Development and Validation of a Novel RNA Sequencing–Based Prognostic Score for Acute Myeloid Leukemia

Abstract

Background

Recent progress in sequencing technologies allows us to explore comprehensive genomic and transcriptomic information to improve the current European LeukemiaNet (ELN) system of acute myeloid leukemia (AML).

Methods

We compared the prognostic value of traditional demographic and cytogenetic risk factors, genomic data in the form of somatic aberrations of 25 AML-relevant genes, and whole-transcriptome expression profiling (RNA sequencing) in 267 intensively treated AML patients (Clinseq-AML). Multivariable penalized Cox models (overall survival [OS]) were developed for each data modality (clinical, genomic, transcriptomic), together with an associated prognostic risk score.

Results

Of the three data modalities, transcriptomic data provided the best prognostic value, with an integrated area under the curve (iAUC) of a time-dependent receiver operating characteristic (ROC) curve of 0.73. We developed a prognostic risk score (Clinseq-G) from transcriptomic data, which was validated in the independent The Cancer Genome Atlas AML cohort (RNA sequencing, n = 142, iAUC = 0.73, comparing the high-risk group with the low-risk group, hazard ratio [HR]_OS = 2.42, 95% confidence interval [CI] = 1.51 to 3.88). Comparison between Clinseq-G and ELN score iAUC estimates indicated strong evidence in favor of the Clinseq-G model (Bayes factor = 26.78). The proposed model remained statistically significant in multivariable analysis including the ELN and other well-known risk factors (HR_os = 2.34, 95% CI = 1.30 to 4.22). We further validated the Clinseq-G model in a second independent data set (n = 458, iAUC = 0.66, adjusted HR_OS = 2.02, 95% CI = 1.33 to 3.08; adjusted HR_EFS = 2.10, 95% CI = 1.42 to 3.12).

Conclusions

Our results indicate that the Clinseq-G prediction model, based on transcriptomic data from RNA sequencing, outperforms traditional clinical parameters and previously reported models based on genomic biomarkers.

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