Pharmacogenomics Validation for Imatinib in Chronic Myeloid Leukemia


This is a multicenter, retrospective, observational study to validate a pharmacogenetics model for imatinib metabolism and resistance in patients with chronic myeloid leukemia among patients in different independent cohort.

Full Title of Study: “Retrospective Study to Validate Pharmacogenetics Model for Imatinib Metabolism in Patients With Chronic Myeloid Leukemia”

Study Type

  • Study Type: Observational
  • Study Design
    • Time Perspective: Retrospective
  • Study Primary Completion Date: September 2012

Detailed Description

1. The activity of Imatinib(IM) is mediated by blocking the activity of BCR/ABL tyrosine kinase in CML cells. However, some of the patients failed to achieve optimal response, and a substantial proportion of patients develop resistance to IM. 2. IM is a substrate for the adenosine triphosphate binding cassette (ABC) transporters, ABCB1 and ABCG2, while the active uptake of IM into cells is mediated by the human organic cationic transporter-1 (hOCT1). Also, IM is metabolized through first pass drug metabolism by the cytochrome P450 – CYP3A4 and CYP3A5. In addition, it is delivered in a bound form with a plasma protein referred to α1-acid glycoprotein (AGP). 3. Accordingly, the intracellular or systemic level of imatinib should be influenced by these factors such as ABCB1, ABCG2, hOCT1, CYP3A4, CYP3A5 or AGP genes. Inter-individual variability of 5 candidate genes associated with drug transport/metabolism (i.e. ABCB1, ABCG2, hOCT1, CYP3A4/3A5 and AGP) could affect the expression of corresponding proteins, thus influencing the treatment outcomes of imatinib therapy. 4. In the investigators' previous study, the investigators reported the cumulative incidences of MCyR and CCyR was significantly affected by the predictive model using 2 genotypes and disease stage. These predictive models for CCyR/MMoR or LOR/treatment failure seemed to work well. However, external validation of these predictive models is warranted especially using ethnically different independent cohort.

Arms, Groups and Cohorts

  • high risk group
    • Identified by the predictive model using 2 genotypes and disease stage
  • intermediate risk group
    • Identified by the predictive model using 2 genotypes and disease stage
  • Low risk group
    • Identified by the predictive model using 2 genotypes and disease stage

Clinical Trial Outcome Measures

Primary Measures

  • Median time to CCyR (complete cytogenetic response)

Secondary Measures

  • Variance of Genotypes from CML patients with Korean ethnicity
  • Median time to MCyR (Major cytogenetic responses)

Participating in This Clinical Trial

Inclusion Criteria

  • Chronic myeloid leukemia of any stage including chronic phase, accelerated or blastic phase. – Age>18 years – Complete set of clinical data available for review (demographic data, stage, treatment history, cytogenetic reports, and latest BCR/ABL RQ-PCR results) – Treated with imatinib mesylate at least 3 months Exclusion Criteria:

  • Treated with imatinib mesylate less than 3 months – Not agree with the intention of this study

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Asan Medical Center
  • Provider of Information About this Clinical Study
    • Principal Investigator: Dae-Young Kim, Assistant Professor – Asan Medical Center
  • Overall Official(s)
    • Jong Won Kim, MD, PhD, Study Chair, Samsung Medical Center, Sungjyunkwan University School of Medicine, Seoul, Korea
    • Dae-Young Kim, MD, Principal Investigator, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea


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Citations Reporting on Results

Kim DH, Sriharsha L, Xu W, Kamel-Reid S, Liu X, Siminovitch K, Messner HA, Lipton JH. Clinical relevance of a pharmacogenetic approach using multiple candidate genes to predict response and resistance to imatinib therapy in chronic myeloid leukemia. Clin Cancer Res. 2009 Jul 15;15(14):4750-8. doi: 10.1158/1078-0432.CCR-09-0145. Epub 2009 Jul 7.

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