Validation of risk stratification models in acute myeloid leukemia using sequencing-based molecular profiling

Abstract

Risk stratification of acute myeloid leukemia (AML) patients needs improvement. Several AML risk classification models based on somatic mutations or gene-expression profiling have been proposed. However, systematic and independent validation of these models is required for future clinical implementation. We performed whole-transcriptome RNA-sequencing and panel-based deep DNA sequencing of 23 genes in 274 intensively treated AML patients (Clinseq-AML). We also utilized the The Cancer Genome Atlas (TCGA)-AML study (N=142) as a second validation cohort. We evaluated six previously proposed molecular-based models for AML risk stratification and two revised risk classification systems combining molecular- and clinical data. Risk groups stratified by five out of six models showed different overall survival in cytogenetic normal-AML patients in the Clinseq-AML cohort (P-value<0.05; concordance index >0.5). Risk classification systems integrating mutational or gene-expression data were found to add prognostic value to the current European Leukemia Net (ELN) risk classification. The prognostic value varied between models and across cohorts, highlighting the importance of independent validation to establish evidence of efficacy and general applicability. All but one model replicated in the Clinseq-AML cohort, indicating the potential for molecular-based AML risk models. Risk classification based on a combination of molecular and clinical data holds promise for improved AML patient stratification in the future.

Figure 1

Overall survival of CN-AML patients stratified by gene signature, Marcucci-7-gene, Li-24-gene, Eppert-LSCR, Eppert-HSCR, Metzeler-86-probe and Bullinger-133-gene in the Clinseq-AML (a) and the TCGA-AML (b). P-value is the P-value of log-rank test comparing two groups. HR is the HR and 95% CI comparing high-risk group to low-risk group. (c) HRs (95% CI) in the Clinseq-AML, the TCGA-AML cohort (blue) and HRs reported in the validation cohorts from the original studies (grey). *Not CN-AML only. (d) C-index (95% CI) in the Clinseq and the TCGA AML-CN patients.

Figure 2

Risk group distribution and overall survival of AML risk classifications in the Clinseq-AML cohort (a, c, e and g) and the TCGA-AML cohort (b, d, f and h). Patients with acute promyelocytic leukemia were excluded. (a) and (b) are based on cytogenetic risk classification, (c) and (d) are based on the ELN classification system, (e) and (f) are based on the Patel-mutation panel revised risk classification, and (g) and (h) are based on the LI-24-gene revised ELN risk classification.

Figure 3

Reclassification from cytogenetic risk to the ELN (a and b), from the ELN to the Patel’s revised risk stratification (c and d), and from the ELN to the Li’s revised risk classification (e and f) in the Clinseq and the TCGA cohorts.