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.
References
Kantarjian H, O’Brien S, Cortes J et al (2004) Survival advantage with imatinib mesylate therapy in chronic-phase chronic myelogenous; leukemia (CML-CP) after IFN-alpha failure and in late CML-CP, comparison with historical controls. Clin Cancer Res 10:68–75
Hochhaus A, O’Brien SG, Guilhot F et al (2009) Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia 23(6):1054–1061
Gurion R, Gafter-Gvili A, Vidal L et al (2013) Has the time for first-line treatment with second generation tyrosine kinase inhibitors in patients with chronic myelogenous leukemia already come? Systematic review and meta-analysis. Haematologica 98:95–102
Ohnishi K, Nakaseko C, Takeuchi J et al (2012) Long-term outcome following imatinib therapy for chronic myelogenous leukemia, with assessment of dosage and blood levels: the JALSG CML202 study. Cancer Sci 103(6):1071–1078
Hehlmann R, Müller MC, Lauseker M et al (2014) Deep molecular response is reached by the majority of patients treated with imatinib, predicts survival, and is achieved more quickly by optimized high-dose imatinib: results from the randomized CML-study IV. J Clin Oncol 32(5):415–423
Baccarani M, Druker BJ, Branford S et al (2014) Long-term response to imatinib is not affected by the initial dose in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: final update from the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) study. Int J Hematol. doi:10.1007/s12185-014-1566-2
De Lavallade H, Apperley JF, Khorashad JS et al (2008) Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol 26(20):3358–3363
Shami PJ, Deininger M (2012) Evolving treatment strategies for patients newly diagnosed with chronic myeloid leukemia: the role of second-generation BCR-ABL inhibitors as first-line therapy. Leukemia 26(2):214–224
Roychowdhury S, Talpaz M (2011) Managing resistance in chronic myeloid leukemia. Blood Rev 25(6):279–290
Gafter-Gvili A, Leader A, Gurion R et al (2011) High-dose imatinib for newly diagnosed chronic phase chronic myeloid leukemia patients—systematic review and meta-analysis. Am J Hematol 86(8):657–662
Klümpen HJ, Samer CF, Mathijssen RHJ et al (2011) Moving towards dose individualization of tyrosine kinase inhibitors. Cancer Treat Rev 37:251–260
Summary of Product Characteristics—Glivec 400 mg film-coated tablets. http://www.glivec.com/files/Glivec-400mg-coated.pdf
Baccarani M, Pileri S, Steegmann J-L et al (2012) Chronic myeloid leukemia: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 23(Suppl 7):vii72–vii77
NCCN Guidelines Version 2.2012 Chronic Myelogenous Leukemia. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site
Gao B, Yeap S, Clements A et al (2012) Evidence for therapeutic drug monitoring of targeted anticancer therapies. J Clin Oncol 30(32):4017–4025
Cortes JE, Egorin MJ, Guilhot F et al (2009) Pharmacokinetic/pharmacodynamic correlation and blood-level testing in imatinib therapy for chronic myeloid leukemia. Leuk Off J Leuk Soc Am Leuk Res Fund 23:1537–1544
Teng JFT, Mabasa VH, Ensom MHH (2012) The role of therapeutic drug monitoring of imatinib in patients with chronic myeloid leukemia and metastatic or unresectable gastrointestinal stromal tumors. Ther Drug Monit 34(1):85–97
Gotta V, Buclin T, Csajka C, Widmer N (2013) Systematic review of population pharmacokinetic analyses of imatinib and relationships with treatment outcomes. Ther Drug Monit 35(2):150–167
Larson RA, Druker BJ, Guilhot F et al (2008) Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood 111(8):4022–4028
Picard S, Titier K, Etienne G et al (2007) Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 109(8):3496–3499
Cortes JE, Egorin MJ, Guilhot F et al (2009) Pharmacokinetic/pharmacodynamic correlation and blood-level testing in imatinib therapy for chronic myeloid leukemia. Leukemia 23(9):1537–1544
Buclin T, Widmer N, Biollaz J, Decosterd LA (2011) Who is in charge of assessing therapeutic drug monitoring? The case of imatinib. Lancet Oncol. 12(1):9–11
