Molecular characterization of normal cytogenetics AML in older patients

老年患者正常细胞遗传学 AML 的分子特征

• 批准号: 7614313
• 负责人: GUIDO MARCUCCI
• 金额: $ 16.88万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-15 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7614313
• 关键词: Acute Myelocytic Leukemia; Adult; Adverse effects; Age; Biology; Blast Cell; Blood; Bone Marrow; CEBPA gene; Cancer and Leukemia Group B; Characteristics; Chemotherapy-Oncologic Procedure; Classification; Clinical; Clinical Management; Cytogenetics; Detection; Diagnosis; Disease; EVI1 gene; Elderly; Employee Strikes; FLT3 gene; Frequencies; Future; Gene Expression; Gene Expression Profile; Gene Mutation; Genes; Goals; Hematopoietic; Heterogeneity; Incidence; Karyotype; MLL gene; Malignant - descriptor; Molecular; Molecular Abnormality; Molecular Profiling; Mutation; Myelogenous; NPM1 gene; Oblimersen; Outcome; Patients; Phase III Clinical Trials; Population; Predictive Value; Prognostic Factor; Prognostic Marker; Protocols documentation; Randomized; Research; Risk; Stratification; Subgroup; Supportive care; Therapeutic; Therapeutic Intervention; Therapy Clinical Trials; United States; base; cell growth; chemotherapy; cohort; human old age (65+); improved; molecular marker; new therapeutic target; novel; novel strategies; older patient; prognostic; public health relevance; response; treatment response; treatment strategy

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.

描述（由申请人提供）：最近的分子分析显示，在诊断时，急性髓性白血病（AML）和正常核型患者中获得性基因突变和基因表达变化的存在显著的异质性，最大的细胞遗传学亚群（即，40-49%）的AML。已发现多种具有预后意义的亚显微遗传学改变，包括FLT 3基因的内部串联重复、MLL基因的部分串联重复、NPM 1和CEBPA基因突变以及ERG和BAALC基因的高表达。基因表达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管理产生重大影响， 细胞遗传学正常的AML，不仅在诊断上，而且在选择适当的治疗上，因为许多鉴定的遗传改变构成或可能成为特异性治疗干预的靶点。然而，大多数在年轻患者中鉴定和验证这些预后标志物的研究（即，<60岁），而其在细胞遗传学正常的老年AML患者（>60岁）中的预测价值仍有待充分评估。这一问题至关重要，因为在美国，如果仅考虑65岁以上的成年人，每100，000人中诊断出12.6例AML病例，老年AML患者的缓解率明显低于年轻患者。虽然这些差异可能与多个临床预后不良因素的过度表达有关，但老年组中不同分子标志物的贡献仍有待充分评估，以完善风险适应性分层策略，将不太可能对常规化疗治疗有反应的患者分配到研究性治疗试验中。使用癌症和白血病组B（CALGB）10201研究作为平台，这是一项多中心III期试验（CALGB），将老年AML患者随机分配至含Bcl-2反义Genasense的强化化疗组，我们建议进行确定性分析，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）在具有正常细胞遗传学的老年AML患者中确定已经被证明可预测年轻AML结果的单基因标志物的频率和预后价值; 2）鉴定与具有正常细胞遗传学的老年AML患者的诊断和结果的临床特征相关的微阵列多基因表达特征; 3）鉴定与具有正常骨髓增生异常综合征的老年AML患者的诊断和结果的临床特征相关的特异性微阵列多miR表达特征， 细胞遗传学 公共卫生相关性：急性髓系白血病（acute myeloid leukemia，AML）是一种以骨髓和血液中的髓系原始细胞增殖和成熟停滞为特征的恶性异质性疾病。在美国，这种疾病在65岁以上的成年人中的发病率升高，目前治疗方法的结果非常令人沮丧，<10%的病例获得长期生存。因此，非常需要新的战略。在这里，我们建议对具有正常细胞遗传学的老年AML患者进行表征，这是老年AML中最大的亚组（约占整个老年AML人群的50%），可以预测结果的特定分子标志物。这种方法最终将允许患者分层为风险适应性治疗，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进行治疗的可能性，而不必首先遭受目前使用的副作用，但无效的强化化疗方案。