title: Impact of additional chromosomal aberrations and BCR-ABL kinase domain mutations on the response to nilotinib in Philadelphia chromosome-positive chronic myeloid leukemia.
abstract: BACKGROUND
  Additional chromosomal aberrations in Philadelphia chromosome-positive chronic myeloid leukemia are non-random and strongly associated with disease progression, but their prognostic impact and effect on treatment response is not clear. Point mutations in the BCR-ABL kinase domain are probably the most common mechanisms of imatinib resistance.
  
  
  METHODS
  We assessed the influence of additional chromosomal aberrations and BCR-ABL kinase domain mutations on the response to the second-generation tyrosine kinase inhibitor nilotinib after imatinib-failure. Standard cytogenetic analysis of metaphases was performed to detect additional chromosomal aberrations and the BCR-ABL kinase domain was sequenced to detect point mutations.
  
  
  RESULTS
  Among 53 patients with a median follow-up of 16 months, of whom 38, 5 and 10 were in chronic phase, accelerated phase and blast crisis, respectively, 19 (36%) had additional chromosomal aberrations and 20 (38%) had BCR-ABL kinase domain mutations. The 2-year overall survival rate of all patients with-out additional chromosomal aberrations (89%) was higher than that of patients with such aberrations (54%) (P=0.0025). Among patients with chronic phase disease, overall survival at 2 years was 100% and 62% for patients without or with additional chromosomal aberrations, respectively (P=0.0024). BCR-ABL kinase domain mutations were associated with lower remission rates in response to nilotinib, with 9 of 20 (45%) of these patients achieving a major cytogenetic remission as compared to 26 of 33 (79%) patients without mutations (P<0.05). However, overall survival was not affected by BCR-ABL kinase domain mutations.
  
  
  CONCLUSIONS
  Whereas BCR-ABL kinase domain mutations may confer more specific resistance to nilotinib, which will predominantly affect response rates, the presence of additional chromosomal aberrations may reflect genetic instability and, therefore, intrinsic aggressiveness of the disease which will be less amenable to subsequent alternative treatments and thus negatively affect overall survival. Conventional cytogenetic analyses remain mandatory during follow-up of patients with chronic myeloid leukemia under tyrosine kinase inhibitor therapy.
authors.affiliation: Klinik für Hämatologie und Onkologie, Charité - Universitätsmedizin Berlin, Campus Virchow- Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany. theo.kim@charite.de
authors.forename: Theo D
authors.initials: TD
authors.lastname: Kim
authors.forename: Seval
authors.initials: S
authors.lastname: Türkmen
authors.forename: Michaela
authors.initials: M
authors.lastname: Schwarz
authors.forename: Gökben
authors.initials: G
authors.lastname: Koca
authors.forename: Hendrik
authors.initials: H
authors.lastname: Nogai
authors.forename: Christiane
authors.initials: C
authors.lastname: Bommer
authors.forename: Bernd
authors.initials: B
authors.lastname: Dörken
authors.forename: Peter
authors.initials: P
authors.lastname: Daniel
authors.forename: Philipp
authors.initials: P
authors.lastname: le Coutre
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001549:Benzamides; D002869:Chromosome Aberrations; D002986:Clinical Trials as Topic; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D000068877:Imatinib Mesylate; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010677:Philadelphia Chromosome; D010879:Piperazines / Q000627:therapeutic use; D017354:Point Mutation / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000627:therapeutic use*; D012074:Remission Induction; D016879:Salvage Therapy; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib