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OCT1 genetic variants are associated with long term outcomes in imatinib treated chronic myeloid leukemia patients

Maya Koren-Michowitz1, Zehavit Buzaglo, Elena Ribakovsky

  • 1Division of Hematology, Chaim Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

European Journal of Haematology
|November 13, 2013
PubMed
Abstract

Insights

Genetic variants in the SLC22A1 transporter (hOCT1) impact imatinib treatment outcomes in chronic myeloid leukemia (CML) patients. Specific rs628031 genotypes are linked to poorer response and survival, suggesting potential for personalized therapy.

Area of Science:

  • Pharmacogenomics
  • Hematologic Malignancies
  • Molecular Biology

Background:

  • First-line imatinib therapy in chronic myeloid leukemia (CML) can lead to suboptimal responses or treatment failure in one-third of patients.
  • Imatinib cellular uptake is mediated by the SLC22A1 transporter (hOCT1), and its genetic variations may influence drug efficacy.
  • Investigating the role of SLC22A1 genetic variants in imatinib response is crucial for understanding treatment variability.

Purpose of the Study:

  • To investigate the association between SLC22A1 genetic variants and long-term outcomes in CML patients treated with imatinib.
  • To determine if specific SLC22A1 genotypes correlate with treatment response, resistance, and survival.
  • To explore the potential of pre-treatment genetic profiling for optimizing CML therapy.

Main Methods:

  • Genotyping of 167 CML patients (94% in chronic phase) for key SLC22A1 variants (rs41267797, rs683369, rs12208357, rs628031) using Sequenom MassARRAY.
  • Analysis of clinical endpoints including complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMolR).
  • Evaluation of event-free survival (EFS) and overall survival (OS) in relation to identified genotypes.

Main Results:

  • No significant differences in initial response rates (CHR, MCyR, CCyR, MMolR) were observed based on allelic variants.
  • Patients with AA or GA rs628031 genotypes showed a higher incidence of poor response (47% vs. 29%) and increased detection of BCR-ABL kinase domain (KD) mutations.
  • rs628031 genotypes AA/AG were associated with shorter median EFS (61 months vs. not reached) and lower 5-year OS rates (88% vs. 97%) compared to the GG genotype.

Conclusions:

  • SLC22A1 genetic variants, particularly rs628031, significantly influence long-term outcomes in imatinib-treated CML patients.
  • The presence of specific rs628031 genotypes is linked to increased risk of secondary resistance and poorer survival.
  • Pre-treatment assessment of SLC22A1 genetic variants could inform treatment decisions and personalize TKI therapy for CML.
Keywords:
CMLhOCT1kinase domain mutationsresistancetyrosine kinase inhibitor

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