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Chronic myelogenous leukemia

Patients with low OCT-1 activity and high ABCB1 fold rise have poor long-term outcomes in response to tyrosine kinase inhibitor therapy

Leukemia volume 32, pages 2288–2291 (2018)Cite this article

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We recently reported the clinical significance of monitoring ABCB1 mRNA levels in chronic myeloid leukemia (CML) patients undergoing imatinib therapy. This previous study demonstrated that early increases in ABCB1 mRNA expression (fold rise in ABCB1 from diagnosis to day 22 of imatinib therapy) were predictive for long-term patient response to tyrosine kinase inhibitor (TKI) therapy [1]. We have also previously demonstrated that the functional activity of the human organic cation transporter-1 (hOCT-1) is a strong determinant of patient response to imatinib therapy [2,3,4,5]. For the current study, we investigated the predictive potential of patient ABCB1 fold rise status when assessed in conjunction with OCT-1 activity (OA).

Patients enrolled to the Therapeutic intensification in de novo leukemia (TIDEL)-II trial (a Phase II study in adult CML patients of frontline imatinib with a mandatory switch to nilotinib for failure to achieve time-dependent molecular targets or for intolerance) were studied. They were assigned to either the low- or high-fold rise in ABCB1 expression cohort as described previously (<2.2 and ≥2.2 fold change in ABCB1 mRNA at diagnosis and after 3 weeks undergoing imatinib therapy respectively) [1]. Patients were also allocated low or high OA status according to previously defined OA values predictive for patients at a significantly greater risk of failing imatinib therapy (<4 or >4 ng/200,000 cells) [2]. OA [4, 5] is defined as the difference between the intracellular uptake and retention of C14-radiolabelled imatinib in the absence and presence of the potent hOCT-1 inhibitor prazosin. Patients for whom both ABCB1 fold rise and OA status were unavailable were excluded (59 patients). The remaining 151 patients were separated into four groups and patient response to imatinib therapy evaluated: low OA/high ABCB1 fold rise (high risk, n = 39); low OA/low ABCB1 fold rise (intermediate risk 1, n = 33); high OA/high ABCB1 fold rise (intermediate risk 2, n = 49); high OA/low ABCB1 fold rise (low risk, n = 30). We speculated that these two assays might be complementary because they reflect distinct aspects of imatinib uptake and retention; OA being a measure of imatinib influx and ABCB1 fold rise reflecting imatinib efflux. This was supported by the lack of correlation between OA and ABCB1 fold rise (R2 = 0.000369, p = 0.8149).

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Authors and Affiliations

  1. Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia

    Laura N Eadie, Timothy P Hughes & Deborah L White

  2. School of Medicine, Faculty of Health Sciences, University of Adelaide, Adelaide, SA, Australia

    Laura N Eadie, Timothy P Hughes & Deborah L White

  3. Division of Haematology, SA Pathology, Adelaide, SA, Australia

    Timothy P Hughes

  4. School of Paediatrics, Faculty of Health Sciences, University of Adelaide, Adelaide, SA, Australia

    Deborah L White

  5. School of Biological Sciences, Faculty of Sciences, University of Adelaide, Adelaide, SA, Australia

    Deborah L White

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  1. Laura N Eadie
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Correspondence to Deborah L White.

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Conflict of interest

LNE has no conflict of interest to declare. DLW receives honoraria and research funds from Novartis Pharmaceuticals and is a member of Advisory Boards for Novartis. TPH receives honoraria and research funds from Novartis Pharmaceuticals, BMS, and Ariad and is a member of Advisory Boards for Novartis, BMS, and Ariad. However, Novartis, BMS, and Ariad had no role in the design of the study, collection and analysis of data, nor the decision to publish.

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Eadie, L.N., Hughes, T.P. & White, D.L. Patients with low OCT-1 activity and high ABCB1 fold rise have poor long-term outcomes in response to tyrosine kinase inhibitor therapy. Leukemia 32, 2288–2291 (2018). https://doi.org/10.1038/s41375-018-0101-5

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