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

Abstract

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 [14C]-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.

Lysosomal Sequestration Determines Intracellular Imatinib Levels

“…SLC22A1 has been suggested to largely determine the IUR of imatinib, and its expression/activity are thought to predict the long-term outcome of chronic-phase CML cells (Thomas et al, 2004;Crossman et al, 2005;White et al, 2006White et al, , 2007White et al, , 2010Wang et al, 2008;White and Hughes, 2012). SLC22A1 transporter activity is commonly derived from the IUR of imatinib with and without "specific" SLC22A1 inhibitors such as prazosin or amantadine.…”

“…SLC22A1, also referred to as organic cation transporter (OCT) 1, has frequently been implicated in the intracellular uptake and disposition of imatinib in CML cells (Thomas et al, 2004;White et al, 2006), although controversy exists with regard to its precise role (Burger et al, 2013;Nies et al, 2014). SLC22A1 transporter expression/activity toward imatinib is reported to predict the long-term outcome of chronic-phase CML (White et al, 2006(White et al, , 2007(White et al, , 2010Wang et al, 2008). Assessment of SLC22A1 transporter activity in cell lines and clinical CML samples was derived from imatinib IUR experiments in the presence or absence of SLC22A1 inhibitors such as prazosin or amantadine (Thomas et al, 2004;White et al, 2006).…”

“…The putative clinical significance of potential imatinib uptake transporters has extensively been investigated in the last decade as reflected by the numerous (pre-) clinical studies that have been conducted to investigate their role in the pharmacokinetics and/or pharmacodynamics of imatinib (Thomas et al, 2004;Crossman et al, 2005;White et al, 2006White et al, , 2007White et al, , 2010Hu et al, 2008;Wang et al, 2008;White and Hughes, 2012;Nies et al, 2014). SLC22A1, also referred to as organic cation transporter (OCT) 1, has frequently been implicated in the intracellular uptake and disposition of imatinib in CML cells (Thomas et al, 2004;White et al, 2006), although controversy exists with regard to its precise role (Burger et al, 2013;Nies et al, 2014).…”

Imatinib plasma trough concentration and its correlation with characteristics and response in Chinese CML patients

“…Resistance to imatinib caused by BCR-ABL gene amplification or increased levels of mRNA can be overcome by increasing the imatinib dose [6][7][8] . More recently, it has been suggested that variations in imatinib trough plasma concentrations (C mins ) could affect cytogenetic and molecular responses in CML.…”

285 Downregulation of Organic Cation Transporters Oct1 (Slc22a1) and Oct3 (Slc22a3) in Human Hepatocellular Carcinoma and Their Prognostic Significance

“…imatinib, in patients with chronic myeloid leukemia (CML) [12][13][14]. Furthermore, OCTs are determinants of the cytotoxicity of platin derivates, which is relevant for the responsiveness towards platin-containing chemotherapies [11].…”