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Pharmacologic markers and predictors of responses to imatinib

Pharmacologic markers and predictors of responses to imatinib therapy in patients with chronic myeloid leukemia.
Clark RE, Davies A, Pirmohamed M, Giannoudis A.

University Department of Haematology, Royal Liverpool University Hospital, Liverpool, UK. clarkre@liverpool.ac.uk

Clinical resistance to imatinib often occurs in the absence of a mutation in the BCR-ABL kinase domain. Imatinib is transported out of cells by the efflux transporter ABCB1 (MDR1, whose product is p-glycoprotein). By contrast, the influx transporter, human organic cation transporter 1 (hOCT1) (also known as SLC22A1), transports imatinib into cells. Recent studies have identified that patients with low expression or activity of hOCT1 have a lower probability of achieving a cytogenetic or molecular remission. Prospective studies are currently investigating whether early trends in transporter expression can be used to guide treatment decisions. Plasma imatinib levels are higher in patients responding well to treatment, and may be useful in patients with suboptimal response or dubious compliance. Uptake of the second generation tyrosine kinase inhibitors, dasatinib and nilotinib, is less dependent upon hOCT1. These two drugs may therefore achieve adequate intracellular concentrations even in patients with low hOCT1 expression.

PMID: 18398725 [PubMed - indexed for MEDLINE)

Blood.
2007 Dec 1;110(12):4064-72.
Epub 2007 Aug 30.

Most CML patients who have a suboptimal response to imatinib have low OCT-1 activity: higher doses of imatinib may overcome the negative impact of low OCT-1 activity.

White DL, Saunders VA, Dang P, Engler J, Venables A, Zrim S, Zannettino A, Lynch K, Manley PW, Hughes T.

Division of Haematology, Institute of Medical and Veterinary Science, Adelaide, Australia. deb.white@imvs.sa.gov.au

Interpatient variability in intracellular uptake and retention (IUR) of imatinib may be due to variable function of the OCT-1 influx pump. OCT-1 activity was measured in pretherapy blood from chronic myeloid leukemia (CML) patients by calculating the difference in IUR of [(14)C]-imatinib with and without OCT-1 inhibition. Of patients with higher than median (high) OCT-1 activity, 85% achieved major molecular response (MMR) by 24 months, versus 45% with no more than a median (low) OCT-1 activity. Assessing patients receiving 600 mg imatinib per day and those averaging fewer than 600 mg over 12 months of therapy revealed patients with high OCT-1 activity achieved excellent molecular response regardless of dose, whereas response of patients with low OCT-1 activity was highly dose dependent. Of patients with low OCT-1 activity who received fewer than 600 mg, 45% failed to achieve a 2-log reduction by 12 months, and 82% failed to achieve a MMR by 18 months, compared with 8% and 17% in the cohort with high OCT-1 activity and dose less than 600 mg/day (P = .017 and P = .022). OCT-1 activity is an important determinant of molecular response to imatinib, with predictive value closely linked to dose. This pretherapy assay identifies patients at greatest risk of suboptimal response where dose intensity is critical, and those likely to respond equally well to standard dose imatinib.

PMID: 17761829 [PubMed - indexed for MEDLINE]

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