Targeted therapies are revolutionizing oncology. Patients with chronic myeloid leukemia treated with the tyrosine kinase inhibitors (TKI) now have life expectancies approaching that of the general population.(1) Imatinib (Gleevec®, Gilvec®) the first TKI approved has substantial efficacy in chronic myeloid leukemia (CML) and gastrointestinal stromal tumors.(2, 3) Read More
Since imatinib was approved two additional TKIs, dasatinib (Sprycel®) and nilotinib (Tasigna®) have also been approved for front line CML therapy.(4, 5) The newer drugs are effective in cases of imatinib resistance, and generate faster cytogenetic and major molecular responses in the first 12 months of therapy when compared to imatinib 400 mg QD.(6, 7) However, to date no long term benefit in survival has been demonstrated compared to imatinib.(8, 9) Multiple studies have established the same therapeutic threshold for imatinib trough concentrations (Ctrough or Cmin) in CML.(10-17). Recently the first results from a prospective randomized trial practicing therapeutic drug monitoring (PK-guided dose adjustment) demonstrated that imatinib with therapeutic drug monitoring could be as effective as the newer first line TKI drugs.(18)
Suboptimal response to imatinib therapy has been linked to mutations, genetic poly morphisims, pharmacokinetic variability and adherence.(19-23) Measuring imatinib plasma levels can give insight into poor therapeutic response.
1. Bower H, Bjorkholm M, Dickman PW, et al. Life Expectancy of Patients With Chronic Myeloid Leukemia Approaches the Life Expectancy of the General Population. J Clin Oncol. 2016;34:2851-2857.
2. Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001;344:1038-1042.
3. Savage DG and Antman KH. Imatinib mesylate--a new oral targeted therapy. N Engl J Med. 2002;346:683-693.
4. Brave M, Goodman V, Kaminskas E, et al. Sprycel for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant to or intolerant of imatinib mesylate. Clin Cancer Res. 2008;14:352-359.
5. Hazarika M, Jiang X, Liu Q, et al. Tasigna for chronic and accelerated phase Philadelphia chromosome--positive chronic myelogenous leukemia resistant to or intolerant of imatinib. Clin Cancer Res. 2008;14:5325-5331.
6. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362:2260-2270.
7. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362:2251-2259.
8. Cortes JE, Saglio G, Kantarjian HM, et al. A Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Naive Chronic Myeloid Leukemia Patients Trial. J Clin Oncol. 2016;34:2333-2340.
9. Hochhaus A, Saglio G, Hughes TP, et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016;30:1044-1054.
10. Guilhot F, Hughes TP, Cortes J, et al. Plasma exposure of imatinib and its correlation with clinical response in the Tyrosine Kinase Inhibitor Optimization and Selectivity Trial. Haematologica. 2012;97:731-738.
11. Larson RA, Druker BJ, Guilhot F, et al. Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood. 2008;111:4022-4028.
12. Bouchet S, Poulette S, Titier K, et al. Relationship between imatinib trough concentration and outcomes in the treatment of advanced gastrointestinal stromal tumours in a real-life setting. Eur J Cancer. 2016;57:31-38.
13. Picard S, Titier K, Etienne G, et al. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood. 2007;109:3496-3499.
14. Singh N, Kumar L, Meena R and Velpandian T. Drug monitoring of imatinib levels in patients undergoing therapy for chronic myeloid leukaemia: comparing plasma levels of responders and non-responders. Eur J Clin Pharmacol. 2009;65:545-549.
15. Ishikawa Y, Kiyoi H, Watanabe K, et al. Trough plasma concentration of imatinib reflects BCR-ABL kinase inhibitory activity and clinical response in chronic-phase chronic myeloid leukemia: a report from the BINGO study. Cancer Sci. 2010;101:2186-2192.
16. Sohn SK, Oh SJ, Kim BS, et al. Trough plasma imatinib levels are correlated with optimal cytogenetic responses at 6 months after treatment with standard dose of imatinib in newly diagnosed chronic myeloid leukemia Leuk Lymphoma. 2011;52:1024-1029.
17. Koren-Michowitz M, Volchek Y, Naparstek E, et al. Imatinib plasma trough levels in chronic myeloid leukaemia: results of a multicentre study CSTI571AIL11TGLIVEC. Hematol Oncol. 2012;30:200-205.
18. Rousselot P, Johnson-Ansah H, Huguet F, et al. Personalized Daliy Doses of Imatinib By Therapeutic Drug Monitoring Increase teh Rates of Molecular Responses in Patients with Chronic Myeloid Leukemia. Final Results of teh Randomized OPTIM Imatinib Study. Blood. 2015;126.
