Article

Low initial trough concentration of rituximab is associated with unsatisfactory response of first-line R-CHOP treatment in patients with follicular lymphoma with grade 1/2

Authors: Shu Liu1,2, He Huang2, Rong-xin Chen3, Zhao Wang2, Yan-ping Guan4, Chen Peng5, Xiao-jie Fang2, Zhuo-jia Chen2, Shao-xing Guan1, Xia Zhu1, Quan-guang Ren2, Yu-yi Yao2, Hong-bing Huang2, Min Huang1, Xue-ding Wang1, Tong-yu Lin2
1 Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
2 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
3 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510006, China
4 Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
5 Medical Department, University of Hong Kong-Shen Zhen Hospital, Hong Kong, China
Correspondence to: Xue-ding Wang: wangxd@mail.sysu.edu.cn, Tong-yu Lin: tongyu_lin@163.com,
DOI: 10.1038/s41401-020-0479-2
Received: 23 April 2020
Accepted: 7 July 2020
Advance online: 31 July 2020

Abstract

For follicular lymphoma (FL) with grade 1/2, the complete response (CR) rate of the first-line R-CHOP treatment was significantly low. In this study, we assessed the rationality of the administration of rituximab for FL patients with grade 1/2 based on concentration–response relationship analyses. Thus, we conducted a prospective pharmacokinetic (PK) study in 68 FL patients with grades 1–3 treated with R-CHOP at 21-day intervals. Plasma rituximab concentrations were quantified using ELISA and the population PK modeling was established with Phoenix® NLMETM. The first cycle trough concentration (C1-trough) of rituximab was a significant independent risk factor for achieving CR in matched-pair logistic regression analysis, rather than the concentrations in later cycles; the recommendatory minimum optimal C1-trough was 13.60 μg/mL. Patients with grade 1/2 had significantly lower C1-trough compared with grade 3 (12.21 μg/mL vs. 23.45 μg/mL, P < 0.001), only 30% patients with grade 1/2 could reach 13.60 μg/mL, compared with 91.67% in patients with grade 3, which was in accord with its unsatisfactory CR rates (43.33% vs. 76.32%). The stage indicating the tumor burden (the target) was a crucial influence factor for C1-trough, accounting for 40.70% of its variability, 70% patients with grade 1/2 were stage IV in this study, since the systemic therapy only started at the disseminated disease stage. The initial dose of 1800 mg was recommended by Monte Carlo simulation for patients with grade 1/2. In summary, low C1-trough accounted for low-grade FL’s unsatisfactory CR rate, designing the first dosage of rituximab should be a very important component of individualized therapy for FL.
Keywords: follicular lymphoma; rituximab; R-CHOP; tumor grade; pharmacokinetics; trough concentration

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