Long-term efficacy of imatinib in a practical setting is correlated with imatinib trough concentration that is influenced by body size: a report by the Nagasaki CML Study Group

Abstract

Imatinib has dramatically improved long-term survival of chronic myelogenous leukemia (CML) patients. To analyze its efficacy in a practical setting, we registered most of CML patients in Nagasaki Prefecture of Japan. Of these, 73 patients received imatinib as an initial therapy. The overall survival rate of these patients was 88.7% at 6 years, and the cumulative complete cytogenetic response rate was 82.5% at 18 months. These results are comparable with the data of other reports including the IRIS study; however, the administered imatinib dose was smaller in our study than that in other reports. To address these discrepancies, we measured the trough concentration of imatinib among 35 patients. Although 39% of the patients were administered less than 400 mg/day, the trough level was comparable to those of previous reports. The trough level of imatinib showed a significant relationship with its efficacy, and was clearly related to dose of imatinib administrated and dose of imatinib divided by body surface area (BSA). Considering the smaller BSA of Japanese patients as compared to those of foreign origin, the results suggest that a lower dose of imatinib could maintain enough trough level and provided excellent results for the treatment of CML in our registry.

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

“…The mean trough plasma IM level of patients administered 400 mg/day was higher in our analysis than that reported in a Western study (1058 + 557 ng/mL) [16,17]. A Japanese group reported a similar mean trough plasma IM level (1244 + 495 ng/mL) in Japanese patients with CML taking IM 400 mg/day, compared to our data (1378 + 725 ng/mL) [20]. Although BSA was not found to be a clinically significant determinant of the trough plasma IM level [10,11], the smaller body size of Asian patients as compared to Western patients might cause the difference in mean trough plasma IM level between Western and Asian patients with CML [20].…”

Molecular analysis of the BCR-ABL1 kinase domain in chronic-phase chronic myelogenous leukemia treated with tyrosine kinase inhibitors in practice: Study by the Nagasaki CML Study Group

“…This treatment failure may have been due to the standard dose of dasatinib not being tolerated. Some studies, including ours, reported that the amount of TKI administered in practice was often less than the standard dose [17,18,[35][36][37]. Therefore, tolerability for a standard dose must be considered when selecting a TKI.…”

Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia

“…5 Although several important clinical trials indicated that 400 mg of IM should be the standard daily dose for chronic phase CML patients, 1,2 in clinical practice, lower doses of IM are administered to B40% of Japanese patients. 6,7 This is largely because of the fact that for some Japanese patients, lower IM doses have sufficient trough concentration for therapeutic CML treatment. 7 Although this interindividual variability in IM pharmacokinetics is observed among Japanese CML patients, little is known about potential pharmacogenetic variation influencing IM metabolism and drug transport efficacy.…”

“…6,7 This is largely because of the fact that for some Japanese patients, lower IM doses have sufficient trough concentration for therapeutic CML treatment. 7 Although this interindividual variability in IM pharmacokinetics is observed among Japanese CML patients, little is known about potential pharmacogenetic variation influencing IM metabolism and drug transport efficacy.…”