title: Additional chromosome abnormalities, BCR-ABL tyrosine kinase domain mutations and clinical outcome in Hungarian tyrosine kinase inhibitor-resistant chronic myelogenous leukemia patients.
abstract: BACKGROUND
  Additional chromosome abnormalities (ACAs), mutations of the BCR-ABL tyrosine kinase domain (TKD) and BCR-ABL splice variants may cause resistance to first- and second-generation tyrosine kinase inhibitors (TKIs) in chronic myelogenous leukemia (CML) and Philadelphia-positive (Ph+) acute lymphoid leukemia (ALL).
  
  
  METHODS
  Karyotyping and BCR-ABL TKD mutation screening were performed in 71 imatinib-resistant CML patients and 6 Ph+ ALL patients. A total of 56 out of these 77 patients received second-generation TKI.
  
  
  RESULTS
  ACAs were present in 30 of 65 imatinib-resistant patients (46%). In 27 of 74 imatinib-resistant patients (36%), 15 different BCR-ABL TKD mutations were detected. Mutations were found in 25% of chronic-phase patients (12/47), 33% of accelerated-phase patients (5/15), 71% of blast crisis CML patients (5/7) and 100% of ALL patients. In nilotinib-resistant patients, Y253H, T315I and F359I/V mutations were detected; in dasatinib-resistant patients, L248M, E279K and T315I mutations were detected. T315I was found more frequently in patients on dasatinib than on imatinib therapy. The presence of ACAs predicted shorter survival during first- and second-generation TKI therapy, while TKD mutations only influenced survival during second-generation TKI therapy.
  
  
  CONCLUSIONS
  For patients with TKI resistance, mutation and ACA screening may play a role in identifying patients with poorer prognosis.
authors: Laboratory of Molecular Diagnostics, Hungarian National Blood Transfusion Service, St. István-St. László Hospital, Budapest, Hungary. nora.meggyesi@kkk.org.hu
authors: Nóra
authors: N
authors: Meggyesi
authors: András
authors: A
authors: Kozma
authors: Gabriella
authors: G
authors: Halm
authors: Sarolta
authors: S
authors: Nahajevszky
authors: Arpád
authors: A
authors: Bátai
authors: Sándor
authors: S
authors: Fekete
authors: Anikó
authors: A
authors: Barta
authors: György
authors: G
authors: Ujj
authors: Sándor
authors: S
authors: Lueff
authors: Andrea
authors: A
authors: Sipos
authors: Emma
authors: E
authors: Adám
authors: András
authors: A
authors: Bors
authors: Péter
authors: P
authors: Reményi
authors: Tamás
authors: T
authors: Masszi
authors: Attila
authors: A
authors: Tordai
authors: Hajnalka
authors: H
authors: Andrikovics
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002648:Child; D002869:Chromosome Aberrations; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics*; D006801:Humans; D006814:Hungary; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology / Q000401:mortality; D008297:Male; D008875:Middle Aged; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D015996:Survival Rate
chemical_list: D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl