Zaidi Syed Z, Owaidah Tarek, Al Sharif Fahad, Ahmed Said Y, Chaudhri Naeem, Aljurf Mahmoud
Adult Hematology & SCT Department, Prince Sultan Hematology Oncology Center, King Fahad Medical City, Riyadh, Saudi Arabia.
Hematol Oncol Stem Cell Ther. 2008 Jul-Sep;1(3):141-58. doi: 10.1016/s1658-3876(08)50023-9.
Cytogenetic aberrations have long been recognized as the most important prognostic variable in acute myeloid leukemia (AML) and are now a major stratification tool for post-remission therapy. Cytogenetics-based stratification improves survival. Patients with AML and normal cytogenetics, the largest single subgroup, have had a very heterogeneous outcome with standard chemotherapy in multiple clinical trials. Hence it is difficult to recommend a "one size fits all" kind of treatment for this heterogeneous population of AML patients. New emerging data from preclinical, retrospective, and large, randomized controlled studies indicate that in addition to cytogenetic abnormalities, many other molecular aberrations are operative in the response to treatment as well as in the risk of relapse. Such molecular markers are being tested for developing targeted therapies and may help in improved stratification of patients in the selection of post-remission therapy. Emerging evidence reveals that at the submicroscopic level, AML with normal cytogenetics may carry poor prognostic genetic lesions or "molecular signatures" as is the case with FLT3 mutations and overexpression of BAALC, ERG or MN1, or may have aberrations that predict better risk as is the case with isolated NPM1 or CEBPA mutations. Later studies have tried to explore the interaction of various prognostically important genes in this group of AML patients. The utility of the evolving data for bedside management of such patients is expected to improve with the wider application of modern tools, using the proposed clinical outcome models, and probably by development of a risk-scoring system based on the relative risk associated with each molecular aberration. The goals include identifying those patients most likely to benefit from upfront allogeneic HSCT and sparing good-prognosis patients from unnecessary transplant-related morbidity. The following is an outline of the most common molecular changes, their impact on the outcome of AML patients with normal cytogenetics and challenges in their wide scale application in risk stratification.
细胞遗传学异常长期以来一直被认为是急性髓系白血病（AML）最重要的预后变量，如今已成为缓解后治疗的主要分层工具。基于细胞遗传学的分层可提高生存率。AML且细胞遗传学正常的患者是最大的单一亚组，在多项临床试验中接受标准化疗后，其预后差异很大。因此，很难为这一异质性AML患者群体推荐“一刀切”的治疗方法。来自临床前、回顾性以及大型随机对照研究的新出现数据表明，除细胞遗传学异常外，许多其他分子异常在治疗反应以及复发风险中也起作用。此类分子标志物正在接受检测以开发靶向治疗，可能有助于在缓解后治疗选择中更好地对患者进行分层。新出现的证据显示，在亚微观水平上，细胞遗传学正常的AML可能携带预后不良的遗传损伤或“分子特征”，如FLT3突变以及BAALC、ERG或MN1的过表达，或者可能具有预测风险较低的异常，如孤立的NPM1或CEBPA突变。后来的研究试图探索这组AML患者中各种预后重要基因之间的相互作用。随着现代工具的更广泛应用、使用所提出的临床结局模型以及可能通过基于与每个分子异常相关的相对风险开发风险评分系统，这些不断演变的数据在这类患者床边管理中的效用有望得到改善。目标包括识别那些最有可能从前期异基因造血干细胞移植中获益的患者，并使预后良好的患者避免不必要的移植相关并发症。以下是最常见分子变化的概述、它们对细胞遗传学正常的AML患者预后的影响以及在风险分层中广泛应用这些变化所面临的挑战。
