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Chronic myeloid leukemia patients sensitive and resistant to imatinib treatment show different metabolic responses.

ABSTRACT: The BCR-ABL tyrosine kinase inhibitor imatinib is highly effective for chronic myeloid leukemia (CML). However, some patients gradually develop resistance to imatinib, resulting in therapeutic failure. Metabonomic and genomic profiling of patients' responses to drug interventions can provide novel information about the in vivo metabolism of low-molecular-weight compounds and extend our insight into the mechanism of drug resistance. Based on a multi-platform of high-throughput metabonomics, SNP array analysis, karyotype and mutation, the metabolic phenotypes and genomic polymorphisms of CML patients and their diverse responses to imatinib were characterized. The untreated CML patients (UCML) showed different metabolic patterns from those of healthy controls, and the discriminatory metabolites suggested the perturbed metabolism of the urea cycle, tricarboxylic acid cycle, lipid metabolism, and amino acid turnover in UCML. After imatinib treatment, patients sensitive to imatinib (SCML) and patients resistant to imatinib (RCML) had similar metabolic phenotypes to those of healthy controls and UCML, respectively. SCML showed a significant metabolic response to imatinib, with marked restoration of the perturbed metabolism. Most of the metabolites characterizing CML were adjusted to normal levels, including the intermediates of the urea cycle and tricarboxylic acid cycle (TCA). In contrast, neither cytogenetic nor metabonomic analysis indicated any positive response to imatinib in RCML. We report for the first time the associated genetic and metabonomic responses of CML patients to imatinib and show that the perturbed in vivo metabolism of UCML is independent of imatinib treatment in resistant patients. Thus, metabonomics can potentially characterize patients' sensitivity or resistance to drug intervention.

SUBMITTER: A J

PROVIDER: S-EPMC2951899 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Chronic myeloid leukemia patients sensitive and resistant to imatinib treatment show different metabolic responses.

A Jiye J Qian Sixuan S Wang Guangji G Yan Bei B Zhang Sujiang S Huang Qing Q Ni Lingna L Zha Weibin W Liu Linsheng L Cao Bei B Hong Ming M Wu Hanxin H Lu Hua H Shi Jian J Li Mengjie M Li Jianyong J

PloS one 20101008 10

The BCR-ABL tyrosine kinase inhibitor imatinib is highly effective for chronic myeloid leukemia (CML). However, some patients gradually develop resistance to imatinib, resulting in therapeutic failure. Metabonomic and genomic profiling of patients' responses to drug interventions can provide novel information about the in vivo metabolism of low-molecular-weight compounds and extend our insight into the mechanism of drug resistance. Based on a multi-platform of high-throughput metabonomics, SNP a ...[more]

PMID: 20949032

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Project description:Imatinib has been found to substantially improve outcomes in patients with chronic myeloid leukemia (CML) compared with previously available therapies. However, its use is complicated by development of resistance or drug intolerance, prompting dose escalation or a trial of dasatinib or nilotinib, the second-generation tyrosine kinase inhibitors (TKIs).This article reviews the mechanisms of TKI resistance; discusses the tolerability and efficacy of high-dose imatinib, dasatinib, and nilotinib; and provides background for the rational use of second-line treatment options.MEDLINE (1966-December 2009) and EMBASE (1993-December 2009) were searched for pertinent English-language publications using search terms that included, but were not limited to, chronic myeloid leukemia, imatinib, dasatinib, nilotinib, and clinical trial. Abstracts from American Society of Hematology annual meetings (2005-2009) were also reviewed. There were no prespecified inclusion or exclusion criteria.Major and complete cytogenetic responses (MCyR and CCyR, respectively) to second-line treatment with high-dose (600-800 mg/d PO) imatinib were restricted to CML patients who had achieved a CyR to standard-dose imatinib: >90% of patients without a previous CyR failed to respond. The expected durability of the response to this approach remains unclear. Grade 3/4 thrombocytopenia, neutropenia, and anemia occurred in 14%, 39%, and 8%, respectively, of patients receiving high-dose imatinib. In patients who failed first-line treatment with imatinib, dasatinib (70 mg BID PO) was associated with higher rates of CCyR at 2 years compared with imatinib (44% vs 18%, respectively; P = 0.003), as well as higher estimated rates of progression-free survival at 2 years (86% vs 65%; P = 0.001). Dasatinib use was complicated by grade 3/4 thrombocytopenia and neutropenia in 57% and 63% of patients, respectively, and pleural effusion in 5%. Nilotinib treatment was effective in patients who were resistant to or unable to tolerate imatinib, with 46% and 58% achieving a CCyR and MCyR, respectively, at 2 years. Nilotinib use was complicated by grade 3/4 thrombocytopenia and neutropenia in 28% and 40% of patients, respectively, and QTc-interval prolongation in 1% to 10% of patients. Neither agent was clinically effective in patients with the common T315I mutation.Dasatinib and nilotinib were effective and generally well tolerated as second-line treatments for CML patients with a suboptimal response to standard doses of imatinib or imatinib intolerance.

Dataset Information

Chronic myeloid leukemia patients sensitive and resistant to imatinib treatment show different metabolic responses.

Publications

Chronic myeloid leukemia patients sensitive and resistant to imatinib treatment show different metabolic responses.

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