Therapy of acute myeloid leukemia: towards a patient-oriented, risk-adapted approach.
Therapy of acute myeloid leukemia: towards a patient-oriented, risk-adapted approach.
复制标题
急性髓系白血病的治疗：采取以患者为导向、适应风险的方法。
作者：
Franco Mandelli;M. Petti;F. Coco
背景与目的
急性早幼粒细胞白血病（APL）患者的分化治疗的成功使用表明，其他急性髓性白血病（AML）可能受益于定制和亚型特异性治疗。尽管尚未开发出专门针对AML遗传病变的新药，但已确定了不同的核型类别，可能需要进行差异化治疗。此外，分子检测，以评估对治疗的反应更敏感，现在可用于几个AML子集。在这篇综述中，我们讨论了遗传特征在AML治疗中的作用，以及我们认为仍然需要为每一位患有这种疾病的患者设计量身定制的治疗方法的调查工作。
设计和方法
作者在这一领域工作多年，并提供了原始论文，其数据被纳入本文。此外，本概述中分析的材料包括Science Citation Index和Medline所涵盖的文章和评论以及一些最近未发表的个人观察。
结果
AML的现代治疗方法倾向于根据细胞遗传学定义的风险类别区分诱导后治疗强度。这种预后分类在很大程度上是不令人满意的。事实上，随着新开发的分子检测（如RT-PCR和FISH）的出现，在核型明显正常的患者中经常发现特异性和病理学相关病变，因此，这些患者被重新分配到更合适的预后类别。此外，最近的研究表明，一些患者可能会受益于诱导强度的增加;快速遗传特征将需要未来的初始治疗的分化。然而，通过综合核型/分子分析对AML进行的初步研究表明，至少有一半病例未检测到特异性异常。因此，目前仅在一部分患者中使用遗传标准进行预后分层是可行的。
解释和结论
目前通过核型研究确定的遗传病变的预后作用，需要在大量AML患者中进行验证，这些患者的前瞻性特征是通过先进的分子/细胞遗传学分析和统一治疗。此外，迫切需要寻找新的临床相关的遗传异常和快速识别的诊断工具，以更好地识别预后类别。AML基因改变的阐明应促进旨在开发针对个体患者特定病变的新药的基础研究。在这些更具体的治疗药物被开发出来之前，诊断性遗传特征应添加到其他已确立的预后因素中，以优化目前可用的治疗方法的使用。
BACKGROUND AND OBJECTIVE
The successful use of differentiating treatment for patients with acute promyelocytic leukemia (APL) suggests that other acute myeloid leukemias (AML) may benefit from tailored and subtype-specific therapy. Despite the fact that new drugs specifically targeting AML genetic lesions have not yet been developed, distinct karyotypic categories have been identified which may deserve differentiated treatment. In addition, molecular assays to assess response to therapy more sensitively are now available for several AML subsets. In this review, we discuss the role of genetic characterization in the therapy of AML, and the investigative efforts which we believe are still needed for the design of tailored treatment for each and every patient with this disease.
DESIGN AND METHODS
The authors have been working in this field for many years and have contributed original papers, the data of which are incorporated in this article. In addition, the material analyzed in this overview includes articles and reviews covered by the Science Citation Index and Medline as well as some more recent unpublished personal observations.
RESULTS
Modern therapeutic approaches to AML tend to differentiate post-induction treatment intensity according to cytogenetically defined risk categories. Such prognostic categorization is largely unsatisfactory. In fact, following the advent of newly developed molecular assays (e.g. RT-PCR and FISH), specific and prognostically relevant lesions are frequently found in patients with an apparently normal karyotype, and these patients are, therefore, re-assigned to more appropriate prognostic categories. In addition, recent studies suggest that some patients may benefit from an increase in induction intensity; rapid genetic characterization will be needed for future differentiation of initial therapy. However, preliminary investigation of AML by integrated karyotypic/molecular analyses show that no specific abnormalities are detectable in at least half of the cases. Therefore, use of genetic criteria for prognostic stratification is currently feasible in only a proportion of patients.
INTERPRETATIONS AND CONCLUSIONS
The prognostic role of genetic lesions, currently identified by karyotypic studies, needs to be validated in large series of AML patients prospectively characterized by advanced molecular/cytogenetic analyses and treated uniformly. In addition, searches for new clinically relevant genetic abnormalities, and diagnostic tools for their rapid identification are urgently needed to identify prognostic categories better. Elucidation of AML gene alterations should foster basic investigation aimed at developing new drugs targeted to the specific lesion in the individual patient. Before these more specific therapeutic agents are developed, diagnostic genetic characterization should add to other well-established prognostic factors to optimize the use of the presently available therapies.