Molecular characterization of normal cytogenetics AML in older patients

描述(申请人提供)：最近的分子分析显示，在诊断时，在急性髓细胞白血病(AML)患者和正常核型(AML最大的细胞遗传学亚群，即40%-49%)患者中，存在获得性基因突变和基因表达变化的显著异质性。已经发现了多种具有预后意义的亚微观遗传改变，包括Flt3基因的内部串联重复，MLL基因的部分串联复制，NPM1和CEBPA基因的突变，ERG和BAALC基因的高表达。基因表达图谱的应用也确定了一个基因表达特征，似乎将细胞遗传学正常的AML患者分为预后亚组。这些和类似的未来发现可能会对临床治疗产生重大影响。 细胞遗传学正常的AML，不仅在预后方面，而且在选择适当的治疗方面也是如此，因为许多已发现的基因改变构成或将成为特定治疗干预的目标。然而，大多数已经在年轻患者(即60岁)中确认和验证了这些预后标志物的研究，而它们在细胞遗传学正常的老年患者(&gt；60岁)中的预测价值仍有待全面评估。这一问题至关重要，因为在美国，如果只考虑65岁的成年人，每10万例急性髓细胞白血病患者中有12.6例被诊断出来，而且老年急性髓细胞白血病患者的应答率明显低于年轻患者。尽管这些差异可能与几个临床预后不良因素的过度代表有关，但在老年组中，不同的分子标志物的作用仍有待充分评估，以完善风险适应分层策略，将对常规化疗不太可能有效的患者分配到研究治疗试验中。以癌症和白血病B组(CALGB)10201研究为平台，我们建议进行权威性分析，评估细胞遗传学正常的老年AML患者中分子异常的频率和预测价值。为了实现这些目标，我们提出了以下具体目标：1)在细胞遗传学正常的老年AML患者中，确定已被证明可以预测年轻AML患者预后的单基因标记物的频率和预后价值；2)确定与细胞遗传学正常的老年AML患者的临床特征和预后相关的微阵列多基因表达特征；3)确定与老年AML患者诊断时的临床特征和预后相关的特定微阵列多miR表达特征 细胞遗传学。 公共卫生相关性：急性髓系白血病(AML)是一种恶性的异质性疾病，其特征是骨髓和血液中的髓系原始细胞增殖并成熟停滞。在美国，这种疾病在65岁以上的成年人中的发病率上升，目前的治疗方法的结果非常令人沮丧，10%的病例实现了长期生存。因此，迫切需要新的战略。在这里，我们建议对具有正常细胞遗传学的老年AML患者进行特征描述，这是老年AML中最大的亚群(约占整个老年AML人群的50%)，以寻找可以预测预后的特定分子标志物。这种方法最终将允许患者分层进行风险适应治疗，并为那些不太可能用标准方法治愈的患者提供在研究新化合物的研究中接受治疗的可能性，而不必首先遭受目前使用的但无效的强化化疗方案的副作用。

DESCRIPTION (provided by applicant): Recent molecular analyses have revealed at diagnosis, a striking heterogeneity with regard to the presence of acquired gene mutations and changes in gene expression in patients with acute myeloid leukemia (AML) and a normal karyotype, the largest cytogenetic subset (i.e., 40-49%) of AML. Multiple submicroscopic genetic alterations with prognostic significance have been discovered, including internal tandem duplication of the FLT3 gene, partial tandem duplication of the MLL gene, mutations in the NPM1 and CEBPA genes high expression of the ERG and BAALC genes. Application of gene-expression profiling has also identified a gene-expression signature that appears to separate cytogenetically normal AML patients into prognostic subgroups. These and similar future findings are likely to have a major impact on the clinical management of cytogenetically normal AML, not only in prognostication but also in selection of appropriate treatment, since many of the identified genetic alterations constitute or will potentially become targets for specific therapeutic intervention. However, most of the studies that have identified and validated these prognostic markers in younger patients (i.e., <60 years), while their predicting value in older patients (>60 years) with normal cytogenetics AML remains to be fully evaluated. This issue is of paramount importance as in the United States 12.6 AML cases per 100,000 are diagnosed if only adults >65 years are considered and the response rates of older AML patients are significantly worse than those of the younger patients. Although these differences could be related to overrepresentation of several clinical poor-prognostic factors, the contribution of distinct molecular markers in the older group remains to be fully evaluated in order to refine risk-adapted stratification strategies that allocate patients who are not likely to respond to conventional chemotherapy treatment, to investigational therapeutic trials. Using as a platform the Cancer and Leukemia Group B (CALGB) 10201 study, a multicenter phase III trial (CALGB) that randomized older AML patients to intensive chemotherapy w/wo the Bcl-2 antisense Genasense, we propose to conduct definitive analyses that assess the frequency and predictive value of molecular abnormalities in older AML patients with normal cytogenetics. To achieved these goals we are proposing the following specific aims: 1) to determine in older AML patients with normal cytogenetics the frequency and the prognostic value of single-gene markers that have been already shown to be predictive of outcome in younger AML; 2) to identify microarray multi-gene expression signatures that correlate with clinical characteristics at diagnosis and outcome in older AML patients with normal cytogenetics; 3) to identify specific microarray multi-miR expression signatures that correlate with clinical characteristics at diagnosis and outcome in older AML patients with normal cytogenetics. PUBLIC HEALTH RELEVANCE: Acute myeloid leukemia (AML) is a malignant, heterogeneous disease characterized by proliferation with maturation arrest of myeloid blasts in bone marrow and blood. In the United States, the incidence of this disease in adults older than 65 years is elevated and the outcome with current treatment approaches is extremely dismal with <10% of the cases achieving long-term survival. Therefore, novel strategies are highly needed. Here, we propose to characterize older AML patients with normal cytogenetics, the largest subgroup of elderly AML (~50% of the entire elderly AML population) for specific molecular markers that can predict outcome. This approach will ultimately allow patients' stratification into risk-adapted treatments and give to those patients who are unlikely to be cured with standard approaches, the possibility to be treated on studies investigating novel compounds without having to suffer first the side effects of the currently used, but ineffective intensive chemotherapy regimens.