title: Frequency of ABL gene mutations in chronic myeloid leukemia patients resistant to imatinib and results of treatment switch to second-generation tyrosine kinase inhibitors.
abstract: OBJECTIVE
  Tyrosine kinase inhibitors (TKI) have improved the management of patients with chronic myeloid leukemia (CML). However, a significant proportion of patients do not achieve the optimal response or are resistant to TKI. ABL kinase domain mutations have been extensively implicated in the pathogenesis of TKI resistance. Treatment with second-generation TKI has produced high rates of hematologic and cytogenetic responses in mutated ABL patients. The aim of this study was to determine the type and frequency of ABL mutations in patients who were resistant to imatinib or had lost the response, and to analyze the effect of second-generation TKI on their outcome.
  
  
  METHODS
  The presence of ABL mutations in 45 CML patients resistant to imatinib was evaluated by direct sequencing and was correlated with the results of the cytogenetic study (performed in 39 cases). The outcome of these patients after therapy with nilotinib or dasatinib was analyzed.
  
  
  RESULTS
  ABL mutations were detected in 14 out of 45 resistant patients. Patients with clonal cytogenetic evolution tended to develop mutations more frequently than those without clonal evolution. Nine out of the 15 patients with ABL mutation responded to a treatment switch to nilotinib (n=4), dasatinib (n=2), interferon (n=1) or hematopoietic stem cell transplantation (n=2).
  
  
  CONCLUSIONS
  The frequency of ABL mutations in CML patients resistant to imatinib is high and is more frequent among those with clonal cytogenetic evolution. The change to second-generation TKI can overcome imatinib resistance in most of the mutated patients.
authors: Hematology Department, ICO Badalona-Hospital Germans Trias i Pujol, Instituto de Investigación contra la Leucemia Josep Carreras, Universitat Autònoma de Barcelona, Badalona, Barcelona, Spain.
authors: Silvia
authors: S
authors: Marcé
authors: Lurdes
authors: L
authors: Zamora
authors: Marta
authors: M
authors: Cabezón
authors: Blanca
authors: B
authors: Xicoy
authors: Concha
authors: C
authors: Boqué
authors: Cristalina
authors: C
authors: Fernández
authors: Javier
authors: J
authors: Grau
authors: José-Tomás
authors: JT
authors: Navarro
authors: Alberto
authors: A
authors: Fernández de Sevilla
authors: Josep-Maria
authors: JM
authors: Ribera
authors: Evarist
authors: E
authors: Feliu
authors: Fuensanta
authors: F
authors: Millá
mesh_terms: D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D001752:Blast Crisis / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D002999:Clone Cells / Q000378:metabolism / Q000473:pathology; D004273:DNA, Neoplasm / Q000235:genetics; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D057915:Drug Substitution; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics; D016313:Genes, abl; D006801:Humans; D000068877:Imatinib Mesylate; D007621:Karyotyping; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000145:classification / Q000494:pharmacology / Q000627:therapeutic use*; D017434:Protein Structure, Tertiary / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D017422:Sequence Analysis, DNA; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D001549:Benzamides; D004273:DNA, Neoplasm; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D013844:Thiazoles; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib; D000069439:Dasatinib
keywords: ABL mutations; Chronic myeloid leukemia; Clonal cytogenetic evolution; Evolución citogenética clonal; Imatinib resistance; Inhibidores de tirosina-cinasa de segunda generación; Leucemia mieloide crónica; Mutaciones de ABL; Resistencia a imatinib; Second-generation tyrosine kinase inhibitors