1887
Volume 2014, Issue 1
  • E-ISSN: 2223-506X

Abstract

Imatinib is failing as a first line treatment in more than 40% of chronic myeloid leukemia (CML) patients in Qatar. We thus investigated kinase domain mutations and additional chromosomal abnormalities (ACAs) as underlying mechanisms to explain this high rate of treatment failure. Between November 2006 and December 2011, all CML patients in Qatar were studied for kinase domain mutations and ACAs. Total RNA was extracted and cDNA was produced via reverse transcriptase polymerase chain reaction (RT-PCR). PCR was used with special precautions to avoid amplification of wild type ; the kinase domain was then screened for mutations by direct DNA sequencing technology to detect the emergence of mutant clone.

Cytogenetic analysis of bone marrow (BM) metaphases and fluorescence hybridization (FISH) of peripheral blood (PB) and BM interphases were performed according to standard protocols. European Leukemia Net (ELN) response criteria were employed to identify the failing cases. 26 out of 33 CML patients were eligible for the study, 22 CP and 4 AP. 14 failed Imatinib treatment, 2 had kinase domain mutations; one patient had the G1739A mutation which leads to the exchange of glutamic acid at position 459 to lysine (E459K) (rs1064156) in the c-terminal loop while the other patient had a unique insertion of three nucleotides (AAG) at position 1432 which adds an amino acid Lysine to position 356 of the catalytic domain and a complex karyotyping at diagnosis, 6 had additional chromosomal abnormalities as an underlying mechanism of resistance, 4 patients had no identifiable cause of resistance and 2 patients were intolerant to treatment. There was a significant difference in median overall survival between patients with Ph chromosome only and patients with ACAs. In this study as we continued observing CML patients for nearly 5 years, the Imatinib failure reached as high as 54%. The resistance rate observed in Qatar is still higher than that reported by the IRIS study which is as high as 35%. In our cohort of CML patients, point mutation and unique tri-nucleotide insertions were identified. However, these mutations could explain only 14% of treatment failure. Additional chromosomal abnormalities were the most common cause of Imatinib failure in our patients' cohort and were documented in 50% of cases. 14% of patients stopped IM due to intolerance; and the mechanisms of resistance remained unknown in 28% of patients. Other causes such as patients' adherence to Imatitinb is being prospectively investigated.

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2014-07-01
2019-08-17
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