title: Validation of a prognostic model and the impact of mutations in patients with lower-risk myelodysplastic syndromes.
abstract: OBJECTIVE
  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.
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Rafael
authors.initials: R
authors.lastname: Bejar
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Stevenson
authors.forename: Bennett A
authors.initials: BA
authors.lastname: Caughey
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.forename: David P
authors.initials: DP
authors.lastname: Steensma
authors.forename: Naomi
authors.initials: N
authors.lastname: Galili
authors.forename: Azra
authors.initials: A
authors.lastname: Raza
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Ebert
mesh_terms: D004252:DNA Mutational Analysis; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D063151:Polycomb Repressive Complex 2 / Q000032:analysis / Q000235:genetics*; D011237:Predictive Value of Tests; D011379:Prognosis; D015203:Reproducibility of Results; D016019:Survival Analysis
chemical_list: C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2