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Tyrosine kinase inhibitor (TKI) compliance is a real problem in the treatment of patients with chronic myeloid leukemia (CML). What data are available concerning inter- and intrapatient variability in the pharmacokinetics of these drugs, and is measurement of their pharmacology possible or valuable in management. —William P. Peters, MD, PhD
Chronic myeloid leukemia (CML) represents 5% of leukemia cases. It typically starts with a relatively indolent chronic phase (CP) and goes through a triphasic pattern of chronic followed by accelerated and ending with blastic phases, each more aggressive than the prior phase.
The current first-line treatment for CML is imatinib (Gleevec), nilotinib (Tasigna), and dasatinib (Sprycel). With these very effective medications, progression to the later stages is rarely seen. Treatment outcome is typically such that the longer the patient stays in remission, the less likely they are to later relapse, which is quite unique to the oncology world. Highly effective later-line treatments (ie, bosutinib [Bosulif] and ponatinib [Iclusig]) are now commercially available for patients who do not respond well or who are intolerant and/or resistant to first-line therapy. Based on current guidelines for response milestones, very few patients end up requiring a curative stem cell transplant, as the risk of this procedure is far beyond that of the oral medications.
When imatinib was first introduced, not much recourse was available for those patients who had a less than optimal response. Pharmacokinetics started to become popular with imatinib when it was the only game in town, and there were some practical methods for assessing response and resistance to the drug. But the mechanisms behind resistance are quite complex and not simply found in maintaining serum drug levels. The other issue is that there are already established goals to monitor efficacy such as cytogenetic remission within a reasonable timeframe as a significant determinant of outcome. In conclusion, routine pharmacokinetic testing to customize a treatment for CML is likely to remain a noncommercial activity. —Donald R. Fleming, MD
SOURCES
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(8):4022-4028.
Gotta V, Widmer N, Montemurro M, et al. Therapeutic drug monitoring of imatinib: Bayesian and alternative methods to predict trough levels. Clin Pharmacokinet. 2012;51(3):187-201.
Sheiner LB, Beal S, Rosenberg B, Marathe VV. Forecasting individual pharmacokinetics. Clin Pharmacol Ther. 1979;26(3):294-305.
Faber E, Friedecky D, Micova K, et al. Imatinib trough plasma levels do not correlate with the response to therapy in patients with chronic myeloid leukemia in routine clinical setting. Ann Hematol. 2012;91(6):923-929.
