Engen Caroline B N, Hajjar Ehsan, Gjertsen Bjørn T
Department of Internal Medicine, Haematology Section, Haukeland University Hospital, Bergen, Norway.
Curr Pharm Biotechnol. 2016;17(1):20-9. doi: 10.2174/1389201016666150930115024.
Acute myeloid leukemia (AML) is characterized by extensive clinical and biological heterogeneity. Despite vast advances in understanding the molecular pathology in AML during the last two decades few new AML therapeutics have been approved by the European Medicines Agency. Since 2005 only the epigenetic modulators decitabine and azacytidine, as well as histamine (plus interleukin- 2) have been approved against AML. None of these have outstanding efficiency, and decitabine and azacytdine have only been incorporated in frontline therapy of AML with limited enthusiasm. The majority of AML patients are frail and elderly, and lack of mild but effective agents for this patient cohort constitutes a major unmet need as overall survival remains poor. Along with the recent advancements in the molecular characterization of AML, numerous targeted therapies have been tested in clinical trials. In this review, we discuss the biological rationale for a selection of these novel therapeutic approaches, including epigenetic modifiers, agents targeting signalling pathways and inhibitors of nuclear-cytoplasmic shuttling. Further we discuss some of the possible shortcomings in current trial design that could explain the apparent incoherence between our improved biological knowledge and the lack of progress in therapy development of AML.
急性髓系白血病（AML）具有广泛的临床和生物学异质性。尽管在过去二十年里对AML分子病理学的理解有了巨大进展，但欧洲药品管理局批准的新的AML治疗药物却很少。自2005年以来，只有表观遗传调节剂地西他滨和阿扎胞苷以及组胺（加白细胞介素-2）被批准用于治疗AML。这些药物都没有显著的疗效，地西他滨和阿扎胞苷在AML一线治疗中的应用也缺乏热情。大多数AML患者体弱且年老，对于这一患者群体而言，缺乏温和但有效的药物是一个主要的未满足需求，因为总体生存率仍然很低。随着AML分子特征研究的最新进展，许多靶向治疗药物已在临床试验中进行了测试。在这篇综述中，我们讨论了选择这些新型治疗方法的生物学原理，包括表观遗传修饰剂、靶向信号通路的药物和核质穿梭抑制剂。此外，我们还讨论了当前试验设计中一些可能的缺点，这些缺点可以解释我们在生物学知识不断进步与AML治疗开发缺乏进展之间明显的不一致。
