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.

Prognostic significance of recurring chromosomal abnormalities in transplanted patients with acute myeloid leukemia

“…Notwithstanding the incorporation of novel innovative molecular risk stratification models into modern prognostication schemas of AML patients [8,19,20], baseline cytogenetic studies still serve as an invaluable prognostic tool for prediction of outcome at key clinical time points during the therapeutic sequence of AML patients [7]. Indeed, cytogenetic abnormalities have been previously established as robust predictors of the risk of primary induction resistance [21], risk of relapse [22,23], and outcome following transplant for primary refractory disease [24].…”

Association of Second Allogeneic Hematopoietic Cell Transplant vs Donor Lymphocyte Infusion With Overall Survival in Patients With Acute Myeloid Leukemia Relapse

“…G rowing understanding of molecular aspects of acute myeloid leukemia (AML) revealed an increasingly heterogeneous disease and challenged traditional treatment algorithms that relied solely on clinical and cytogenetic characteristics. [1][2][3] Although new therapies have been added to the armamentarium of AML management, 4,5 the disease remains incurable, particularly when adverse risk features are present and in patients with relapsed and/or refractory AML. 6 Allogeneic hematopoietic cell transplant (allo-HCT) is potentially curative in AML.…”

RNA splicing alterations induce a cellular stress response associated with poor prognosis in AML

“…To validate these findings, we analyzed an independent cohort of AML patients from the Scandinavian Clinseq study 39,45 . Selecting the patients similarly to the TCGA cohort, we performed differential splicing analyses between Clinseq-ELN Fav (n=47) and ELN Adv (n= 75) patients ( Fig 1G).…”

“…Data from two adult AML cohorts were used in the discovery phase of the study: The Cancer Genome Atlas (TCGA)-AML cohort 38 and the Clinseq-AML cohort 39 . Data from the Beat-AML cohort 7 was used to validate significance of the splicing signature.…”