title: Emergence of BCR-ABL kinase domain mutations associated with newly diagnosed chronic myeloid leukemia: a meta-analysis of clinical trials of tyrosine kinase inhibitors.
abstract: BACKGROUND
  Tyrosine kinase inhibitors (TKIs) are a mainstay of treatment for patients suffering from chronic myeloid leukemia (CML). Testing for various mutations in the BCR-ABL gene may help predict lack of response to specific TKIs where resistance has developed.
  
  
  OBJECTIVE
  To estimate the emergence of BCR-ABL kinase domain mutations associated with newly diagnosed CML patients exposed to first-line TKI treatment.
  
  
  METHODS
  Published studies were identified using a structured search of online databases. Original research studies were included if they reported the incidence of specific BCR-ABL kinase domain point mutations after first-line TKI treatment failure or baseline mutations for second-line TKI treatment following first-line treatment failure. Meta-analysis of mutation rates across studies was based on DerSimonian and Laird's random-effects model.
  
  
  RESULTS
  Of 1,323 citations, 12 studies met the inclusion criteria, involving a total of 1,698 patients. Overall mutation rates (95% CI) were imatinib 9.7% (6.2%-13.3%); dasatanib 1.7% (0.0%-4.3%); and nilotinib 3.3% (0.0%-7.7%). The most common specific mutations were T315I, E255K, and M351T. T315I mutations constituted 58% (7 of 12) of dasatinib-related mutations and 13% (15 of 117) of imatinib-related mutations.
  
  
  CONCLUSIONS
  Lack of response to TKIs associated with mutation in the BCR-ABL gene was significantly higher in imatinib-treated patients, and all mutations arose after treatment. T315I was a common treatment-emergent mutation. Further research is needed to assess the prognostic value of testing for mutations and the economic implications of treatment-emergent mutations.
authors.affiliation: University of Illinois College of Pharmacy, 833 S. Wood St., Rm. 254, M/C 871, Chicago, IL 60612. pickard1@uic.edu.
authors.forename: Iulia D
authors.initials: ID
authors.lastname: Ursan
authors.forename: Ruixuan
authors.initials: R
authors.lastname: Jiang
authors.forename: Evan M
authors.initials: EM
authors.lastname: Pickard
authors.forename: Todd A
authors.initials: TA
authors.lastname: Lee
authors.forename: Daniel
authors.initials: D
authors.lastname: Ng
authors.forename: A Simon
authors.initials: AS
authors.lastname: Pickard
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002986:Clinical Trials as Topic; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl