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. Conclusion: For patients with TKI resistance, mutation and ACA screening may play a role in identifying patients with poorer prognosis.

Impact of T315i Mutation on the Outcome of Imatinib-Resistant CML in Egyptian Patients.

“…(13)(14)(15)(16) This variability may be related to sensitivities of the technical methods used to detect the mutation (9,16) , the time point of analysis, the treatment response (15) , the proportion of patients in primary versus secondary resistance in the different studies. In agreement with previous studies (17,18) , more patients with secondary resistance (10/47, 21.3%) developed T315I mutation during IM treatment than those with primary resistance (4/32, 12.5%).…”

Polymorphic Variation in Glutathione-S-transferase Genes and Risk of Chronic Myeloid Leukaemia in the Kashmiri Population

“…A number of factors have been implicated to play role in the development of this disease. Several studies have shown the assoc iation between genetic alteration/s in the precursor hematopoietic cells with the risk to develop CML ( Meggyesi et al, 2011). Exposure to endogenous or exogenous toxic substances can lead to genetic alterations and hence increased susceptibility to cancer.…”

Chronic myeloid leukemia treatment guidelines: Brazilian Association of Hematology, Hemotherapy and Cell Therapy. Brazilian Medical Association Guidelines Project - 2012

“…In CML patients under treatment using first-generation (imatinib) and second-generation (dasatinib or nilotinib) TKIs, the presence of additional chromosomal abnormalities reduces disease-free and overall survival at 5 years (21) (B).…”

“…The presence of mutations during nilotinib or dasatinib treatment is predictive of a worse prognosis in these patients (21) (B).…”