Clinical trial NCT01437202: Pharmacogenomics Validation for Imatinib in Chronic Myeloid Leukemia
Official title: Retrospective Study to Validate Pharmacogenetics Model for Imatinib Metabolism in Patients With Chronic Myeloid Leukemia
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Keywords: imatinib
drug resistance
pharmacogenetics
Lead sponsor: Asan Medical Center
Sponsor class: OTHER
First posted: 2011-09-20
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients who were diagnosed as chronic myeloid leukemia, treated with imatinib more than 3 months, at Asan Medical Center, Seoul, Korea.

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Median time to CCyR (complete cytogenetic response)
Secondary outcomes:
measure: Variance of Genotypes from CML patients with Korean ethnicity
measure: Median time to MCyR (Major cytogenetic responses)
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: Princess Margaret Hospital, University of Toronto
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center, University of Ulsan College of Medicine
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center, Sungkyunkwan University School of Medicine
Study officials:
affiliation: Samsung Medical Center, Sungjyunkwan University School of Medicine, Seoul, Korea
name: Jong Won Kim, MD, PhD
role: STUDY_CHAIR
affiliation: Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
name: Dae-Young Kim, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kantarjian HM, Cortes JE, O'Brien S, Luthra R, Giles F, Verstovsek S, Faderl S, Thomas D, Garcia-Manero G, Rios MB, Shan J, Jones D, Talpaz M. Long-term survival benefit and improved complete cytogenetic and molecular response rates with imatinib mesylate in Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia after failure of interferon-alpha. Blood. 2004 Oct 1;104(7):1979-88. doi: 10.1182/blood-2004-02-0711. Epub 2004 Jun 15.
citation: Kantarjian HM, Talpaz M, Giles F, O'Brien S, Cortes J. New insights into the pathophysiology of chronic myeloid leukemia and imatinib resistance. Ann Intern Med. 2006 Dec 19;145(12):913-23. doi: 10.7326/0003-4819-145-12-200612190-00008.
citation: Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, Sawyers CL. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001 Aug 3;293(5531):876-80. doi: 10.1126/science.1062538. Epub 2001 Jun 21.
citation: Mahon FX, Belloc F, Lagarde V, Chollet C, Moreau-Gaudry F, Reiffers J, Goldman JM, Melo JV. MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood. 2003 Mar 15;101(6):2368-73. doi: 10.1182/blood.V101.6.2368.
citation: Awidi A, Salem II, Najib N, Mefleh R, Tarawneh B. Determination of imatinib plasma levels in patients with chronic myeloid leukemia by high performance liquid chromatography-ultraviolet detection and liquid chromatography-tandem mass spectrometry: methods' comparison. Leuk Res. 2010 Jun;34(6):714-7. doi: 10.1016/j.leukres.2009.08.005. Epub 2009 Sep 9.
citation: Gardner ER, Burger H, van Schaik RH, van Oosterom AT, de Bruijn EA, Guetens G, Prenen H, de Jong FA, Baker SD, Bates SE, Figg WD, Verweij J, Sparreboom A, Nooter K. Association of enzyme and transporter genotypes with the pharmacokinetics of imatinib. Clin Pharmacol Ther. 2006 Aug;80(2):192-201. doi: 10.1016/j.clpt.2006.05.003.
citation: 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.