ena-STUDY-UNIVERSITY OF TORONTO-20-11-2016-18:48:14:551-1688
Longitudinal tracking of myelodysplatic syndrome patients using next generation sequencing provides a predictive measure for azacitidine response and acute myeloid leukemia progression
Hypomethylating agents such as azacitidine (AZA) are commonly used to treat myelodysplastic syndrome as a frontline therapy. Although its survival benefits are well documented, the underlying genetics and clonal dynamics upon AZA treatment have not been systematically examined using serial samples. In this study, we performed targeted serial sequencing on 285 bone marrow samples from 95 MDS patients treated with AZA. Genes involved in DNA methylation, spliceosome, and chromatin modification were the most frequently mutated. When assessing the mutation dynamics with clinical measures, we found significant VAF reduction in responders compared to non-responders. Multivariate analyses revealed that mutation burden in different genes and biological pathways have distinct impact on AZA response, leukemia progression, and overall survival. Most notably, mutations in activated signaling pathway genes are associated with AML progression. In addition, we could not detect decreased allelic burden in activated signaling pathway genes even in responders. Patients with SRSF2 mutations tended to respond to AZA. Mutations in tumor suppressors and myeloid transcription factors were adverse prognostic factors in overall survival. Interestingly, mutations in DNA methylation pathway genes were not an independent prognostic factor for any of the three measures. Our study shows that longitudinal tracking of MDS patients using next generation sequencing can be used to improve criteria for AZA response and for early detection of AML progression.
Hypomethylating agents such as azacitidine (AZA) are commonly used to treat myelodysplastic syndrome as a frontline therapy. Although its survival benefits are well documented, the underlying genetics and clonal dynamics upon AZA treatment have not been systematically examined using serial samples. In this study, we performed targeted serial sequencing on 285 bone marrow samples from 95 MDS patients treated with AZA. Genes involved in DNA methylation, spliceosome, and chromatin modification were the most frequently mutated. When assessing the mutation dynamics with clinical measures, we found significant VAF reduction in responders compared to non-responders. Multivariate analyses revealed that mutation burden in different genes and biological pathways have distinct impact on AZA response, leukemia progression, and overall survival. Most notably, mutations in activated signaling pathway genes are associated with AML progression. In addition, we could not detect decreased allelic burden in activated signaling pathway genes even in responders. Patients with SRSF2 mutations tended to respond to AZA. Mutations in tumor suppressors and myeloid transcription factors were adverse prognostic factors in overall survival. Interestingly, mutations in DNA methylation pathway genes were not an independent prognostic factor for any of the three measures. Our study shows that longitudinal tracking of MDS patients using next generation sequencing can be used to improve criteria for AZA response and for early detection of AML progression.