Bardin C, Veal G, Paci A et al (2014) Therapeutic drug monitoring in cancer—are we missing a trick? Eur J Cancer 50(12):2005–2009
Widmer N, Bardin C, Chatelut E et al (2014) Review of therapeutic drug monitoring of anticancer drugs part two—targeted therapies. Eur J Cancer 50(12):2020–2036
Gotta V, Vallotton L, Widmer N, Buclin T (2011) Need of reduced and harmonized bureaucracy in multi-centre clinical research—a case-report from a swiss trial. Br J Clin Pharmacol 72:7
Gotta V, Widmer N, Montemurro M et al (2012) Therapeutic drug monitoring of imatinib bayesian and alternative methods to predict trough levels. Clin Pharmacokinet 51(3):187–201
Haouala A, Zanolari B, Rochat B et al (2009) Therapeutic Drug Monitoring of the new targeted anticancer agents imatinib, nilotinib, dasatinib, sunitinib, sorafenib and lapatinib by LC tandem mass spectrometry. J Chromatogr, B: Anal Technol Biomed Life Sci 877(22):1982–1996
Haouala A, Widmer N, Guidi M et al (2013) Prediction of free imatinib concentrations based on total plasma concentrations in patients with gastrointestinal stromal tumours. Br J Clin Pharmacol 75(4):1007–1018
Cross NC (2009) Standardisation of molecular monitoring for chronic myeloid leukaemia. Best Pract Res Clin Haematol 22(3):355–365
Klumpen HJ, Samer CF, Mathijssen RH et al (2011) Moving towards dose individualization of tyrosine kinase inhibitors. Cancer Treat Rev 37(4):251–260
Study of Dose Escalation Versus no Dose Escalation of Imatinib in Metastatic Gastrointestinal Stromal Tumors (GIST) Patients. http://clinicaltrials.gov/ct2/show/NCT01031628
Druker BJ, Guilhot F, O’Brien SG et al (2006) Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 355(23):2408–2417
Baccarani M, Deininger MW, Rosti G et al (2013) European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 122(6):872–884
Gotta V, Bouchet S, Widmer N et al (2014) Large-scale imatinib dose-concentration-effect study in CML patients under routine care conditions. Leuk Res 38(7):764–772
Jabbour E, Hochhaus A, Cortes J et al (2010) Choosing the best treatment strategy for chronic myeloid leukemia patients resistant to imatinib: weighing the efficacy and safety of individual drugs with BCR-ABL mutations and patient history. Leukemia 24(1):6–12
Kantarjian HM, Larson RA, Guilhot F et al (2009) Efficacy of imatinib dose escalation in patients with chronic myeloid leukemia in chronic phase. Cancer 115(3):551–560
Kantarjian H, Pasquini R, Hamerschlak N et al (2007) Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood 109(12):5143–5150
Gandia P, Arellano C, Lafont T et al (2013) Should therapeutic drug monitoring of the unbound fraction of imatinib and its main active metabolite N-desmethyl-imatinib be developed? Cancer Chemother Pharmacol 71(2):531–536
Seong SJ, Lim M, Sohn SK et al (2013) Influence of enzyme and transporter polymorphisms on trough imatinib concentration and clinical response in chronic myeloid leukemia patients. Ann Oncol 24:756–760
Li RJ, Zhang GS, Chen YH et al (2010) Down-regulation of mitochondrial ATPase by hypermethylation mechanism in chronic myeloid leukemia is associated with multidrug resistance. Ann Oncol 21(7):1506–1514
Le Coutre P, Kreuzer K-A, Pursche S et al (2004) Pharmacokinetics and cellular uptake of imatinib and its main metabolite CGP74588. Cancer Chemother Pharmacol 53(4):313–323
Judson I (2012) Therapeutic drug monitoring of imatinib-new data strengthen the case. Clin Cancer Res 18:5517–5519
Marin D, Bazeos A, Mahon F-X et al (2010) Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol 28(14):2381–2388
Hsyu P-H, Mould DR, Upton RN, Amantea M (2013) Pharmacokinetic-pharmacodynamic relationship of bosutinib in patients with chronic phase chronic myeloid leukemia. Cancer Chemother Pharmacol 71(1):209–218
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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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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DOI: https://doi.org/10.1007/s00280-014-2599-1