Abstract
DNA sequencing-based measurable residual disease (MRD) detection has shown to be clinically relevant in AML. However, the same methodology cannot be applied to fusion gene-driven subtypes of AML such as core-binding factor AML (CBF-AML). Here in this study, we evaluated the effectiveness of using DNA and RNA sequencing in MRD detection and in tracking clonal dynamics in CBF-AML. Using RNA-seq, we were able to quantify expression levels of RUNX1-RUNX1T1 and CBFB-MYH11 at diagnosis and their levels of reduction during remission (P < 6.3e−05 and P < 2.2e−13). The level of reduction of RUNX1-RUNX1T1 as measured by RNA-seq and qPCR were highly correlated (R2 = 0.74, P < 5.4e−05). A decision tree analysis, based on 3-log reduction of RUNX1-RUNX1T1 and cKIT-D816mut at diagnosis, stratified RUNX1-RUNX1T1 AML patients into three subgroups. These three subgroups had 2-year overall survival rates at 87%, 74%, and 33% (P < 0.08) and 2-year relapse incidence rates at 13%, 42%, and 67% (P < 0.05). On the other hand, although low residual allelic burden was common, it was not associated with long-term outcome, indicating that mutation clearance alone cannot be interpreted as MRD-negative. Overall, our study demonstrates that the clinical utility of RNA sequencing as a potential tool for MRD monitoring in fusion gene-driven AML such as RUNX1-RUNX1T1 AML.
Highlights
DNA sequencing-based measurable residual disease (MRD) detection has shown to be clinically relevant in acute myeloid leukemia (AML)
Among 155 samples subjected for DNA sequencing, 151 samples were taken from bone-marrow (BM) and other 4 samples were taken from peripheral blood (PB)
Current study demonstrated that RNA sequencing (RNA-seq) can measure reduction levels of RUNX1-RUNX1T1 and CBFB-MYH11 from diagnosis to complete remission (CR)
Summary
DNA sequencing-based measurable residual disease (MRD) detection has shown to be clinically relevant in AML. We describe a study to evaluate DNA and RNA sequencing on longitudinal samples taken at diagnosis and at CR, as potential MRD detection tools for post-remission monitoring of CBF-AML With this approach, we hoped to gain additional insights on how NGS can be applied to monitor MRD in CBF-AML, as well as reveal comprehensive dynamics of somatic mutations, transcripts, and gene rearrangements from diagnosis till CR. We hoped to gain additional insights on how NGS can be applied to monitor MRD in CBF-AML, as well as reveal comprehensive dynamics of somatic mutations, transcripts, and gene rearrangements from diagnosis till CR To address these questions, we conducted DNA sequencing (DNA-seq) on 223 DNA samples collected from 87 patients including 62 patients with t(8;21) and 25 patients with inv[16] taken at time points including diagnosis, CR, and relapse. For a subset of patients with available samples, we conducted RNA-seq on 90 samples consisted of 42 pairs of diagnosis-CR samples as well as 6 relapse samples
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