Somatic mutation dynamics in MDS patients treated with azacitidine indicate clonal selection in patients-responders

Abstract

Azacitidine (AZA) for higher risk MDS patients is a standard therapy with limited durability. To monitor mutation dynamics during AZA therapy we utilized massive parallel sequencing of 54 genes previously associated with MDS/AML pathogenesis. Serial sampling before and during AZA therapy of 38 patients (reaching median overall survival 24 months (Mo) with 60% clinical responses) identified 116 somatic pathogenic variants with allele frequency (VAF) exceeding 5%. High accuracy of data was achieved via duplicate libraries from myeloid cells and T-cell controls. We observed that nearly half of the variants were stable while other variants were highly dynamic. Patients with marked decrease of allelic burden upon AZA therapy achieved clinical responses. In contrast, early-progressing patients on AZA displayed minimal changes of the mutation pattern. We modeled the VAF dynamics on AZA and utilized a joint model for the overall survival and response duration. While the presence of certain variants associated with clinical outcomes, such as the mutations of CDKN2A were adverse predictors while KDM6A mutations yield lower risk of dying, the data also indicate that allelic burden volatility represents additional important prognostic variable. In addition, preceding 5q- syndrome represents strong positive predictor of longer overall survival and response duration in high risk MDS patients treated with AZA. In conclusion, variants dynamics detected via serial sampling represents another parameter to consider when evaluating AZA efficacy and predicting outcome.

Clonal selection in therapy‐related myelodysplastic syndromes and acute myeloid leukemia under azacitidine treatment

“…Recently, analysis of clonal selection under AZA treatment before allogeneic stem cell transplantation (allo‐SCT) confirmed that AZA could select mutated clones and showed that recurrent clones could re‐emerge at relapse. Other studies established that AZA may influence variant allele frequencies in MDS patients . Nevertheless, these studies suggested a limited selectivity of AZA treatment.…”

“…Other studies established that AZA may influence variant allele frequencies in MDS patients. 31 Nevertheless, these studies suggested a limited selectivity of AZA treatment. Usual response criteria and outcome could be improved by monitoring clonal selection under AZA treatment.…”

“…Usual response criteria and outcome could be improved by monitoring clonal selection under AZA treatment. 31,35 In the present study, we focused our study on therapy-related MDS and AML. T-MDS and t-AML have cytogenetic features and outcome that differ from de novo MDS and AML and belong to a specific subgroup called t-MN in 2016 WHO classification.…”

“…Of note, in MDS and AML, DNMT3A and TET2 mutations have been associated with favorable AZA response. [30][31][32][33] At diagnosis, we detected clones with mutations in genes involved in DNA methylation regulation in five patients (patients #9, #11, #14, #15, and #19; Figure S1). Median VAF of these clones was 39% (range, .…”

Meta-analysis of studies with genome sequencing in myelodysplastic syndrome treated with hypomethylating agents

“…In this study we summarized the results of 12 studies with whole exome/genome sequencing in MDS [10,11,[13][14][15][16][17][18][19][20][21][22].…”