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Clinical usefulness of therapeutic concentration monitoring for imatinib dosage individualization: results from a randomized controlled trial

  • Clinical Trial Report
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Abstract

Purpose

This study assessed whether a cycle of “routine” therapeutic drug monitoring (TDM) for imatinib dosage individualization, targeting an imatinib trough plasma concentration (C min) of 1,000 ng/ml (tolerance: 750–1,500 ng/ml), could improve clinical outcomes in chronic myelogenous leukemia (CML) patients, compared with TDM use only in case of problems (“rescue” TDM).

Methods

Imatinib concentration monitoring evaluation was a multicenter randomized controlled trial including adult patients in chronic or accelerated phase CML receiving imatinib since less than 5 years. Patients were allocated 1:1 to “routine TDM” or “rescue TDM.” The primary endpoint was a combined outcome (failure- and toxicity-free survival with continuation on imatinib) over 1-year follow-up, analyzed in intention-to-treat (ISRCTN31181395).

Results

Among 56 patients (55 evaluable), 14/27 (52 %) receiving “routine TDM” remained event-free versus 16/28 (57 %) “rescue TDM” controls (P = 0.69). In the “routine TDM” arm, dosage recommendations were correctly adopted in 14 patients (median C min: 895 ng/ml), who had fewer unfavorable events (28 %) than the 13 not receiving the advised dosage (77 %; P = 0.03; median C min: 648 ng/ml).

Conclusions

This first target concentration intervention trial could not formally demonstrate a benefit of “routine TDM” because of small patient number and surprisingly limited prescriber’s adherence to dosage recommendations. Favorable outcomes were, however, found in patients actually elected for target dosing. This study thus shows first prospective indication for TDM being a useful tool to guide drug dosage and shift decisions. The study design and analysis provide an interesting paradigm for future randomized TDM trials on targeted anticancer agents.

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Acknowledgments

The development and application of imatinib blood measurement at the Division of Clinical Pharmacology at the Centre Hospitalier Universitaire Vaudois and University of Lausanne (Lausanne, Switzerland) has received an unrestricted grant from Novartis Pharma Schweiz (Bern, Switzerland). The present work was also partly funded by the Swiss National Science Foundation (Bern, Switzerland) through the Nano-Tera Initiative (ISyPeM project). We thank the all involved hematologists and patients for their participation in the study. We also thank Béatrice Ternon, Sandra Cruchon and Nicole Guignard (Laboratory of Clinical Pharmacology, University Hospital Centre, Lausanne) for the imatinib drug level measurements and Ali Maghraoui for creating the study data base.

Conflict of interest

The Division of Clinical Pharmacology at the Centre Hospitalier Universitaire Vaudois and University of Lausanne (Lausanne, Switzerland) has received an unrestricted research grant and logistic support from Novartis Pharma Schweiz (Bern, Switzerland) for this study. N.W. has received two research grants from Novartis in 2012 and 2013 for projects unrelated to this trial. Y.C.: honoraria and advisory board for Novartis, BMS and Pfizer. D.H. and M.G.: Consultancy/advisory for Novartis, Switzerland. M.D.: (postgraduate) funding and medical information: Novartis. The remaining authors have declared no conflict of interest. This work was supported by Novartis Pharma Schweiz (unrestricted grant in support) and the Swiss National Science Foundation through the Nano-Tera initiative (ISyPeM project).

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Correspondence to T. Buclin.

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Gotta, V., Widmer, N., Decosterd, L.A. et al. Clinical usefulness of therapeutic concentration monitoring for imatinib dosage individualization: results from a randomized controlled trial. Cancer Chemother Pharmacol 74, 1307–1319 (2014). https://doi.org/10.1007/s00280-014-2599-1

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