Venetoclax-based therapies for acute myeloid leukemia
Venetoclax-based therapies for acute myeloid leukemia
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DOI：
10.1016/j.beha.2019.05.008
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发表时间：
2019-06-01
影响因子：
2.1
通讯作者：
Konopleva, Marina
中科院分区：
文献类型：
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作者：
Guerra, Veronica A.;DiNardo, Courtney;Konopleva, Marina
成人急性髓细胞白血病（AML）的预后仍然很差，长期生存率低于50%。然而，通过更好地了解疾病遗传学和病理生理学，目前的治疗模式正在发生变化。自2017年以来，美国食品药品监督管理局已批准8种新药用于治疗AML，包括FLT 3抑制剂米多吉丁和gilteritinib、IDH抑制剂ivosidenib和enasidenib、抗CD 33单克隆抗体吉妥珠单抗、脂质体柔红霉素和阿糖胞苷、hedgehog途径抑制剂glasdegib和BCL-2抑制剂venetoclax。临床前数据证明了维奈托克在AML中的抗白血病疗效及其与低甲基化药物或化疗药物联合使用时的协同作用。临床试验已经证明了基于维奈托克的治疗在新诊断的AML中的临床益处，导致最近FDA批准维奈托克与低甲基化剂或低剂量阿糖胞苷联合治疗新诊断的AML老年人。在此，我们重点关注BCL-2单药抑制在AML中的作用，并回顾了基于维奈托克的联合治疗方案的临床研究和耐药机制的演变。
The prognosis of adult acute myeloid leukemia (AML) remains poor, with the long-term survival rate less than 50%. However, the current paradigms of treatment are changing through a better understanding of the disease genetics and pathophysiology. Since 2017, eight new drugs have been approved by the U.S. Food and Drug Administration for the treatment of AML, including the FLT3 inhibitors midostaurin and gilteritinib, the IDH inhibitors ivosidenib and enasidenib, the anti-CD33 monoclonal antibody gemtuzumab ozogamicin, liposomal daunorubicin and cytarabine, the hedgehog pathway inhibitor glasdegib and the BCL-2 inhibitor venetoclax. Preclinical data demonstrated the anti-leukemic efficacy of venetoclax in AML and its synergy when combined with hypomethylating agents or chemotherapy agents. Clinical trials have demonstrated the clinical benefit of venetoclax-based therapies in newly diagnosed AML, leading to the recent FDA approval of venetoclax in combination with hypomethylating agents or low-dose cytarabine for older adults with newly diagnosed AML. Herein, we focus on the role of single-agent BCL-2 inhibition in AML and review the clinical studies of venetoclax-based combination regimens and the evolving mechanisms of resistance.