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，急性髓系白血病 (AML) 和正常核型（AML 最大的细胞遗传学子集（即 40-49%））患者中获得性基因突变和基因表达变化的存在存在显着的异质性。已发现多种具有预后意义的亚显微遗传改变，包括FLT3基因的内部串联重复、MLL基因的部分串联重复、NPM1和CEBPA基因的突变以及ERG和BAALC基因的高表达。基因表达谱的应用还确定了一种基因表达特征，该特征似乎可以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，不仅在预测方面，而且在选择适当的治疗方面，因为许多已识别的基因改变构成或可能成为特定治疗干预的目标。然而，大多数研究已经在年轻患者（即 <60 岁）中鉴定并验证了这些预后标志物，而它们对细胞遗传学正常 AML 的老年患者（>60 岁）的预测价值仍有待充分评估。这个问题至关重要，因为在美国，如果仅考虑 65 岁以上的成年人，则每 100,000 例 AML 病例被诊断出 12.6 例，并且老年 AML 患者的缓解率明显低于年轻患者。尽管这些差异可能与一些临床不良预后因素的过度代表性有关，但老年组中不同分子标记物的贡献仍有待充分评估，以便完善风险适应分层策略，将不太可能对常规化疗治疗产生反应的患者分配到研究性治疗试验中。以癌症和白血病 B 组 (CALGB) 10201 研究为平台，这是一项多中心 III 期试验 (CALGB)，将老年 AML 患者随机分配到使用 Bcl-2 反义 Genasense 进行强化化疗，我们建议进行明确的分析，评估细胞遗传学正常的老年 AML 患者的分子异常频率和预测价值。为了实现这些目标，我们提出以下具体目标：1）确定细胞遗传学正常的老年 AML 患者中单基因标记的频率和预后价值，这些标记已被证明可以预测年轻 AML 的结果； 2) 鉴定与细胞遗传学正常的老年 AML 患者诊断时的临床特征和结果相关的微阵列多基因表达特征； 3) 鉴定与正常老年 AML 患者诊断时的临床特征和结果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、异质性疾病，其特征是骨髓和血液中髓系母细胞的增殖和成熟停滞。在美国，这种疾病在 65 岁以上成年人中的发病率较高，目前的治疗方法的结果极其惨淡，只有不到 10% 的病例实现了长期生存。因此，非常需要新颖的策略。在这里，我们建议对具有正常细胞遗传学的老年 AML 患者进行特征分析，这是老年 AML 的最大亚组（约占整个老年 AML 人群的 50%），以寻找可以预测结果的特定分子标记。这种方法最终将允许患者根据风险进行分层治疗，并为那些不太可能通过标准方法治愈的患者提供在研究新型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。