The Prognostic Impact Of Mutation Status And Burden In Lower-risk Myelodysplastic Syndromes

Research purposes:Patients with lower-risk myelodysplastic syndromes(LR-MDS)as defined by the International Prognostic Scoring System(IPSS)have more favorable prognosis in general,but a subset of LR-MDS have poorer survival than predicted.This study aimed to explore the impact of mutation status and mutation burden on prognosis of LR-MDS.Research methods:This study included 159 patients with LR-MDS(IPSS score≤1.0)upon initial diagnosis who were treated at at the First Affiliated Hospital,Zhejiang University School of Medicine during a period between February 2011 and January 2018.Metaphase cytogenetic analysis and Next Generation Sequencing of 15-MDS-related genes were conducted in the initial diagnosis.Univariate analysis was firstly used to assess the association of mutation status of genes with survival.An R language-based web tool Cutoff Finder was used to analyze the relationship between variant allele frequency(VAF)and prognosis.Multivariate COX regression analysis was used to identify factors with independent significance.Research results:Univariate analysis showed that mutation status of ASXL1(P=0.001),RUNX1(P=0.031),EZH2(P=0.049),TP53(P=0.016),SRSF2(P=0.046),JAK2(P=0.040)and IDH2(P=0.035)were significantly correlated with prognosis.Using R language-based web tool Cutoff Finder,an adjusted TET2 VAF threshold of 17.6% was the optimal cutoff for outcome prediction.Patients with adjusted TET2VAF≥18% were found to have a worse prognosis than those with TET2 wild-type or TET2 adjusted VAF<18%(median: 20.4 vs.47.8 months;P=0.020;HR=2.183,95%CI:1.129-4.224).The results of multivariate COX regression analysis showed that 4 mutational factors including mutation status of ASXL1(P<0.001;HR=4.306,95%CI: 2.144-8.650),TP53(P=0.004;HR=4.863,95%CI: 1.662-14.230)and JAK2(P=0.002;HR=5.466,95%CI: 1.848-16.169),and adjusted TET2 VAF≥18%(P=0.008;HR=2.492,95%CI:1.273-4.876)were independent prognostic predictors,after adjustment of IPSS.Also,OS was increasingly shorter as the number of mutational factors increased(P<0.001).A novel prognostic scoring system incorporating the five independent risk factors including IPSS intermiediate(Int)-1 risk,mutation status of ASXL1,TP53,and JAK2,and adjusted TET2 VAF value≥18% was constructed to stratify LR-MDS patients into three prognostically different groups(P<0.001).The LR-M-PSS could divide lower-risk MDS patients into three groups with significantly different prognosis(P<0.001)and identify 10.1%(16/159)higher-risk patients who could not be predicted by the current prognosis model to accept positive treatment.Conclusion:ASXL1 mutations,TP53 mutations,JAK2 mutations,and adjusted TET2 VAF value≥18% were independent prognostic mutational factors in LR-MDS.Integration of the IPSS with mutation status/burden of certain MDS-relevant genes may improve the prognostication of patients with LR-MDS and could help identify those with worse-than-expected prognosis for more aggressive treatment.