title: Mutational status of the TP53 gene as a predictor of response and survival in patients with chronic lymphocytic leukemia: results from the LRF CLL4 trial.
abstract: OBJECTIVE
  TP53 mutations have been described in chronic lymphocytic leukemia (CLL) and have been associated with poor prognosis in retrospective studies. We aimed to address the frequency and prognostic value of TP53 abnormalities in patients with CLL in the context of a prospective randomized trial.
  
  
  METHODS
  We analyzed 529 CLL samples from the LRF CLL4 (Leukaemia Research Foundation Chronic Lymphocytic Leukemia 4) trial (chlorambucil v fludarabine with or without cyclophosphamide) at the time of random assignment for mutations in the TP53 gene. TP53 mutation status was correlated with response and survival data.
  
  
  RESULTS
  Mutations of TP53 were found in 40 patients (7.6%), including 25 (76%) of 33 with 17p deletion and 13 (3%) of 487 without that deletion. There was no significant correlation between TP53 mutations and age, stage, IGHV gene mutations, CD38 and ZAP-70 expression, or any other chromosomal abnormality other than 17p deletion, in which concordance was high (96%). TP53 mutations were significantly associated with poorer overall response rates (27% v 83%; P < .001) and shorter progression-free survival (PFS) and overall survival (OS; 5-year PFS: 5% v 17%; 5-year OS: 20% v 59%; P < .001 for both). Multivariate analysis that included baseline clinical variables, treatment, and known adverse genetic factors confirmed that TP53 mutations have added prognostic value.
  
  
  CONCLUSIONS
  TP53 mutations are associated with impaired response and shorter survival in patients with CLL. Analysis of TP53 mutations should be performed in patients with CLL who have progressive disease before starting first-line treatment, and those with mutations should be selected for novel experimental therapies.
authors.affiliation: Section of Haemato-Oncology, The Institute of Cancer Research, London, United Kingdom. davidg@icr.ac.uk
authors.forename: David
authors.initials: D
authors.lastname: Gonzalez
authors.forename: Pilar
authors.initials: P
authors.lastname: Martinez
authors.forename: Rachel
authors.initials: R
authors.lastname: Wade
authors.forename: Sarah
authors.initials: S
authors.lastname: Hockley
authors.forename: David
authors.initials: D
authors.lastname: Oscier
authors.forename: Estella
authors.initials: E
authors.lastname: Matutes
authors.forename: Claire E
authors.initials: CE
authors.lastname: Dearden
authors.forename: Sue M
authors.initials: SM
authors.lastname: Richards
authors.forename: Daniel
authors.initials: D
authors.lastname: Catovsky
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Morgan
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002699:Chlorambucil / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000627:therapeutic use; D004252:DNA Mutational Analysis; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D016016:Proportional Hazards Models; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014740:Vidarabine / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D002699:Chlorambucil; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine