title: Prognostic score including gene mutations in chronic myelomonocytic leukemia.
abstract: OBJECTIVE
  Several prognostic scoring systems have been proposed for chronic myelomonocytic leukemia (CMML), a disease in which some gene mutations-including ASXL1-have been associated with poor prognosis in univariable analyses. We developed and validated a prognostic score for overall survival (OS) based on mutational status and standard clinical variables.
  
  
  METHODS
  We genotyped ASXL1 and up to 18 other genes including epigenetic (TET2, EZH2, IDH1, IDH2, DNMT3A), splicing (SF3B1, SRSF2, ZRSF2, U2AF1), transcription (RUNX1, NPM1, TP53), and signaling (NRAS, KRAS, CBL, JAK2, FLT3) regulators in 312 patients with CMML. Genotypes and clinical variables were included in a multivariable Cox model of OS validated by bootstrapping. A scoring system was developed using regression coefficients from this model.
  
  
  RESULTS
  ASXL1 mutations (P < .0001) and, to a lesser extent, SRSF2 (P = .03), CBL (P = .003), and IDH2 (P = .03) mutations predicted inferior OS in univariable analysis. The retained independent prognostic factors included ASXL1 mutations, age older than 65 years, WBC count greater than 15 ×10(9)/L, platelet count less than 100 ×10(9)/L, and anemia (hemoglobin < 10 g/dL in female patients, < 11g/dL in male patients). The resulting five-parameter prognostic score delineated three groups of patients with median OS not reached, 38.5 months, and 14.4 months, respectively (P < .0001), and was validated in an independent cohort of 165 patients (P < .0001).
  
  
  CONCLUSIONS
  A new prognostic score including ASXL1 status, age, hemoglobin, WBC, and platelet counts defines three groups of CMML patients with distinct outcomes. Based on concordance analysis, this score appears more discriminative than those based solely on clinical parameters.
authors.affiliation: Institut Gustave Roussy, Villejuif, France.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Itzykson
authors.forename: Olivier
authors.initials: O
authors.lastname: Kosmider
authors.forename: Aline
authors.initials: A
authors.lastname: Renneville
authors.forename: Véronique
authors.initials: V
authors.lastname: Gelsi-Boyer
authors.forename: Manja
authors.initials: M
authors.lastname: Meggendorfer
authors.forename: Margot
authors.initials: M
authors.lastname: Morabito
authors.forename: Céline
authors.initials: C
authors.lastname: Berthon
authors.forename: Lionel
authors.initials: L
authors.lastname: Adès
authors.forename: Pierre
authors.initials: P
authors.lastname: Fenaux
authors.forename: Odile
authors.initials: O
authors.lastname: Beyne-Rauzy
authors.forename: Norbert
authors.initials: N
authors.lastname: Vey
authors.forename: Thorsten
authors.initials: T
authors.lastname: Braun
authors.forename: Torsten
authors.initials: T
authors.lastname: Haferlach
authors.forename: François
authors.initials: F
authors.lastname: Dreyfus
authors.forename: Nicholas C P
authors.initials: NC
authors.lastname: Cross
authors.forename: Claude
authors.initials: C
authors.lastname: Preudhomme
authors.forename: Olivier A
authors.initials: OA
authors.lastname: Bernard
authors.forename: Michaela
authors.initials: M
authors.lastname: Fontenay
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
authors.forename: Susanne
authors.initials: S
authors.lastname: Schnittger
authors.forename: Daniel
authors.initials: D
authors.lastname: Birnbaum
authors.forename: Nathalie
authors.initials: N
authors.lastname: Droin
authors.forename: Eric
authors.initials: E
authors.lastname: Solary
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D044127:Epigenesis, Genetic / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D015477:Leukemia, Myelomonocytic, Chronic / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D010641:Phenotype; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D019154:Protein Splicing / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics*; D018570:Risk Assessment; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics
chemical_list: C473949:ASXL1 protein, human; C000716967:NPM1 protein, human; D009363:Neoplasm Proteins; D012097:Repressor Proteins; D000090243:Nucleophosmin