Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a prognostically prioritized molecular classification?

Abstract

Recent molecular analyses of leukemic blasts from pretreatment marrow or blood of patients with acute myeloid leukemia (AML) and a normal karyotype, the largest cytogenetic subset (ie, 40%-49%) of AML, have revealed a striking heterogeneity with regard to the presence of acquired gene mutations and changes in gene expression. Multiple submicroscopic genetic alterations with prognostic significance have been discovered, including internal tandem duplication of the FLT3 gene, mutations in the NPM1 gene, partial tandem duplication of the MLL gene, high expression of the BAALC gene, and mutations in the CEBPA gene. Application of gene-expression profiling has also identified a gene-expression signature that appears to separate cytogenetically normal AML patients into prognostic subgroups, although gene-expression signature-based classifiers predicting outcome for individual patients with greater accuracy are needed. 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 already constitute or will potentially become targets for specific therapeutic intervention. In this report, we review prognostic genetic findings in karyotypically normal AML and discuss their clinical implications.

Figure 1

Pie chart based on 246 patients analyzed for the presence or absence of mutations in the NPM1 and CEBPA genes, FLT3-ITD, FLT3-TKD, and MLL-PTD indicating the coexistence of mutations in individual patients. WT indicates patients with only wild-type alleles of genes tested. Adapted by Kenneth X. Probst from Döhner et al with permission.

Figure 2

Proposed schema assigning AML patients with a normal karyotype to risk-adapted postremission therapies using information on currently known prognostic markers as a basis for designing future clinical studies. SCT denotes stem-cell transplantation; ASCT, autologous SCT; and HDAC, high-dose cytarabine. Illustration drawn by Kenneth X. Probst.