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.
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.
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