Blood Disorders Center, Department of Hematology, University of Colorado Hospital, Aurora, CO. Email:
Department of Leukemia at The University of Texas, MD Anderson Cancer Center, Houston, TX. Email:
Am J Manag Care. 2018 Aug;24(16 Suppl):S356-S365.
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy that largely impacts the elderly population. Not all AML patients are candidates for the mainstay induction and consolidation treatment options. In addition, despite available therapies, most patients will eventually relapse on, or be refractory to, standard induction therapy, with limited subsequent choices and poor prognosis. Recently, several new and emerging therapies, with a variety of mechanisms of action, have broadened the treatment landscape in newly diagnosed and relapsed/refractory (R/R) AML, providing patients and healthcare providers with more options and several targeted treatment approaches. Preclinical data indicate that the anti-apoptotic protein myeloid cell leukemia-1 (MCL-1) is important to AML cell survival. Cyclin-dependent kinase 9 (CDK9), a transcriptional activator necessary for the expression of MCL-1, represents a promising target for future AML therapies. A number of CDK9 inhibitors, as well as several direct MCL-1 inhibitors, are currently in clinical or preclinical development. The CDK9 inhibitors alvocidib, atuveciclib, and TG02 have completed phase 1/2 clinical trials, with results available for the alvocidib trial showing improved complete remission rates (70% vs 46%; P = .003) for alvocidib in combination with cytarabine and mitoxantrone, versus cytarabine/daunorubicin, in patients with newly diagnosed AML. In addition, several phase 1 clinical trials with CDK9 inhibitors are currently recruiting for treatment of advanced AML. A phase 1b study is also ongoing to investigate alvocidib in combination with B-cell lymphoma-2 inhibitor venetoclax for R/R AML. Although further research is needed, CDK9 inhibitors represent a promising new approach for the treatment of AML.
急性髓系白血病（AML）是一种侵袭性血液系统恶性肿瘤，主要影响老年人群。并非所有 AML 患者都适合采用主流诱导和巩固治疗方案。此外，尽管有可用的疗法，但大多数患者最终仍会对标准诱导治疗产生耐药或复发，后续选择有限，预后较差。最近，几种具有不同作用机制的新型和新兴疗法拓宽了新诊断和复发/难治性（R/R）AML 的治疗领域，为患者和医疗保健提供者提供了更多选择和几种靶向治疗方法。临床前数据表明，抗凋亡蛋白髓样细胞白血病-1（MCL-1）对 AML 细胞的存活很重要。细胞周期蛋白依赖性激酶 9（CDK9）是 MCL-1 表达所必需的转录激活剂，是未来 AML 治疗的一个有前途的靶点。目前已有多种 CDK9 抑制剂和几种直接的 MCL-1 抑制剂处于临床或临床前开发阶段。CDK9 抑制剂 alvocidib、atuveciclib 和 TG02 已完成 1/2 期临床试验，alvocidib 联合阿糖胞苷和米托蒽醌治疗新诊断 AML 的临床试验结果显示，与阿糖胞苷/柔红霉素相比，完全缓解率（70%比 46%；P =.003）得到改善。此外，目前正在招募接受 CDK9 抑制剂治疗的晚期 AML 的多项 1 期临床试验。一项 1b 期研究也正在进行，以研究 alvocidib 联合 B 细胞淋巴瘤-2 抑制剂 venetoclax 治疗 R/R AML。尽管还需要进一步的研究，但 CDK9 抑制剂代表了治疗 AML 的一种很有前途的新方法。
