Risk-stratification of intermediate-risk acute myeloid leukemia: integrative analysis of a multitude of gene mutation and expression markers.

Abstract

Numerous molecular markers have been recently discovered as potential prognostic factors in acute myeloid leukemia (AML). It has become of critical importance to thoroughly evaluate their interrelationships and relative prognostic importance. We set out to investigate a comprehensive set of biomarkers with an emphasis on the statistical assessment of their collective utility in the stratification of intermediate-risk AML using model selection in the frameworks of survival tree and regression methodologies. Gene expression profiling was conducted in a well-characterized cohort of 439 patients under age 60 with newly diagnosed AML to determine expression levels of EVI1, WT1, BCL2, ABCB1, BAALC, FLT3, CD34, INDO, ERG and MN1. A variety of AML-specific mutations were evaluated, i.e. FLT3, NPM1, N-RAS, K-RAS, IDH1, IDH2 and CEBPA(DM/SM) (double/single). Univariable survival analysis shows that (I) patients with FLT3(ITD) mutations have inferior overall survival (OS) and event free survival (EFS), whereas CEBPA(DM) and NPM1 mutations indicate favourable OS and EFS in intermediate-risk AML, (II) high transcript levels of BAALC, CD34, MN1, EVI1 and ERG predict inferior OS and EFS. In multivariable survival analysis, CD34, ERG and CEBPA(DM) remain significant. Using survival tree methodology, we show that a reduced combination of CEBPA(DM), CD34 and IDH2 is capable of separating the intermediate group into two AML subgroups with highly distinctive survival characteristics (OS at 60 months: 51.9% versus 14.9%). The integrated statistical approach demonstrates that from the multitude of biomarkers a greatly condensed subset can be selected for improved stratification of intermediate-risk AML.