title: Biallelic ATM inactivation significantly reduces survival in patients treated on the United Kingdom Leukemia Research Fund Chronic Lymphocytic Leukemia 4 trial.
abstract: OBJECTIVE
  The prognostic significance of ATM mutations in chronic lymphocytic leukemia (CLL) is unclear. We assessed their impact in the context of a prospective randomized trial.
  
  
  METHODS
  We analyzed the ATM gene in 224 patients treated on the Leukemia Research Fund Chronic Lymphocytic Leukemia 4 (LRF-CLL4) trial with chlorambucil or fludarabine with and without cyclophosphamide. ATM status was analyzed by denaturing high-performance liquid chromatography and was related to treatment response, survival, and the impact of TP53 alterations for the same patient cohort.
  
  
  RESULTS
  We identified 36 ATM mutations in 33 tumors, 16 with and 17 without 11q deletion. Mutations were associated with advanced disease stage and involvement of multiple lymphoid sites. Patients with both ATM mutation and 11q deletion showed significantly reduced progression-free survival (median, 7.4 months) compared with those with ATM wild type (28.6 months), 11q deletion alone (17.1 months), or ATM mutation alone (30.8 months), but survival was similar to that in patients with monoallelic (6.7 months) or biallelic (3.4 months) TP53 alterations. This effect was independent of treatment, immunoglobulin heavy chain variable gene (IGHV) status, age, sex, or disease stage. Overall survival for patients with biallelic ATM alterations was also significantly reduced compared with those with ATM wild type or ATM mutation alone (median, 42.2 v 85.5 v 77.6 months, respectively).
  
  
  CONCLUSIONS
  The combination of 11q deletion and ATM mutation in CLL is associated with significantly shorter progression-free and overall survival following first-line treatment with alkylating agents and purine analogs. Assessment of ATM mutation status in patients with 11q deletion may influence the choice of subsequent therapy.
authors.affiliation: University of Birmingham, Birmingham, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Skowronska
authors.forename: Anton
authors.initials: A
authors.lastname: Parker
authors.forename: Gulshanara
authors.initials: G
authors.lastname: Ahmed
authors.forename: Ceri
authors.initials: C
authors.lastname: Oldreive
authors.forename: Zadie
authors.initials: Z
authors.lastname: Davis
authors.forename: Sue
authors.initials: S
authors.lastname: Richards
authors.forename: Martin
authors.initials: M
authors.lastname: Dyer
authors.forename: Estella
authors.initials: E
authors.lastname: Matutes
authors.forename: David
authors.initials: D
authors.lastname: Gonzalez
authors.forename: A Malcolm R
authors.initials: AM
authors.lastname: Taylor
authors.forename: Paul
authors.initials: P
authors.lastname: Moss
authors.forename: Peter
authors.initials: P
authors.lastname: Thomas
authors.forename: David
authors.initials: D
authors.lastname: Oscier
authors.forename: Tatjana
authors.initials: T
authors.lastname: Stankovic
mesh_terms: D000368:Aged; D000483:Alleles; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics*; D002699:Chlorambucil / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000008:administration & dosage; D004268:DNA-Binding Proteins / Q000235:genetics*; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015973:Gene Expression Regulation, Leukemic; D020868:Gene Silencing; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D011446:Prospective Studies; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D016019:Survival Analysis; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D006113:United Kingdom; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D002699:Chlorambucil; D003520:Cyclophosphamide; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D014740:Vidarabine; C024352:fludarabine