MDS-254: SF3B1 Splicing Mutation in the Context of Therapy-Related MDS

Abstract

Context: Acquired SF3B1 splicing mutation is the sole somatic mutation associated with favorable outcome in MDS and is described among 80% of patients with the ring sideroblasts subtype. Objective: Evaluate clinical characteristics and outcomes of SF3B1-mt in therapy-related MDS (t-MDS) Design: We identified all patients with MDS harboring the SF3B1 mutation at Moffitt Cancer Center and compared t-MDS to de novo MDS. Additionally, we evaluated those with t-MDS and further stratified them into wild-type SF3B1 (SF3B1-WT) and SF3B1-mut and compared these two groups. Results: In a large cohort of patients with MDS, we identified 320 patients with SF3B1 mutations. These were further stratified to de novo MDS (n=289) and those with therapy-related MDS (n=31). Baseline characteristics and concomitant mutations were similar among both groups, except for concomitant CBL in de novo MDS vs in t-MDS (1% vs 10%; p = 0.002). Transformation to AML between dn-MDS SF3B1-mut vs t-MDS SF3B1-mut was 12.5% vs 12.9%, respectively (p = 0.943). Median overall survival in those with de novo MDS SF3B1-mut vs t-MDS SF3B1-mut was 103 months vs 59 months, p = 0.001. During further investigation of all therapy-related MDS patients, were then stratified by wild-type SF3B1 (SF3B1-WT) and SF3B1-mut. Of the 272 t-MDS, 31 were SF3B1-mut (11%). Complex cytogenetics was seen in 37.4% vs 10.3% of patients with SF3B1-WT vs SF3B1-mut, p = 0.009. Concomitant TP53 mutations were seen in 36.1% SF3B1-WT vs 10% SF3B1-mut, p = 0.004. AML transformation was 34.4% in SF3B1-WT compared to 12.9% SF3B1-mut, p-value 0.016. Median overall survival was 17 months in SF3B1-WT vs 43 months in SF3B1-mut, p = 0.004. Conclusions: SF3B1 mutations are more commonly seen de novo than in therapy-related MDS. After comparison, baseline characteristics and concomitant mutations were similar; however, de novo MDS SF3B1-mut had better outcomes versus t-MDS SF3B1-mut, although incidence of transformation to AML was similar. In patients with therapy-related MDS, those with SF3B1-mut had better outcomes than those with SF3B1-WT. Additionally, complex cytogenetics, concomitant TP53 mutation, and transformation to AML occurred more with SF3B1-WT than with SF3B1-mut. Our data suggest that SF3B1-mut compared to SF3B1-WT in t-MDS may portend a better prognosis; however, further studies are warranted to confirm this finding.