早期阶段，但在初治和复发环境中，这可能是一种有效的策略。venetoclax 抑制 BCL-2 在新诊断的 AML 老年患者中具有良好的耐受性和活性，在复发环境中具有活性，与其他治疗方法联合使用可能会改善其活性。它可能在 MDS 中有效，并为髓系恶性肿瘤提供了一种令人兴奋的治疗策略。
