Al-Dewik, Nader (2012) Mechanism(s) of resistance of Chronic Myelocytic Leukaemia (CML) to Glivec in a patient population in the State of Qatar. (PhD thesis), Kingston University, .
Abstract
Despite the significant improvement in CML treatment since the introduction of Glivec, resistance to synthetic Tyrosine Kinase Inhibitors is emerging as a major limitation. 50%-90% of patients acquire resistance through point mutations that might span the ABL1 kinase domain, while 10%-50% may resist treatment through other mechanisms. Qatar with its limited 1.6 million inhabitants and 15 CML patients diagnosed yearly has the highest rate of disease resistance to Glivec treatment. Through a prospective study, this project examined the rate of resistance to Glivec and the different mechanisms that could be responsible for this problem. Thus over a period of 5 years, 26 patients were treated with Glivec as a front line therapy and their response to treatment was monitored objectively according to the ELN 2006 response criteria. 12 of the 26 patients responded optimally to treatment, while 14 patients did not (9 failed the treatment and 5 responded sub-optimally), setting the resistance rate to about 54% which is the highest reported worldwide to date. None of our patients showed any of the reported mutations that are known to confer resistance to Glivec. However in one patient, direct sequencing showed a Single Nucleotide Polymorphism (SNP) that might function as a resistance inflecting mutation. In another patient who resisted treatment a transient insertion of three nucleotides (AAG) at position 1432 which adds an amino acid Lysine to position 356 of the catalytic domain of ABL1 was revealed. To our knowledge this transit insertion of nucleotides and amino acid addition was not reported before. 7 patients showed Additional Chromosomal Abnormalities (ACA) at time of resistance, while 2 patients were intolerant to treatment and 3 had no identifiable cause for their resistance. Patient compliance was ruled out as a cause of resistance in our patients, however the quality of service providing was audited and certain financial and clinical management issues were addressed during the course of this study.
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