title: TP53 mutation and survival in chronic lymphocytic leukemia.
abstract: OBJECTIVE
  The precise prognostic impact of TP53 mutation and its incorporation into treatment algorithms in chronic lymphocytic leukemia (CLL) is unclear. We set out to define the impact of TP53 mutations in CLL.
  
  
  METHODS
  We assessed TP53 mutations by denaturing high-performance liquid chromatography (exons 2 to 11) in a randomized prospective trial (n = 375) with a follow-up of 52.8 months (German CLL Study Group CLL4 trial; fludarabine [F] v F + cyclophosphamide [FC]).
  
  
  RESULTS
  We found TP53 mutations in 8.5% of patients (28 of 328 patients). None of the patients with TP53 mutation showed a complete response. In patients with TP53 mutation, compared with patients without TP53 mutation, median progression-free survival (PFS; 23.3 v 62.2 months, respectively) and overall survival (OS; 29.2 v 84.6 months, respectively) were significantly decreased (both P < .001). TP53 mutations in the absence of 17p deletions were found in 4.5% of patients. PFS and OS for patients with 17p deletion and patients with TP53 mutation in the absence of 17p deletion were similar. Multivariate analysis identified TP53 mutation as the strongest prognostic marker regarding PFS (hazard ratio [HR] = 3.8; P < .001) and OS (HR = 7.2; P < .001). Other independent predictors of OS were IGHV mutation status (HR = 1.9), 11q deletion (HR = 1.9), 17p deletion (HR = 2.3), and FC treatment arm (HR = 0.6).
  
  
  CONCLUSIONS
  CLL with TP53 mutation carries a poor prognosis regardless of the presence of 17p deletion when treated with F-based chemotherapy. Thus, TP53 mutation analysis should be incorporated into the evaluation of patients with CLL before treatment initiation. Patients with TP53 mutation should be considered for alternative treatment approaches.
authors.affiliation: University of Ulm, Ulm, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Zenz
authors.forename: Barbara
authors.initials: B
authors.lastname: Eichhorst
authors.forename: Raymonde
authors.initials: R
authors.lastname: Busch
authors.forename: Tina
authors.initials: T
authors.lastname: Denzel
authors.forename: Sonja
authors.initials: S
authors.lastname: Häbe
authors.forename: Dirk
authors.initials: D
authors.lastname: Winkler
authors.forename: Andreas
authors.initials: A
authors.lastname: Bühler
authors.forename: Jennifer
authors.initials: J
authors.lastname: Edelmann
authors.forename: Manuela
authors.initials: M
authors.lastname: Bergmann
authors.forename: Georg
authors.initials: G
authors.lastname: Hopfinger
authors.forename: Manfred
authors.initials: M
authors.lastname: Hensel
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.forename: Stephan
authors.initials: S
authors.lastname: Stilgenbauer
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D002872:Chromosome Deletion; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D003520:Cyclophosphamide / Q000008:administration & dosage; D004252:DNA Mutational Analysis / Q000706:statistics & numerical data; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D015999:Multivariate Analysis; D009154:Mutation; D011379:Prognosis; D016016:Proportional Hazards Models; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D016159:Tumor Suppressor Protein p53; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine