Relevance of the Daily Dose of Imatinib Mesylate (IM) Rather Than Its Trough Plasma Concentration for Achieving Deep Molecular Response in Patients with Chronic Myeloid Leukemia.
Authors: Yoshida Chikashi , Komeno Takuya , Hori Mitsuo , Kimura Tomofumi , Fujii Masami , Okoshi Yasushi , Suzukawa Kazumi , Chiba Shigeru , Hasegawa Yuichi , Mukai Harumi Yamamoto , Ito Takayoshi , Shimizu Seiichi , Kamoshita Masaharu , Kudo Daisuke , Shinagawa Atsushi , Chikatsu Norio , Monma Yuriko , Watanabe Norimichi , Kojima Hiroshi 
Published: October 2019

Abstract
Abstract 1112
Poster Board I-134

Background and objectives
Although standard dose of IM, namely 400 mg daily, has been recommended for treating patients with chronic phase chronic myeloid leukemia (CML-CP), dose reduction is sometimes inevitable mainly because of adverse events. Previous reports have indicated that the trough plasma concentration (Cmin) of IM is a good indicator for predicting a good clinical response (Picard et al., Blood 2007; Larson et al., Blood 2008). Contrary, Forrest et al. reported that the Cmin correlates with neither cytogenetic nor molecular response (Leuk Res 2008). Therefore, it remains controversial whether the monitoring of IM Cmin is important and whether the dose adjustment should be based on Cmin. We thus assayed the Cmin in patients with CML-CP treated by standard or reduced doses of IM and analyzed their correlation with clinical response in a Japanese population.

Methods
Cmin samples were obtained 22 -26 hours after the last administration of IM from 46 patients with CML-CP treated for at least 12 months with imatinib at 7 hospitals in Ibaraki Prefecture, Japan. Cmin was determined using liquid chromatography-tandem mass spectrometry method. Clinical responses to IM, complete cytogenetic response (CCyR), major molecular response (MMR), and complete molecular response (CMR), were monitored simultaneously. CMR was defined as no detectable BCR-ABL transcripts by nested RT-PCR. Patient information was collected by questionnaire and medical chart review.

Results
Of evaluated 38 patients, 2 (5%), 6 (16%), 15 (39%), and 15 (39%) were treated with 100, 200, 300, and 400 mg of IM daily, respectively. The median duration of IM treatment was 1,777 days (range, 468-2799). The mean (±SD) and median Cmin in all patients were 979 ±599 and 836 ng/ml (range, 105-3,700 ng/ml), respectively. The mean (±SD) Cmin at dose of 100, 200, 300, and 400 mg/day were 210±148, 715±209, 940±394, and 1,226±771 ng/ml, respectively. The Cmin was significantly higher in patients treated with standard dose than those treated with the reduced dose (P= 0.04). A total of 33(86.8%) patients achieved a CCyR. There was no significant difference in the mean Cmin (±SD) between patients who achieved CCyR and who did not (977±605 vs 993±631 ng/ml, P=0.48). No significant difference was observed in the IM daily doses (P=0.17) and in the duration of IM treatment (P=0.96) between patients with and without CCyR. One (50%), 4 (50%), 9 (60%), and 13 (87%) patients treated at IM dose levels of 100, 200, 300, 400 mg/day achieved MMR, respectively. However, there was no significant difference in the IM daily dose (P=0.37) and in the duration of IM treatment (P=0.35) between patients with and without MMR. The mean IM Cmin (±SD) of patients with MMR was 1,044±635 ng/ml, which was not significantly higher than those without MMR (818±488 ng/ml, P=0.17). These data collectively suggest that neither IM Cmin nor daily dose is relevant for achieving CCyR and MMR in our population. However, importantly, 7 of 15 patients treated with 400 mg/day of IM achieved CMR, whereas no patients treated with 100 or 200 mg/day and only one patient with 300 mg/day achieved CMR. Indeed there was significant difference in the daily dose of IM between patients with and without CMR (P=0.02). The mean Cmin (±SD) with CMR was 1,430±988 ng/ml, which was significantly higher than those without CMR (859±389 ng/ml, P=0.04). Contrary to this, Cmin of patients treated with 400 mg/day was not significantly different between patients with and without CMR (P=0.22). The duration of IM treatment was not different between patients with and without CMR (P=0.75). Finally, in multivariate analyses using a logistic regression model, the estimated odds ratio of achieving CMR for patients treated with standard versus reduced dose of IM was 22.1 (95% CI 1.5-330.5). There was no correlation of CMR and age, sex, body surface area, or the IM Cmin.

Conclusions/Methods
We believe that adherence to the standard dose of IM have a greater impact on achieving deep molecular response than adjusting its therapeutic dose based on Cmin in practical clinics.

Disclosures
No relevant conflicts of interest to declare.