Department of Internal Medicine III, University of Ulm, Ulm, Germany.
Department of Clinical Hematology, The Alfred Hospital and Monash University, Melbourne, VIC, Australia.
Nat Rev Clin Oncol. 2021 Sep;18(9):577-590. doi: 10.1038/s41571-021-00509-w. Epub 2021 May 18.
With rapid advances in sequencing technologies, tremendous progress has been made in understanding the molecular pathogenesis of acute myeloid leukaemia (AML), thus revealing enormous genetic and clonal heterogeneity, and paving the way for precision medicine approaches. The successful development of precision medicine for patients with AML has been exemplified by the introduction of targeted FLT3, IDH1/IDH2 and BCL-2 inhibitors. When used as single agents, these inhibitors display moderate antileukaemic activity. However, augmented clinical activity has been demonstrated when they are administered in combination with drugs with broader mechanisms of action targeting epigenetic and/or other oncogenic signalling pathways or with conventional cytotoxic agents. The development of immunotherapies has been hampered by the expression of antigens that are expressed by both leukaemic and non-malignant haematopoietic progenitor cells; nonetheless, a diverse range of immunotherapies are now entering clinical development. This myriad of emerging agents also creates challenges, such as how to safely combine agents with different mechanisms of action, the need to circumvent primary and secondary resistance, and new challenges in future clinical trial design. In this Review, we discuss the current state of precision medicine for AML, including both the potential to improve patient outcomes and the related challenges.
随着测序技术的快速发展，人们在理解急性髓系白血病（AML）的分子发病机制方面取得了巨大进展，从而揭示了巨大的遗传和克隆异质性，并为精准医学方法铺平了道路。AML 患者精准医学的成功发展，体现在靶向 FLT3、IDH1/IDH2 和 BCL-2 抑制剂的引入上。当作为单一药物使用时，这些抑制剂显示出中等的抗白血病活性。然而，当它们与作用机制更广泛的药物联合使用时，靶向表观遗传和/或其他致癌信号通路或与传统细胞毒性药物联合使用时，已证明具有增强的临床活性。免疫疗法的发展受到白血病和非恶性造血祖细胞都表达的抗原的限制；尽管如此，现在有多种免疫疗法正在进入临床开发。这些新兴药物也带来了挑战，例如如何安全地将具有不同作用机制的药物联合使用，需要规避原发性和继发性耐药性，以及未来临床试验设计的新挑战。在这篇综述中，我们讨论了 AML 的精准医学现状，包括改善患者预后的潜力和相关挑战。
