Additional Chromosome Abnormalities, BCR-ABL Tyrosine Kinase Domain Mutations and Clinical Outcome in Hungarian Tyrosine Kinase Inhibitor-Resistant Chronic Myelogenous Leukemia PatientsMeggyesi N. · Kozma A. · Halm G. · Nahajevszky S. · Bátai Á. · Fekete S. · Barta A. · Ujj G. · Lueff S. · Sipos A. · Ádám E. · Bors A. · Reményi P. · Masszi T. · Tordai A. · Andrikovics H.
aLaboratory of Molecular Diagnostics, Hungarian National Blood Transfusion Service, bDepartment of Hematology and Stem Cell Transplantation, St. István-St. László Hospital, Budapest, and cGéza Hetényi Hospital, Szolnok, Hungary
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. Conclusion: For patients with TKI resistance, mutation and ACA screening may play a role in identifying patients with poorer prognosis.
Laboratory of Molecular Diagnostics, Hungarian National Blood Transfusion Service
Karolina str. 19–21
HU–1113 Budapest (Hungary)
Tel. +36 1 372 4449, E-Mail firstname.lastname@example.org
Received: May 2, 2011
Accepted after revision: July 28, 2011
Published online: October 14, 2011
Number of Print Pages : 9
Number of Figures : 4, Number of Tables : 2, Number of References : 25
Vol. 127, No. 1, Year 2012 (Cover Date: December 2011)
Journal Editor: Ben-Bassat I. (Qiryat-Ono)
ISSN: 0001-5792 (Print), eISSN: 1421-9662 (Online)
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