title: Hierarchical cluster analysis of immunophenotype classify AML patients with NPM1 gene mutation into two groups with distinct prognosis.
abstract: BACKGROUND
  The prognostic implication of immunophenotyping in acute myeloid leukemia (AML) patients with NPM1 mutation remains unclear.
  
  
  METHODS
  Ninety-four of 543 AML patients diagnosed with NPM1 mutation between 1987 and 2007 were studied. The expression of surface antigens on leukemic cells was evaluated with respect to clinical manifestations and outcomes. In order to validate the prognostic effect of the immunophenotypic cluster, another 36 patients with NPM1 mutation diagnosed between 2008 and 2010 were analyzed.
  
  
  RESULTS
  Ninety-four patients with NPM1 mutations and complete immunophenotyping data were enrolled for a hierarchical cluster analysis and the result was correlated with clinico-laboratory characteristics. Clustering analysis divided the patients with NPM1 mutations into the following two groups: group I, CD34(-)/CD7(-), but with variable expression of HLA-DR; and group II, HLA DR(+)/CD34(+)/CD7(+). With a median follow-up of 53 months, the group II patients had a significantly shorter relapse-free survival (RFS, median: 3 vs. 23 months, p = 0.006) and overall survival (OS, median: 11 vs. 40 months, p = 0.02) than group I patients. Multivariate analysis of variables, including clinico-laboratory data and other gene mutations revealed that the immunophenotypic cluster is an independent prognostic factor (RFS, p = 0.002; OS, p = 0.024). In order to confirm the prognostic effect of the immunophenotypic cluster, another 36 patients with NPM1 mutation diagnosed between 2008 and 2010 were validated. Hierarchical cluster analysis also showed two distinct clusters, group I patient showed significant better RFS (p = 0.021), and OS (p = 0.055). In total, we stratified 130 NPM1-mutant patients, by FLT3-ITD mutation and immunophenotypic cluster into distinct prognostic groups (RFS, p < 0.001 and OS, p = 0.017).
  
  
  CONCLUSIONS
  Among NPM1-mutated AML, the antigen expression pattern of HLADR(+) CD34(+) CD7(+) is associated with a poor prognosis, independent to the FLT3-ITD mutation.
authors.affiliation: Departments of Internal Medicine, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan. chienyuanchen@ntu.edu.tw
authors.forename: Chien-Yuan
authors.initials: CY
authors.lastname: Chen
authors.forename: Wen-Chien
authors.initials: WC
authors.lastname: Chou
authors.forename: Woei
authors.initials: W
authors.lastname: Tsay
authors.forename: Jih-Luh
authors.initials: JL
authors.lastname: Tang
authors.forename: Ming
authors.initials: M
authors.lastname: Yao
authors.forename: Sheng-Yi
authors.initials: SY
authors.lastname: Huang
authors.forename: Hwei-Fang
authors.initials: HF
authors.lastname: Tien
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D018952:Antigens, CD34 / Q000032:analysis; D019011:Antigens, CD7 / Q000032:analysis; D002648:Child; D016000:Cluster Analysis; D004252:DNA Mutational Analysis; D005260:Female; D006684:HLA-DR Antigens; D006801:Humans; D016130:Immunophenotyping / Q000379:methods; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D011379:Prognosis; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D018952:Antigens, CD34; D019011:Antigens, CD7; D006684:HLA-DR Antigens; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin