Serum α1-Acid Glycoprotein Level Associate with Imatinib Trough Plasma Concentration and Clinical Outcome in CML Patients Treated with Imatinib: Blood Level Testing of Imatinib in Nagoya (BINGO) Study.
Authors: Ishikawa Yuichi , Kiyoi Hitoshi , Watanabe Keisuke , Nakano Yasuyuki , Kitamura Kunio , Kohno Akio , Yokozawa Toshiya , Sugiura Isamu , Hanamura Akitoshi , Iida Hiroatsu , Yamamoto Kazuhito , Suzuki Ritsuro , Miyamura Koichi , Emi Nobuhiko , Ohnishi Kazunori , Naoe Tomoki 
Published: October 2019

Abstract
Abstract 4266

Introduction
Imatinib, which is the most successful molecularly targeting drug, is the first-line agent for the treatment of chronic myeloid leukemia patients (CML) in chronic phase (CP). However, some patients show poor response against imatinib therapy, resulting in the progression to blastic phase. To date, several reports showed that imatinib trough plasma concentration (Cmin) was associated with the clinical response in CML patients, while it remains unclear whether Cmin reflects the actual inhibitory effect on the BCR-ABL kinase activity. In human plasma, imatinib binds to several plasma proteins, such as albumin (ALB) and alpha1-acid glycoprotein (AGP), and the protein-binding-imatinib lacks the kinase inhibitory activity. Especially, AGP is a major imatinib-binding protein, and the high plasma AGP concentration reportedly reduces the clinical efficacy of imatinib. These results indicate that the free-imatinib concentration is a more reliable surrogate marker for predicting the clinical efficacy than the total imatinib concentration. However, since routine measurements of the free-imatinib concentration is difficult, the inhibitory activity of the patient's plasma (PIA) against the BCR-ABL kinase is proposed to be a direct marker reflecting the actual inhibitory effects of the free-imatinib. In this study, we analyzed the association between Cmin of total imatinib and the clinical response in CML-CP patients in considering the AGP concentration. Furthermore, we evaluate the usefulness of PIA for predicting the clinical response in the CML patients treated with imatinib.

Methods
We measured Cmin of the total imatinib and AGP and ALB concentrations at the different two points in CML-CP patients who were treated with imatinib alone. The PIA was quantified by determining the de-phosphorylation levels of BCR-ABL and STAT5 in BCR-ABL-expressing Ba/F3 cells after the treatment with patients' plasma. We evaluated the association of these parameters with clinical response. Informed consent was obtained from all patients to use their samples for this study. This study was approved by the ethical committee of Nagoya university school of medicine.

Results
The study population included 65 CML-CP patients. The mean Cmin of imatinib was 1070 ± 362 ng/ml. Clinical response was evaluated by the achievement of the complete cytogenetic response (CCR) and major molecular response (MMR) at 12 months after the start of imatinib therapy. The CCR and MMR were achieved in 63 (96.9%) and 40 (61.5%) patients, respectively. The mean Cmin of the patients who achieved MMR was significantly higher than that of those who did not (1167 ± 386 ng/ml vs. 913 ± 257ng/ml, P=0.012). The differences of Cmin between the two different points (median interval 28 ± 20 days) in the same patient were not so little (median 123 ± 198 ng/ml, range 12 to 923 ng/ml), but were not associated with clinical outcomes. The PIA was statistically correlated with the Cmin (P=0.018). Although serum AGP level was within normal range (72.8 ± 13.9 mg/dl, range 44 to 106 mg/dl) in most patients, it was notable that the serum AGP level correlated with Cmin of imatinib and clinical outcomes. The Cmin of patients with high AGP level was significantly higher than that of low AGP level (1237 ± 379ng/ml vs. 907 ± 260ng/ml, P=0.0003) and the MMR rate was significantly higher in patients with high AGP level (78%) than in those with low AGP level (45%, P=0.007).

Conclusions
We demonstrate that the Cmin of imatinib predicts clinical response and reflects the actual kinase inhibitory effects in CML patients treated with imatinib. However, the Cmin is not necessarily stable during the treatment in a part of patients, suggesting that it is recommended to examine Cmin at more than two different points for evaluating its suitability. The serum AGP and ALB levels did not affect the relationship between Cmin and PIA. However, since the serum AGP level was correlated with Cmin and clinical response, the AGP level might influence the kinase inhibitory activity in the patients whose Cmin of imatinib were low.

Disclosures:
Kiyoi: Novartis Pharma : Research Funding; Kyowa Hakko Kirin Co., Ltd. : Consultancy. Naoe:Kyowa Hakko Kirin Co., Ltd. : Research Funding; Chugai Pharmaceutical Co.,Ltd.: Research Funding; Wyeth K.K.: Research Funding.