Only Hotspot SF3B1 K700E Mutation Is an Independent Predictor of Overall Survival in Myelodysplastic Syndromes

SF3B1 mutated (SF3B1^mut) MDS is associated with increased ring sideroblasts (RS) and favorable outcome. IWG-PM proposed that SF3B1^mut MDS be considered a distinct entity in the absence of other unfavorable features. However, not all SF3B1^mut MDS have similar clinical course. Hotspot K700E SF3B1^mut leads to aberrant splice junctions and large-scale mRNA downregulation by activating a cryptic splice site. The functional effects of SF3B1^mut outside of K700E is not clear. The outcome can also be altered by concomitant gene mutations and karyotype. In this study, we studied the clinical-pathologic features and outcome in a single-institutional series of 94 SF3B1^mut and 415 SF3B1^wt MDS, and explored the differences between K700E and non-K700E subgroups.

All untreated MDS patients diagnosed over a 3-year duration who underwent NGS were selected. Overall survival was calculated from diagnosis to death/ last follow-up. Univariate (UVA) Cox proportional hazards regression was used to identify any association of variables with outcome followed by multivariate modeling (MVA) (p-value 0.200 cutoff).

Of 509 patients, 94 (19%) had SF3B1^mut: 59 men, 35 women; median age: 74 (39-92) years. Baseline characteristics: Table 1. Compared to SF3B1^wt, SF3B1^mut had a significantly higher median age (74 vs. 70, p=0.0008), MCV (105 vs. 96, p<0.0001), platelet count (188 vs. 78, p<0.0001) and lower BM blasts (2 vs. 4, p=0.003). SF3B1^mut were less frequently therapy-related (18% vs. 34%, p=0.002), significantly enriched in R-IPSS VL/L and WHO MDS-RS and MDS with iso del(5q). Majority (~66%) had concomitant mutations: TET2 (25%), DNMT3A (21%), RUNX1 (15%), TP53 (10%), ASXL1 (7%), BCOR (4%), IDH1/2 (4%), SRSF2 (3%), RAS (3%) and EZH2 (3%) (Fig 1B). ~10% showed complex karyotype (CK). Among SF3B1^mut, hotspot K700E mutation was seen in 55 (~60%). Non K700E mutations (n=39, 40%) frequently involved codons: H662, K666 and R625, seen in 8 patients each (Fig 1A). SF3B1 K700E showed a higher median RS% (50% vs. 34%; p=0.038), ANC (2.4 vs. 1.8, p=0.005) and a trend for higher platelet (196 vs. 124, p=0.05). SF3B1^mut were less likely MDS-EB than non-K700E (22% vs. 49%, p=0.008). All 4 SF3B1^mut patients that fit WHO criteria for MDS with isolated del(5q) had K700E (Table). The frequency of RUNX1 mutation was significantly higher in non-K700E cases (26% vs. 7.3%, p=0.012); mutations in BCOR (p=0.02), IDH2 (p=0.07) and SRSF2 (p=0.07) were exclusively noted in non-K700E cases (Fig 1C). There was no significant difference in TP53^mut or CHIP-associated mutations DNMT3A, ASXL1 and TET2 or SF3B1 VAF. There was no significant differences in diploid vs. CK. However, K700E had lower CCCS categories (0/1, n=39; 2/3/4, n=10 vs. 0/1, n=19; 2/3/4, n=17); p=0.011).

Majority were treated with HMA [16/17 (94%) K700E; 15/19 (79%) non-K700, 217/ 277 (78%) SF3B1^wt]. SF3B1^mut had better OS than SF3B1^wt in all MDS (NR vs. 25.2 months, p=0.0003; fig 1D), low-grade MDS (NR vs. 41.3 months, p=0.0015; fig 1E) and MDS-RS (NR vs. 22.3 months, p=0.0004; fig 1F). Four (7.3%) K700E died compared to 9 (23%; p=0.036) non-K700E. The outcome of non-K700E was similar to SF3B1^wt, in all MDS, low-grade MDS and MDS-RS (median OS, NR for both; p=0.021). By UVA, the following associated with worse outcome: higher BM blasts, lower hemoglobin, platelet and MCV, prior chemo-radiation, CK, higher R-IPSS, absence of mutations in SF3B1 K700E, TET2 and U2AF1 and presence of TP53^mut. Non-K700E did not associate with OS. By MVA, lower hemoglobin, higher R-IPSS, absence of SF3B1 K700E and presence of TP53^mut were independent predictors of worse OS. Within MDS-RS categories, independent prognostic factors of worse OS included lower platelet, presence of mutations in non-K700E SF3B1^mut, ASXL1, SRSF2 and TP53. TP53^mut/CK was seen in 10% SF3B1^mut MDS. No survival differences were noted between SF3B1^mut with or without TP53^mut/CK (median OS, NR) and SF3B1^wt without TP53^mut/CK (44.3 months), but TP53^mut/CK with SF3B1^wt MDS had a worse outcome (median OS, 12.9 months, HR 1.46, p=0.001; fig 1G). Same findings were noted within low-grade MDS and MDS-RS, suggesting SF3B1^mut negates the poor prognostic effect of TP53^mut/CK.

About 40% SF3B1^mut MDS show non K700E mutations. K700E and non K700E SF3B1^mut MDS show distinct clinical and mutational profiles, with K700E showing a significantly better OS compared to non K700E and SF3B1^wt. Only SF3B1 K700E independently predicted for worse OS in MDS.

Figure

View largeDownload slide

Figure

View largeDownload slide

Close modal