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

Abstract

To investigate the correlation of trough imatinib mesylate (IM) levels with cytogenetic or molecular responses, we measured trough IM levels in patients with chronic myeloid leukemia, chronic phase (CML-CP), at 6 months of treatment with a standard dose of IM. Eighty-seven newly diagnosed patients with CML-CP were prospectively enrolled. Seventy-eight patients (89.7%) showed an optimal response (complete or partial cytogenetic response) at 6 months. Trough IM levels were 1378 + 725 ng/mL. When categorized into two groups, there was a statistically significant difference in numbers of patients with optimal and suboptimal responses at 6 months (group with 51000: 80.6% vs. 19.4%; 1000: 94.6% vs. 5.4%; p ¼ 0.032), and in numbers of patients with early major molecular response (early-MMR) and without MMR at 6 months (group with 51000: 3.2% vs. 96.8%; 1000: 21.4% vs. 78.6%; p ¼ 0.047). In conclusion, the incidence of optimal cytogenetic response or early-MMR in patients with CML-CP treated with IM for 6 months was significantly higher in those with a trough level of 1000 compared with those with a level of 51000. Dose escalation of IM can be one option in patients with CML showing suboptimal response or resistance to the standard dose of IM, especially with low trough plasma IM levels (51000 ng/mL).

CD117 (c-kit) Expression on CD34+ Cells Participates in the Cytogenetic Response to Imatinib in Patients with Chronic Myeloid Leukemia in the First Chronic Phase

“…In contrast to other studies [15,19,20], trough plasma concentration of imatinib did not reflect clinical response in chronic CML. Our results showed higher imatinib levels in CCyR, but no significant difference was found.…”

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

“…12) Several studies have also reported that patients with an imatinib C 0 less than 1000 ng/mL have a significantly lower rate of successfully achieving an improved MMR. 13,18,21,26,31) In the combined data set, 12,13,18,21,26,31) the rate of MMR achievement was significantly higher for patients with an imatinib C 0 above 1000 ng/mL than for patients with a C 0 less than 1000 ng/mL (odds ratio, 2.48; 95% CI, 1.82-3.38, p<0.0001) (Fig. 1).…”

“…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.…”

“…11) Consequently, the steadystate plasma trough concentration (C 0 ) of imatinib obtained 24 h after administration of a 400 mg standard daily dose ranged from 109 ng/mL to 4980 ng/mL, [11][12][13][14][15][16][17][18][19][20] and ranged from 140 ng/mL to 2457 ng/mL when limited to Japanese CML patients. [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%.…”

Biomarkers for determining the prognosis in chronic myelogenous leukemia

“…An exploratory analysis from the International Randomized Study of Interferon and STI571 (IRIS) found that imatinib trough levels predicted rates of CCyR, MMR, and EFS [45]. Some subsequent studies have confirmed these findings; others have not [45-48]. Because the clinical benefit of treatment change based on TKI plasma levels is unproven, current guidelines do not recommend routine monitoring of this sort [5].…”