title: IGHV gene mutational status and 17p deletion are independent molecular predictors in a comprehensive clinical-biological prognostic model for overall survival prediction in chronic lymphocytic leukemia.
abstract: BACKGROUND
  Prognostic index for survival estimation by clinical-demographic variables were previously proposed in chronic lymphocytic leukemia (CLL) patients. Our objective was to test in a large retrospective cohort of CLL patients the prognostic power of biological and clinical-demographic variable in a comprehensive multivariate model. A new prognostic index was proposed.
  
  
  METHODS
  Overall survival and time to treatment in 620 untreated CLL patients were analyzed retrospectively to evaluate the multivariate independence and predictive power of mutational status of immunoglobulin heavy chain variable gene segments (IGHV), high-risk chromosomal aberration such as 17p or 11q deletions, CD38 and ZAP-70 expression, age, gender, Binet stage, β2-microglobulin levels, absolute lymphocyte count and number of lymph node regions.
  
  
  RESULTS
  IGHV mutational status and 17p deletion were the sole biological variables with independent prognostic relevance in a multivariate model for overall survival, which included easily measurable clinical parameters (Binet staging, β2-microglobulin levels) and demographics (age and gender). Analysis of time to treatment in Binet A patients below 70 years of age showed that IGHV was the most important predictor. A novel 6-variable clinical-biological prognostic index was developed and internally validated, which assigned 3 points for Binet C stage, 2 points/each for Binet B stage and for age > 65 years, 1 point/each for male gender, high β2-microglobulin levels, presence of an unmutated IGHV gene status or 17p deletion. Patients were classified at low-risk (score = 0-1; 21%), intermediate-risk (score 2-5; 63% of cases), high-risk (score 6-9; 16% of cases). Projected 5-year overall survival was 98%, 90% and 58% in low-, intermediate- and high-risk groups, respectively. A nomogram for individual patient survival estimation was also proposed.
  
  
  CONCLUSIONS
  Data indicate that IGHV mutational status and 17p deletion may be integrated with clinical-demographic variables in new prognostic tools to estimate overall survival.
authors.affiliation: Clinical and Experimental Onco-Hematology Unit, IRCCS Centro di Riferimento Oncologico, via Franco Gallini 2, 33170 Aviano (PN), Italy. pbulian@cro.it
authors.forename: Pietro
authors.initials: P
authors.lastname: Bulian
authors.forename: Davide
authors.initials: D
authors.lastname: Rossi
authors.forename: Francesco
authors.initials: F
authors.lastname: Forconi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Del Poeta
authors.forename: Francesco
authors.initials: F
authors.lastname: Bertoni
authors.forename: Emanuele
authors.initials: E
authors.lastname: Zucca
authors.forename: Marco
authors.initials: M
authors.lastname: Montillo
authors.forename: Gabriele
authors.initials: G
authors.lastname: Pozzato
authors.forename: Giovanni
authors.initials: G
authors.lastname: D'Arena
authors.forename: Dimitar G
authors.initials: DG
authors.lastname: Efremov
authors.forename: Roberto
authors.initials: R
authors.lastname: Marasca
authors.forename: Francesco
authors.initials: F
authors.lastname: Lauria
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
authors.forename: Valter
authors.initials: V
authors.lastname: Gattei
authors.forename: Luca
authors.initials: L
authors.lastname: Laurenti
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002872:Chromosome Deletion; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D050438:Genes, Immunoglobulin Heavy Chain / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D015999:Multivariate Analysis; D009154:Mutation / Q000235:genetics*; D049451:Nomograms; D016016:Proportional Hazards Models; D015203:Reproducibility of Results; D013997:Time Factors; D055815:Young Adult