Mutation status and burden can improve prognostic prediction of patients with lower‐risk myelodysplastic syndromes

Abstract

Patients with lower-risk myelodysplastic syndromes (LR-MDS) as defined by the International Prognostic Scoring System (IPSS) have more favorable prognosis in general, but significant inter-individual heterogeneity exists. In this study, we examined the molecular profile of 15 MDS-relevant genes in 159 patients with LR-MDS using nextgeneration sequencing. In univariate COX regression, shorter overall survival (OS) was associated with mutation status of ASXL1 (P = .001), RUNX1 (P = .031), EZH2 (P = .049), TP53 (P = .016), SRSF2 (P = .046), JAK2 (P = .040), and IDH2 (P = .035). We also found significantly shorter OS in patients with an adjusted TET2 variant allele frequency (VAF) ≥18% versus those with either an adjusted TET2 VAF <18% or without TET2 mutations (median: 20.4 vs 47.8 months; P = .020; HR = 2.183, 95%CI: 1.129-4.224). After adjustment for IPSS, shorter OS was associated with mutation status of ASXL1 (P < .001; HR = 4.306, 95% CI: 2.144-8.650), TP53 (P = .004; HR = 4.863, 95% CI: 1.662-14.230)and JAK2 (P = .002; HR = 5.466, 95%CI: 1.848-16.169), as well as adjusted TET2 VAF ≥18% (P = .008; HR = 2.492, 95% CI: 1.273-4.876). Also, OS was increasingly shorter as the number of mutational factors increased (P < .001). A novel prognostic scoring system incorporating the presence/absence of the four independent mutational factors into the IPSS further stratified LR-MDS patients into three prognostically different groups (P < .001). The newly developed scoring system redefined 10.1% (16/159) of patients as a higher-risk group, who could not be predicted by the currently prognostic models. In conclusion, 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. K E Y W O R D Slower-risk myelodysplastic syndromes, mutation burden, mutation status, prognosis, variant allele frequency | 581 JIANG et Al.

The prognostic impact of variant allele frequency (VAF) in TP53 mutant patients with MDS: A systematic review and meta‐analysis

“…Among them, three studies, including four cohorts, only provided Kaplan‐Meier curves (HRs extracted for OS as described above, which were regarded as universal HRs), and one study reported primary data that could be used to calculate the HR. As previously reported, 23 TP53 mutation was an adverse prognostic factor in MDS patients (HR = 2.59, 95% CI: 1.84‐3.63, P < .0001) from pooled limited data with high heterogeneity (I 2 = 86.5%) (Figure 2).…”

“…Numerous studies have already assessed the adverse prognostic effect of TP53 mutation in MDS, and the pooled HRs for OS in our present analysis confirmed the same view. However, recent studies have discovered that in these high‐risk patient subgroups, some patients still have relatively better survival and longer remission times 23 . In our meta‐analysis, results showed that patients with high VAF in TP53 mutant MDS had a shorter life expectancy than those with low frequency or no mutation.…”

Sex-Related Differences in Chronic Myeloid Neoplasms: From the Clinical Observation to the Underlying Biology

“…The increased burden of somatic mutations in bone marrow samples has been associated with overall worse survival in patients with myeloid neoplasms [ 50 , 51 , 52 , 53 ]. Higher allele burden of somatic mutations in the CD34+ cells has been associated with overall more aggressive MDS sub-types [ 54 ] and congruence of the JAK2V617F CD34+ progenitor and neutrophil allele burdens in MPN patients has been correlated with more advanced disease and MF phenotype [ 55 ].…”

Integration Analysis of JAK2 or RUNX1 Mutation With Bone Marrow Blast Can Improve Risk Stratification in the Patients With Lower Risk Myelodysplastic Syndrome

“…Recently, JAK2 mutations have been reported to not only be associated with inferior survival in MDS receiving hematopoietic stem cell transplantation (HSCT) ( 28 ), but also in LR-MDS ( 29 ). JAK2 mutation leads to constitutive activation of the JAK2/STAT3 pathway which further resulted in growth factor independence, increased proliferation, and differentiation failure ( 30 ).…”