Abstract
Introduction:
The 2016 World Health Organization (WHO) classification of myeloid neoplasms defines myelodysplastic syndrome, ring sideroblasts (MDS-RS) by the presence of dysplasia in single or multiple cell lineages with at least 15% ring sideroblasts (RS) or as few as 5% RS in the presence of SF3B1 mutations (Arber et al. Blood 2016). MDS-RS is further categorized into: MDS-RS with single lineage dysplasia (SLD, previously refractory anemia with RS) & MDS-RS with multi-lineage dysplasia (MLD, previously refractory cytopenias with MLD & RS). We carried out this study to define clinical & molecular differences between MDS-RS-SLD versus MDS-RS-MLD & assess survival outcomes.
Methods:
Successive cases of MDS-RS, meeting the 2016 WHO criteria were identified from our institutional database. In compliance with the WHO definition, only de novo cases were included. All patients had bone marrow (BM) biopsies & cytogenetics at diagnosis. Bone marrow slides including Prussian blue stains for RS were re-reviewed. Targeted exome sequencing for the following genes; TET2, ASXL1, DNMT3A, IDH1, IDH2, TP53, SRSF2, SF3B1, SH2B3, NPM1, FLT3, U2AF1, ZRSR2, JAK2, CSF3R, MPL, MFSD11, CEBPA, SETBP1, ZRSR2, RUNX1, IKZF1, CALR, KRAS, NRAS, CBL, PTPN11, STAG2, BCOR & GATA2, were carried out on BM specimens obtained at diagnosis . Statistics were performed via JMP Pro software (version 10).
Results:
Eighty seven patients with MDS-RS were included in the study, median age 73 years (range: 44-88), 30 (34%) males. Of these, 63 (72%) were categorized as MDS-RS-SLD & 24 (28%) as MDS-RS-MLD. Twenty-two (25%) had an abnormal karyotype, of which 8 (33%) had MDS-RS-MLD (p=0.30). Overall R-IPSS stratification included 2 (2%) very low, 51 (59%) low, 22 (25%) intermediate, 9 (10%) high & 3 (4%) very high risk categories, respectively. Targeted exome sequencing in 82 patients demonstrated the following mutational frequencies; SF3B1 61%, ASXL1 18%, DNMT3A 10%, TET2 5%, TP53 4%, IDH-1 2%, SRSF2 2%, and 1% each for PTPN11, ZRSR2, CSF3R & U2AF1 (Table 1).
With the exception for a higher frequency of SF3B1 (63% vs 42%, p=0.02) and DNMT3A (13% vs 0%, p=0.02); and a lower frequency of ASXL1 (10% vs 38%, p=0.005) mutations in the MDS-RS-SLD group, there were no other differences between the two groups.
At a median follow-up of 34 months, 77 (89%) deaths & 4 (4.6%) leukemic transformations were documented. Median overall survival (OS) for the entire MDS-RS cohort was 49 months (Range: 0-190); 60 (range: 0-190) and 47 (range 0-123) months for MDS-RS-SLD and MDS-RS-MLD groups respectively (p=0.2). On a univariate survival analysis that included age, sex, hemoglobin (Hb), white blood cell (WBC) count with individual differential counts, platelet counts, peripheral blood blasts, BM blasts, karyotype and the aforementioned gene mutations; only abnormal karyotype (p=0.03), lack of SF3B1 mutations (p=0.03) & presence of ASXL1 mutations (p=0.01, figure 1A) adversely impacted OS. Interestingly, the presence or absence of multilineage dysplasia did not impact outcomes (p=0.18) (Figure 1B). In a multivariate model that included the presence of ASXL1, absence of SF3B1 mutations and abnormal karyotype, only the presence of ASXL1 mutations (p=0.007, HR 2.3, 95% CI 1.2-4.18) retained prognostic significance. Given the small number of events, leukemia free survival analysis was not carried out.
Conclusions:
In the revised 2016 WHO category of MDS-RS, overall survival was independently and adversely impacted by the presence of ASXL1 mutations, with the extent of bone marrow dysplasia not affecting outcomes.
No relevant conflicts of interest to declare.
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