title: Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients: by the GIMEMA Working Party on Chronic Myeloid Leukemia.
abstract: OBJECTIVE
  ABL kinase domain mutations have been implicated in the resistance to the BCR-ABL inhibitor imatinib mesylate of Philadelphia-positive (Ph+) leukemia patients.
  
  
  METHODS
  Using denaturing high-performance liquid chromatography and sequencing, we screened for ABL kinase domain mutations in 370 Ph+ patients with evidence of hematologic or cytogenetic resistance to imatinib.
  
  
  RESULTS
  Mutations were found in 127 of 297 (43%) evaluable patients. Mutations were found in 27% of chronic-phase patients (14% treated with imatinib frontline; 31% treated with imatinib post-IFN failure), 52% of accelerated-phase patients, 75% of myeloid blast crisis patients, and 83% of lymphoid blast crisis/Ph+ acute lymphoblastic leukemia (ALL) patients. Mutations were associated in 30% of patients with primary resistance (44% hematologic and 28% cytogenetic) and in 57% of patients with acquired resistance (23% patients who lost cytogenetic response; 55% patients who lost hematologic response; and 87% patients who progressed to accelerated phase/blast crisis). P-loop and T315I mutations were particularly frequent in advanced-phase chronic myeloid leukemia and Ph+ ALL patients, and often accompanied progression from chronic phase to accelerated phase/blast crisis.
  
  
  CONCLUSIONS
  We conclude that (a) amino acid substitutions at seven residues (M244V, G250E, Y253F/H, E255K/V, T315I, M351T, and F359V) account for 85% of all resistance-associated mutations; (b) the search for mutations is important both in case of imatinib failure and in case of loss of response at the hematologic or cytogenetic level; (c) advanced-phase chronic myeloid leukemia and Ph+ ALL patients have a higher likelihood of developing imatinib-resistant mutations; and (d) the presence of either P-loop or T315I mutations in imatinib-treated patients should warn the clinician to reconsider the therapeutic strategy.
authors.affiliation: Department of Hematology/Oncology L. and A. Seràgnoli, University of Bologna, Bologna, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Soverini
authors.forename: Sabrina
authors.initials: S
authors.lastname: Colarossi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Gnani
authors.forename: Gianantonio
authors.initials: G
authors.lastname: Rosti
authors.forename: Fausto
authors.initials: F
authors.lastname: Castagnetti
authors.forename: Angela
authors.initials: A
authors.lastname: Poerio
authors.forename: Ilaria
authors.initials: I
authors.lastname: Iacobucci
authors.forename: Marilina
authors.initials: M
authors.lastname: Amabile
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Abruzzese
authors.forename: Ester
authors.initials: E
authors.lastname: Orlandi
authors.forename: Franca
authors.initials: F
authors.lastname: Radaelli
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Ciccone
authors.forename: Mario
authors.initials: M
authors.lastname: Tiribelli
authors.forename: Roberto
authors.initials: R
authors.lastname: di Lorenzo
authors.forename: Clementina
authors.initials: C
authors.lastname: Caracciolo
authors.forename: Barbara
authors.initials: B
authors.lastname: Izzo
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
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D002851:Chromatography, High Pressure Liquid; D004252:DNA Mutational Analysis / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005787:Gene Frequency; D016313:Genes, abl / Q000502:physiology*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D009154:Mutation / Q000502:physiology*; D009367:Neoplasm Staging; D010879:Piperazines / Q000627:therapeutic use*; D011494:Protein Kinases / Q000235:genetics; 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; D011494:Protein Kinases