Tallman Martin S
Northwestern University Feinberg School of Medicine, Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, 676 N. St. Clair Street, Suite 850, Chicago, IL 60611, USA.
Hematology Am Soc Hematol Educ Program. 2005:143-50. doi: 10.1182/asheducation-2005.1.143.
The prognosis for younger adults (< or = 55-60 years) with acute myeloid leukemia (AML) has improved during the last four decades. However, there has been little progress in the treatment of older adults. This disappointing observation is important because the median age of patients with AML is about 70 years. Approximately 60%-80% of younger adults with AML achieve complete remission (CR) with the cytotoxic agents cytarabine and an anthracycline such as daunorubicin or idarubicin or the anthracenedione mitoxantrone. However, only 30%-40% of such patients are alive and disease-free at 5 years. Among older adults, CR is achieved in 40%-55%, but there are very few long-term survivors. Many studies have evaluated the impact of alternative doses and schedules, as well as additional cytotoxic drugs, on the prognosis for this group of patients. The outcome has not improved substantially beyond that achieved with conventional doses of an anthracycline and cytarabine followed by high-dose cytarabine consolidation.Several factors identified at diagnosis can predict outcome. The most important of these is the karyotype of the leukemic cells. Another critical factor is the presence of transmembrane transporter proteins, which confer multidrug resistance and mutations in or overexpression of specific genes such as WT1, C/EBPalpha, BAX, and BCL-2/BAX ratio, BAALC, EVI1, KIT and FLT3. The development of specific agents directed at gene mutations, signal transduction pathways and unique cell surface antigens provide the foundation for new therapeutic strategies. Such agents include the immunoconjugate gemtuzumab ozogamicin, multidrug resistance inhibitors, farnesyltransferase inhibitors, histone deacetylase and proteosome inhibitors, antiangiogenesis agents, FLT3 inhibitors, apoptosis inhibitors, and nucleoside analogs. All of these agents can potentially address the heterogeneous abnormalities in AML and significantly improve the outcome for patients.
在过去四十年中，年轻成人（≤55 - 60岁）急性髓系白血病（AML）的预后有所改善。然而，老年成人的治疗进展甚微。这一令人失望的观察结果很重要，因为AML患者的中位年龄约为70岁。大约60% - 80%的年轻AML成人患者使用细胞毒性药物阿糖胞苷和蒽环类药物（如柔红霉素、伊达比星）或蒽二酮米托蒽醌可实现完全缓解（CR）。然而，这类患者中只有30% - 40%在5年后仍存活且无疾病。在老年成人中，40% - 55%可实现CR，但长期存活者极少。许多研究评估了替代剂量和给药方案以及其他细胞毒性药物对该组患者预后的影响。除了传统剂量的蒽环类药物和阿糖胞苷随后进行大剂量阿糖胞苷巩固治疗所取得的效果外，结果并未有实质性改善。诊断时确定的几个因素可以预测预后。其中最重要的是白血病细胞的核型。另一个关键因素是跨膜转运蛋白的存在，其赋予多药耐药性以及特定基因（如WT1、C/EBPα、BAX和BCL - 2/BAX比值、BAALC、EVI1、KIT和FLT3）的突变或过表达。针对基因突变、信号转导途径和独特细胞表面抗原的特异性药物的开发为新的治疗策略奠定了基础。这类药物包括免疫偶联物吉妥单抗、多药耐药抑制剂、法尼基转移酶抑制剂、组蛋白去乙酰化酶和蛋白酶体抑制剂、抗血管生成药物、FLT3抑制剂、凋亡抑制剂和核苷类似物。所有这些药物都有可能解决AML中的异质性异常，并显著改善患者的预后。
