Jabbour, E., Kantarjian, H., Jones, D., Talpaz, M., Bekele, N., O'Brien, S. et al. Frequency and clinical significance of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate. Leukemia 20, 1767-1773

Department of Leukemia, The University of Texas, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
Leukemia (Impact Factor: 10.43). 11/2006; 20(10):1767-73. DOI: 10.1038/sj.leu.2404318
Source: PubMed


Mutations of the BCR-ABL kinase domain are a common mechanism of resistance to imatinib in chronic myeloid leukemia. We screened for mutations 171 patients failing imatinib therapy. Sixty-six mutations in 23 amino acids were identified in 62 (36%) patients not responding to imatinib. Phosphate-binding loop (P-loop) mutations were the most frequent (n=24; 36%). By multivariate analysis, factors associated with development of mutations were older age (P=0.026) prior interferon therapy (P=0.026), and accelerated phase or blast phase at time of imatinib failure (P=0.001). After a median follow-up of 38 months (range, 4-68 months) from the start of imatinib therapy, seven patients with non-P-loop and two with P-loop mutation died. By multivariate analysis, development of clonal evolution and higher percentage of peripheral blood basophils were associated with worse survival from the time of imatinib failure. Mutation status had no impact on survival. When survival was measured from the time therapy started, non-P-loop mutations together with duration of response and transformation at the time of failure to imatinib were associated with shorter survival. In conclusion, P-loop mutations were not associated with poor outcome, suggesting that the prognosis of patients who fail imatinib is multifactorial.

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Available from: Frank Giles, May 29, 2015
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    • "Acquired resistance is defined as progression to advanced disease or loss of response with a 5–10-fold increase in BCR-ABL transcripts. Acquired resistance may be caused by mutations in the BCR-ABL kinase domain, amplification of the BCR-ABL fusion gene, overexpression of drug transporter genes, and overexpression of tyrosine kinases such as the SRC family kinases [17, 18]. Second-line treatment options include higher doses of Imatinib, a second-generation tyrosine kinase inhibitor (TKI), or allogeneic stem cell transplant (allo-SCT) [19, 20]. "
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    ABSTRACT: Deregulated protein tyrosine kinase activity is central to the pathogenesis of human cancers. Targeted therapy in the form of selective tyrosine kinase inhibitors (TKIs) has transformed the approach to management of various cancers and represents a therapeutic breakthrough. Imatinib was one of the first cancer therapies to show the potential for such targeted action. Imatinib, an oral targeted therapy, inhibits tyrosine kinases specifically BCR-ABL, c-KIT, and PDGFRA. Apart from its remarkable success in CML and GIST, Imatinib benefits various other tumors caused by Imatinib-specific abnormalities of PDGFR and c-KIT. Imatinib has also been proven to be effective in steroid-refractory chronic graft-versus-host disease because of its anti-PDGFR action. This paper is a comprehensive review of the role of Imatinib in oncology.
    05/2014; 2014(2):357027. DOI:10.1155/2014/357027
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    • "Despite the outstanding results obtained with IM for the treatment of CML, a significant proportion of patients show suboptimal response or develop resistance to IM. Mechanism of resistance to IM in CML patients involve BCR-ABL dependent and BCR-ABL independent pathways. BCR-ABL dependent mechanism which mainly involve point mutations in the tyrosine kinase domain (TKD) and amplification of BCR-ABL gene, account for approximately 50% of patients who develop resistance [1]. For the CML patients who do not fit into the BCR-ABL dependent mechanisms of resistance, several other BCR-ABL independent mechanisms have been postulated. "
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    ABSTRACT: The introduction and success of imatinib mesylate (IM) has become a paradigm shift in chronic myeloid leukemia (CML) treatment. However, the high efficacy of IM has been hampered by the issue of clinical resistance that might due to pharmacogenetic variability. In the current study, the contribution of three common single nucleotide polymorphisms (SNPs) of ABCB1 (T1236C, G2677T/A and C3435T) and two SNPs of ABCG2 (G34A and C421A) genes in mediating resistance and/or good response among 215 CML patients on IM therapy were investigated. Among these patients, the frequency distribution of ABCG2 421 CC, CA and AA genotypes were significantly different between IM good response and resistant groups (P = 0.01). Resistance was significantly associated with patients who had homozygous ABCB1 1236 CC genotype with OR 2.79 (95%CI: 1.217–6.374, P = 0.01). For ABCB1 G2677T/A polymorphism, a better complete cytogenetic remission was observed for patients with variant TT/AT/AA genotype, compared to other genotype groups (OR = 0.48, 95%CI: 0.239–0.957, P = 0.03). Haplotype analysis revealed that ABCB1 haplotypes (C1236G2677C3435) was statistically linked to higher risk to IM resistance (25.8% vs. 17.4%, P = 0.04), while ABCG2 diplotype A34A421 was significantly correlated with IM good response (9.1% vs. 3.9%, P = 0.03). In addition, genotypic variant in ABCG2 421C>A was associated with a major molecular response (MMR) (OR = 2.20, 95%CI: 1.273–3.811, P = 0.004), whereas ABCB1 2677G>T/A variant was associated with a significantly lower molecular response (OR = 0.49, 95%CI: 0.248–0.974, P = 0.04). However, there was no significant correlation of these SNPs with IM intolerance and IM induced hepatotoxicity. Our results suggest the usefulness of genotyping of these single nucleotide polymorphisms in predicting IM response among CML patients.
    Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 04/2014; 68(3). DOI:10.1016/j.biopha.2014.01.009 · 2.02 Impact Factor
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    • "It is consistent with an other study which showed that mutations conferring resistance to IM, including T315I, were found infrequently in them [20]. Another study showed that P-loop mutations are not associated with poor outcome and suggested that the prognosis was dependent on several other factors [35]. It becomes evident that the presence of mutations does not explain all cases of IM resistance and the emerging problem is the primary resistance associated with BCR/ABL-independent mechanisms [16, 23]. "
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    ABSTRACT: Chronic myeloid leukemia (CML) results from the clonal expansion of pluripotent hematopoietic stem cells containing the active BCR/ABL fusion gene produced by a reciprocal translocation of the ABL1 gene to the BCR gene. The BCR/ABL protein displays a constitutive tyrosine kinase activity and confers on leukemic cells growth and proliferation advantage and resistance to apoptosis. Introduction of imatinib (IM) and other tyrosine kinase inhibitors (TKIs) has radically improved the outcome of patients with CML and some other diseases with BCR/ABL expression. However, a fraction of CML patients presents with resistance to this drug. Regardless of clinical profits of IM, there are several drawbacks associated with its use, including lack of eradication of the malignant clone and increasing relapse rate resulting from long-term therapy, resistance, and intolerance. Second and third generations of TKIs have been developed to break IM resistance. Clinical studies revealed that the introduction of second-generation TKIs has improved the overall survival of CML patients; however, some with specific mutations such as T315I remain resistant. Second-generation TKIs may completely replace imatinib in perspective CML therapy, and addition of third-generation inhibitors may overcome resistance induced by every form of point mutations.
    01/2014; 2014:596483. DOI:10.1155/2014/596483
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