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

Acta Pharmacologica Sinica (2020)Cite this article

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.

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Fig. 1: The distributions of C1-trough in the matched-pair groups for CR vs. non-CR patients.
Fig. 2: The distribution of the rituximab trough concentration in the first cycle (C1-trough) for patients with different grades.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 81730103, 81473283, 81973398, 81573507); Higher Education Discipline Innovation Project (the 111 Project, No. B16047); the Natural Science Foundation of Guangdong Province (No. 2019A1515010742); and Wu Jie-ping Medical Foundation of Clinical Pharmacy (No. 320.6750.19090-14).

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Author notes

  1. These authors contributed equally: Shu Liu, He Huang, Rong-xin Chen

Affiliations

  1. Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China

    Shu Liu, Shao-xing Guan, Xia Zhu, Min Huang & Xue-ding Wang

  2. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China

    Shu Liu, He Huang, Zhao Wang, Xiao-jie Fang, Zhuo-jia Chen, Quan-guang Ren, Yu-yi Yao, Hong-bing Huang & Tong-yu Lin

  3. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510006, China

    Rong-xin Chen

  4. Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China

    Yan-ping Guan

  5. Medical Department, University of Hong Kong-Shen Zhen Hospital, Hong Kong, China

    Chen Peng

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  1. Shu Liu
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Contributions

TYL, XDW, MH, and SL designed the research, analyzed data, and wrote the manuscript; TYL, HH, CP, ZW, XJF, QGR, and YYY contributed study materials/patients and collected, analyzed, and interpreted data; SL, RXC, YPG, ZJC, SXG, and XZ performed experiments; SL, YPG, and RXC performed PK and statistical analyses; and RXC, HH, HBH, and MH reviewed the manuscript.

Corresponding authors

Correspondence to Xue-ding Wang or Tong-yu Lin.

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Liu, S., Huang, H., Chen, Rx. et al. 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. Acta Pharmacol Sin (2020). https://doi.org/10.1038/s41401-020-0479-2

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Keywords

  • follicular lymphoma
  • rituximab
  • R-CHOP
  • tumor grade
  • pharmacokinetics
  • trough concentration

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