19. Yamakawa Y, Hamada A, Nakashima R, et al. Association of genetic polymorphisms in the influx transporter SLCO1B3 and the efflux transporter ABCB1 with imatinib pharmacokinetics in patients with chronic myeloid leukemia. Ther Drug Monit. 2011;33:244-250.
20. Cortes JE, Egorin MJ, Guilhot F, Molimard M and Mahon FX Pharmacokinetic/pharmacodynamic correlation and blood-level testing in imatinib therapy for chronic myeloid leukemia. Leukemia. 2009;23:1537-1544.
21. Jabbour E, Branford S, Saglio G, et al. Practical advice for determining the role of BCR-ABL mutations in guiding tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia Cancer. 2010; 117:1800-1811.
22. Marin D, Bazeos A, Mahon FX, et al. 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. 2010;28:2381-2388.
23. Ibrahim AR, Eliasson L, Apperley JF, et al. Poor adherence is the main reason for loss of CCyR and imatinib failure for chronic myeloid leukemia patients on long-term therapy. Blood. 2011;117:3733-3736.
24. Marin D, Ibrahim AR, Lucas C, et al. Assessment of BCR-ABL1 transcript levels at 3 months is the only requirement for predicting outcome for patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. J Clin Oncol. 2012;30:232-238.
Publications of Interest
Personalized daily doses of imatinib by therapeutic drug monitoring increase the rates of molecular responses in patients with chronic myeloid leukemia. Final results of the randomized OPTIM imatinib study.
Rousselot P, Johnson-Ansah H, Huguet F, et al. Blood. 2015;126.
In this study sixty-five percent of CML patients had imatinib levels below the established therapeutic threshold (Cmin or Ctrough). Measuring patient’s Cmin and adjusting dosage resulted in significantly higher imatinib plasma levels and molecular responses (63%) compared to standard management for patients below the Cmin target (37%). The patients receiving TDM achieved similar (not statistically different) molecular responses as patients in the therapeutic range.
Therapeutic drug monitoring of imatinib in chronic myeloid leukemia: experience from 1216 patients at a centralized laboratory.
Bouchet S, Titier K, Moore N, et al. Fundam Clin Pharmacol. 2013;27:690-697.
This first very large scale analysis of the potential utility of TDM in real clinical practice demonstrated that the optimal response threshold of 1,000 ng/mL Cmin, was associated with major molecular response and complete molecular response independent of treatment duration. In practice there was high interpatient variability (60%) and the majority of patients (61%) had Cmin levels below the therapeutic threshold. The study demonstrated that TDM with a Cmin therapeutic threshold of 1,000 ng/mL could be important for dose optimization to achieve molecular responses.
Imatinib plasma levels are correlated with clinical benefit in patients with unresectable/metastatic gastrointestinal stromal tumors.
Demetri GD, Wang Y, Wehrle E, et al. J Clin Oncol. 2009;27(19):3141-47.
This phase II randomized trial explored the relationship between imatinib plasma levels and clinical outcomes. The steady state Cmin values were associated with clinical benefits including time to progression and objective response.
Plasma exposure of imatinib and its correlation with clinical response in the tyrosine kinase inhibitor optimization and selectivity trial.
Guilhot F, Hughes TP, Cortes J, et al. Haematologica. 2012;97(5):731-38.
The TOPS trial evaluated clinical response and safety in CML patients treated with imatinib. The empirical therapeutic threshold here was consistent with earlier studies. Patients with an imatinib Cmin above threshold at steady state achieved faster major molecular response and higher rates of major molecular response and complete cytogenetic response than those patients with the lowest imatinib levels (1st quartile).
Imatinib pharmacokinetics and its correlation with response plasma exposure of imatinib and its correlation with clinical response in the tyrosine kinase inhibitor optimization and selectivity trial.
Larson RA, Druker BJ, Guilhot F, et al. Blood. 2008;111:4022-28.
This phase III randomized study demonstrated that patients who achieved complete cytogenetic response had significantly higher imatinib trough (or Cmin) levels than those who did not. Plasma trough levels of imatinib were a significant prognostic covariate for midterm and long term clinical response: complete cytogenetic response, major molecular response and event-free survival. Patients with the lowest imatinib levels more frequently discontinued imatinib for “unsatisfactory therapeutic effect”.
Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia
Picard S, Titier K, Etienne G, et al. Blood. 2007;109:3496-99.
This was the first study that examined the impact of pharmacokinetics on imatinib treatment; testing the hypothesis that ineffective treatment or lack of response could be associated with imatinib trough levels. Compared to patients who did not respond mean trough imatinib plasma levels were significantly higher in patients who had achieved either a complete cytogenetic response or major molecular response.