PURPOSE: A subset of patients with myelodysplastic syndromes (MDS) who are 
predicted to have lower-risk disease as defined by the International Prognostic 
Scoring System (IPSS) demonstrate more aggressive disease and shorter overall 
survival than expected. The identification of patients with 
greater-than-predicted prognostic risk could influence the selection of therapy 
and improve the care of patients with lower-risk MDS.
PATIENTS AND METHODS: We performed an independent validation of the MD Anderson 
Lower-Risk Prognostic Scoring System (LR-PSS) in a cohort of 288 patients with 
low- or intermediate-1 IPSS risk MDS and examined bone marrow samples from these 
patients for mutations in 22 genes, including SF3B1, SRSF2, U2AF1, and DNMT3A.
RESULTS: The LR-PSS successfully stratified patients with lower-risk MDS into 
three risk categories with significant differences in overall survival (20% in 
category 1 with median of 5.19 years [95% CI, 3.01 to 10.34 years], 56% in 
category 2 with median of 2.65 years [95% CI, 2.18 to 3.30 years], and 25% in 
category 3 with median of 1.11 years [95% CI, 0.82 to 1.51 years]), thus 
validating this prognostic model. Mutations were identified in 71% of all 
samples, and mutations associated with a poor prognosis were enriched in the 
highest-risk LR-PSS category. Mutations of EZH2, RUNX1, TP53, and ASXL1 were 
associated with shorter overall survival independent of the LR-PSS. Only EZH2 
mutations retained prognostic significance in a multivariable model that 
included LR-PSS and other mutations (hazard ratio, 2.90; 95% CI, 1.85 to 4.52).
CONCLUSION: Combining the LR-PSS and EZH2 mutation status identifies 29% of 
patients with lower-risk MDS with a worse-than-expected prognosis. These 
patients may benefit from earlier initiation of disease-modifying therapy.