title: Finding of kinase domain mutations in patients with chronic phase chronic myeloid leukemia responding to imatinib may identify those at high risk of disease progression.
abstract: OBJECTIVE
  Kinase domain (KD) mutations in the BCR-ABL gene are associated with resistance to imatinib in chronic myeloid leukemia (CML) but their incidence and prognostic significance in chronic phase (CP) patients without resistance are unclear.
  
  
  METHODS
  We analyzed outcome for 319 patients with CML-CP who were treated with imatinib; 171 were in early CP (ECP) and 148 were in late CP (LCP). Patients were screened routinely for mutations using direct sequencing regardless of response status. The 5-year cumulative incidence of mutations was 6.6% for ECP and 17% for LCP patients.
  
  
  RESULTS
  Of the 319 patients, 214 (67%) achieved complete cytogenetic responses (CCyR). The identification of a mutation without other evidence of imatinib resistance was highly predictive for loss of CCyR (RR, 3.8; P = .005) and for progression to advanced phase (RR, 2.3; P = .01), though the intervals from first identification to loss of CCyR and disease progression were relatively long (median, 21 and 16 months, respectively). Mutations in the P-loop (excluding residue 244) were associated with a higher risk of progression than mutations elsewhere.
  
  
  CONCLUSIONS
  We conclude that routine mutation screening of patients who appear to be responding to imatinib may identify those at high risk of disease progression.
authors.affiliation: Department of Haematology, Hammersmith Hospitals Trust, Imperial College London, Du Cane Rd, London W12 0NN, United Kingdom.
authors.forename: Jamshid S
authors.initials: JS
authors.lastname: Khorashad
authors.forename: Hugues
authors.initials: H
authors.lastname: de Lavallade
authors.forename: Jane F
authors.initials: JF
authors.lastname: Apperley
authors.forename: Dragana
authors.initials: D
authors.lastname: Milojkovic
authors.forename: Alistair G
authors.initials: AG
authors.lastname: Reid
authors.forename: Marco
authors.initials: M
authors.lastname: Bua
authors.forename: Richard
authors.initials: R
authors.lastname: Szydlo
authors.forename: Eduardo
authors.initials: E
authors.lastname: Olavarria
authors.forename: Jaspal
authors.initials: J
authors.lastname: Kaeda
authors.forename: John M
authors.initials: JM
authors.lastname: Goldman
authors.forename: David
authors.initials: D
authors.lastname: Marin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D002908:Chronic Disease; D018450:Disease Progression; D005260:Female; D016313:Genes, abl / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010770:Phosphotransferases / Q000235:genetics*; D010879:Piperazines / Q000627:therapeutic use; D017434:Protein Structure, Tertiary / Q000235:genetics*; D011743:Pyrimidines / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D010770:Phosphotransferases