Epigenetic Regulators and Response to Hypomethylating Agents in Higher-Risk Myelodysplastic Syndromes

Abstract

Fewer than half of patients respond to hypomethylating agents, and sequencing has been expected to identify which. It has, but not in the way the field assumed: the mutations that predict response are not the mutations that predict survival, and treating the two questions as one produces a marker that answers neither. Objectives: To review the published evidence on somatic mutations in epigenetic regulators as predictors of response to hypomethylating agents in higher-risk myelodysplastic syndromes: which mutations predict response, which predict survival, how the two differ, and how the apparent signal depends on how variants are counted.
Material and Methods: Narrative review of sequencing cohorts, randomised trials, meta-analyses and mechanistic work indexed in PubMed and the major haematology journals. Studies were eligible if they reported the association between somatic mutation and response or survival after hypomethylating agent treatment in a defined myelodysplastic syndrome population. No new patient data were generated and no patients were recruited; every estimate quoted is one published by the original investigators. Results: Sequencing 40 recurrently mutated genes in 213 patients before treatment found that 94 per cent carried at least one driver mutation, most frequently ASXL1 in 46 per cent, TET2 in 27, RUNX1 in 20, TP53 in 18 and DNMT3A in 16 per cent. The overall response rate was 47 per cent and did not differ between azacitidine and decitabine. Clonal TET2 mutation predicted response with an odds ratio of 1.99 (p = 0.036) when variants below 10 per cent allele fraction were treated as wild-type, and response was highest in TET2-mutant patients without clonal ASXL1 mutation at an odds ratio of 3.65 (p = 0.009). When all variants were counted regardless of allele fraction, TET2 alone ceased to predict response. Mutations of TP53 (HR 2.01, p = 0.002) and PTPN11 (HR 3.26, p = 0.006) were associated with shorter overall survival but not with drug response. Conclusion: Response and survival are governed by different mutations, and a patient with TP53 mutation may respond while still dying early. The TET2 signal exists only under a clonality filter, which makes the predictor a variant allele frequency threshold as much as a gene. Abbreviations: MDS – Myelodysplastic Syndrome, HMA – Hypomethylating Agent, AZA – Azacitidine, DEC – Decitabine, AML – Acute Myeloid Leukaemia, VAF – Variant Allele Frequency, OR – Odds Ratio, HR – Hazard Ratio, WT – Wild-Type, IPSS-R – Revised International Prognostic Scoring System, IPSS-M – Molecular International Prognostic Scoring System, CR – Complete Remission.