Long‐term outcome following imatinib therapy for chronic myelogenous leukemia, with assessment of dosage and blood levels: the JALSG CML202 study

Abstract

A prospective multicenter Phase II study was performed to examine the efficacy and safety of imatinib therapy in newly diagnosed Japanese patients with chronic‐phase CML. Patients were scheduled to receive imatinib 400 mg daily. Plasma imatinib concentrations were measured by liquid chromatography–tandem mass spectrometry. In 481 evaluable patients, estimated 7‐year overall survival (OS) and event‐free survival (EFS) at a median follow‐up of 65 months were 93% and 87%, respectively. Because imatinib dosage was reduced in many patients due mainly to adverse events, subgroup analysis was performed according to the mean daily dose during the first 24 months of treatment: ≥360 mg (400‐mg group; n = 294), 270–359 mg (300‐mg group; n = 90) and <270 mg (200‐mg group; n = 67). There were no significant differences in OS and EFS between the 300‐ and 400‐mg groups; however, cumulative rates of complete cytogenetic and major molecular responses differed significantly between the two groups. There were no significant differences in mean imatinib trough levels between these two groups for the patients in whom trough levels had been measured. Survival and efficacy in the 200‐mg group were markedly inferior to the former two groups. These results suggest that, although a daily dose of 400 mg imatinib is associated with better outcomes, 300 mg imatinib may be adequate for a considerable number of Japanese patients who are intolerant to 400 mg imatinib. Blood level monitoring would be useful to determine the optimal dose of imatinib. (Cancer Sci 2012; 103: 1071–1078)

Therapeutic Drug Monitoring of Imatinib, Nilotinib, and Dasatinib for Patients with Chronic Myeloid Leukemia

“…23) In the same report, the estimated cumulative rate of CCyR or MMR during the first 18 months was significantly lower for patients taking the 200 mg daily dose than for patients in the 400 mg or 300 mg groups. 23) Even for patients intolerant of the 300-400 mg dose of imatinib, excessive dose reductions to ≤200 mg imatinib should be avoided, and such patients should be switched to a 2nd generation TKI. 23) A complete molecular response (CMR) is defined as ≤0.0032% of BCR-ABL 1 transcript levels.…”

“…According to results from the previous 14 reports, the mean steady-state imatinib C 0 obtained 24 h after taking a 400 mg standard daily dose was 1226 ng/mL, which is greater than the 1000 ng/mL target concentration. [11][12][13][14][15][16][17][18][19][21][22][23][24][25]32) However, patients obtaining an imatinib C 0 above 1000 ng/mL administered the lower dose of 200 mg were very rare.…”

“…[21][22][23][24][25][26] In Japanese CML patients, the inter-patient imatinib C 0 coefficient of variation (CV) ranged from 38.2% to 62.9%. [21][22][23][24][25] Several studies have investigated whether the imatinib C 0 reflects the clinical response of patients taking imatinib, namely exposure-response relationships.…”

“…[21][22][23][24][25][26] In Japanese CML patients, the inter-patient imatinib C 0 coefficient of variation (CV) ranged from 38.2% to 62.9%. [21][22][23][24][25] Several studies have investigated whether the imatinib C 0 reflects the clinical response of patients taking imatinib, namely exposure-response relationships. 11,12,[20][21][22][25][26][27][28][29][30] In Japanese CML patients, we have reported that the imatinib C 0 was significantly higher in patients with a MMR than in those without a MMR; the mean values were 1107±594 ng/ mL and 873±529 ng/mL, respectively (p=0.002).…”

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.…”