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

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.

References

  1. 1.

    Dada R. Diagnosis and management of follicular lymphoma: a comprehensive review. Eur J Haematol. 2019;103:152–63.

    Article  Google Scholar 

  2. 2.

    Martin AR, Weisenburger DD, Chan WC, Ruby EI, Anderson JR, Vose JM, et al. Prognostic value of cellular proliferation and histologic grade in follicular lymphoma. Blood. 1995;85:3671–8.

    CAS  Article  Google Scholar 

  3. 3.

    Relander T, Johnson NA, Farinha P, Connors JM, Sehn LH, Gascoyne RD. Prognostic factors in follicular lymphoma. J Clin Oncol. 2010;28:2902–13.

    CAS  Article  Google Scholar 

  4. 4.

    Jaffe ES. The 2008 WHO classification of lymphomas: implications for clinical practice and translational research. Eur. J. Haematol. 2008;80:523–31.

    Article  Google Scholar 

  5. 5.

    Katzenberger T, Ott G, Klein T, Kalla J, Muller-Hermelink HK, Ott MM. Cytogenetic alterations affecting BCL6 are predominantly found in follicular lymphomas grade 3B with a diffuse large B-cell component. Am J Pathol. 2004;165:481–90.

    CAS  Article  Google Scholar 

  6. 6.

    Horn H, Schmelter C, Leich E, Salaverria I, Katzenberger T, Ott MM, et al. Follicular lymphoma grade 3B is a distinct neoplasm according to cytogenetic and immunohistochemical profiles. Haematologica. 2011;96:1327–34.

    Article  Google Scholar 

  7. 7.

    Flinn IW, van der Jagt R, Kahl BS, Wood P, Hawkins TE, Macdonald D, et al. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014;123:2944–52.

    CAS  Article  Google Scholar 

  8. 8.

    Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grunhagen U, Losem C, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013;381:1203–10.

    CAS  Article  Google Scholar 

  9. 9.

    Huttmann A, Rekowski J, Muller SP, Hertenstein B, Franzius C, Mesters R, et al. Six versus eight doses of rituximab in patients with aggressive B cell lymphoma receiving six cycles of CHOP: results from the “Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas” (PETAL) trial. Ann Hematol. 2019;98:897–907.

    Article  Google Scholar 

  10. 10.

    Wahlin BE, Sundstrom C, Sander B, Christensson B, Jeppsson-Ahlberg A, Hjalmarsson E, et al. Higher world health organization grades of follicular lymphoma correlate with better outcome in two Nordic Lymphoma Group trials of rituximab without chemotherapy. Leuk Lymphoma. 2014;55:288–95.

    CAS  Article  Google Scholar 

  11. 11.

    Golay J, Semenzato G, Rambaldi A, Foa R, Gaidano G, Gamba E, et al. Lessons for the clinic from rituximab pharmacokinetics and pharmacodynamics. MAbs. 2013;5:826–37.

    Article  Google Scholar 

  12. 12.

    Berinstein NL, Grillo-Lopez AJ, White CA, Bence-Bruckler I, Maloney D, Czuczman M, et al. Association of serum Rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin’s lymphoma. Ann Oncol. 1998;9:995–1001.

    CAS  Article  Google Scholar 

  13. 13.

    Jager U, Fridrik M, Zeitlinger M, Heintel D, Hopfinger G, Burgstaller S, et al. Rituximab serum concentrations during immuno-chemotherapy of follicular lymphoma correlate with patient gender, bone marrow infiltration and clinical response. Haematologica. 2012;97:1431–8.

    Article  Google Scholar 

  14. 14.

    Tout M, Casasnovas O, Meignan M, Lamy T, Morschhauser F, Salles G, et al. Rituximab exposure is influenced by baseline metabolic tumor volume and predicts outcome of DLBCL patients: a Lymphoma Study Association report. Blood. 2017;129:2616–23.

    CAS  Article  Google Scholar 

  15. 15.

    Tran L, Baars JW, Aarden L, Beijnen JH, Huitema AD. Pharmacokinetics of rituximab in patients with CD20 positive B-cell malignancies. Hum Antib. 2010;19:7–13.

    CAS  Article  Google Scholar 

  16. 16.

    Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25:579–86.

    Article  Google Scholar 

  17. 17.

    Munekage M, Ichikawa K, Kitagawa H, Ishihara K, Uehara H, Watanabe J, et al. Population pharmacokinetic analysis of daikenchuto, a traditional Japanese medicine (Kampo) in Japanese and US health volunteers. Drug Metab Dispos. 2013;41:1256–63.

    CAS  Article  Google Scholar 

  18. 18.

    Song L, He CY, Yin NG, Liu F, Jia YT, Liu Y. A population pharmacokinetic model for individualised dosage regimens of vancomycin in Chinese neonates and young infants. