title: ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia.
abstract: OBJECTIVE
  Point mutations within the ABL kinase domain of the BCR-ABL gene have been associated with clinical resistance to imatinib mesylate in chronic myeloid leukemia (CML) patients. To shed further light on the frequency, distribution, and prognostic significance of ABL mutations, we retrospectively analyzed a homogeneous cohort of late chronic phase CML patients who showed primary cytogenetic resistance to imatinib.
  
  
  METHODS
  Using denaturing high-performance liquid chromatography (D-HPLC) and sequencing, we screened for ABL mutations in a total of 178 bone marrow and/or peripheral blood samples from 40 late chronic phase CML patients homogeneously treated with imatinib 400 mg/d, who did not reach a major cytogenetic response at 12 months.
  
  
  RESULTS
  Mutations were found in 19 of 40 patients (48%). Mutations were already detectable by D-HPLC at a median of 3 months from the onset of therapy. The presence of a missense mutation was significantly associated with a greater likelihood of subsequent progression to accelerated phase/blast crisis (P = .0002) and shorter survival (P = .001). Patients carrying mutations falling within the P-loop seemed to have a particularly poor outcome in terms of time to progression (P = .032) and survival (P = .045).
  
  
  CONCLUSIONS
  Our results show that, irrespective of the hematologic response, monitoring for emerging mutations in the first months of therapy may play a role in detecting patients with worse prognosis, for whom a revision of the therapeutic strategy should be considered.
authors.affiliation: Institute of Hematology and Medical Oncology Seràgnoli, University of Bologna, Via Massarenti 9-40138 Bologna, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Soverini
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
authors.forename: Gianantonio
authors.initials: G
authors.lastname: Rosti
authors.forename: Simona
authors.initials: S
authors.lastname: Bassi
authors.forename: Marilina
authors.initials: M
authors.lastname: Amabile
authors.forename: Angela
authors.initials: A
authors.lastname: Poerio
authors.forename: Barbara
authors.initials: B
authors.lastname: Giannini
authors.forename: Elena
authors.initials: E
authors.lastname: Trabacchi
authors.forename: Fausto
authors.initials: F
authors.lastname: Castagnetti
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Testoni
authors.forename: Simona
authors.initials: S
authors.lastname: Luatti
authors.forename: Antonio
authors.initials: A
authors.lastname: de Vivo
authors.forename: Daniela
authors.initials: D
authors.lastname: Cilloni
authors.forename: Barbara
authors.initials: B
authors.lastname: Izzo
authors.forename: Milena
authors.initials: M
authors.lastname: Fava
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Abruzzese
authors.forename: Daniele
authors.initials: D
authors.lastname: Alberti
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Pane
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Saglio
authors.forename: Michele
authors.initials: M
authors.lastname: Baccarani
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D001752:Blast Crisis; D016009:Chi-Square Distribution; D002851:Chromatography, High Pressure Liquid; D020732:Cytogenetic Analysis / Q000379:methods*; D004252:DNA Mutational Analysis; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D016313:Genes, abl / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000627:therapeutic use*; D017354:Point Mutation; D011379:Prognosis; D011743:Pyrimidines / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D016019:Survival Analysis
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate