Trial Information

Retrospective Study to Validate Pharmacogenetics Model for Imatinib Metabolism in Patients With Chronic Myeloid Leukemia

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.