Classification and risk assessment in AML: integrating cytogenetics and molecular profiling

Abstract

In recent years, the composite molecular architecture in acute myeloid leukemia (AML) has been mapped out. We now have a clearer understanding of the key genetic determinants, the major genetic interactions, and the broad order in which these mutations occur. The next impending challenge is to discern how these recent genomic discoveries define disease biology as well as how to use molecular markers to deliver patient-tailored clinical decision support.

Figure 1.

Meta-analysis of Papaemmanuil et al 2016 data for broad patterns of genomic instability in AML shows that ∼20% of patients with AML were defined according to fusion genes, 31% by chromosomal aneuploidies (to include at least 1 aneuploidy), 46% by gene mutations only (in the absence of gene fusions and chromosomal aneuploidies), and 3% with no events.

Figure 2.

Distribution of number of acquired mutations according to AML class and most frequently co-mutated genes. Data shown for (A) AML with fusion genes, (B) AML with aneuploidies, and (C) AML with gene mutations.

Figure 3.

Distribution of number of acquired mutations according to age of diagnosis for each AML class ordered as (A) AML with fusion genes, (B) AML with aneuploidies, and (C) AML with gene mutations.

Figure 4.

Box plot indication age of diagnosis for all patients in AML with chromosomal aneuploidies and TP53 mutations, separated by TP53 mutations status, shows that average age of TP53 wild type is 49 years while TP53 mutated is 58 years.

Figure 5.

Meta-analysis of the Papaemmanuil et al 2016 chromatin-spliceosome subgroup. Kaplan-Meier curves for overall survival are shown for 3 subsets of patients that classify with the chromatin-spliceosome group (n = 299) substratified according to ELN 2017 risk (favorable, n = 8; intermediate, n = 113; and adverse, n = 178). As shown by the graphic, the 113 patients who are classified as intermediate risk have equally adverse outcomes as the patients classified as adverse risk according to RUNX1, ASXL1, or FLT3^ITD high or chromosomal aneuploidies.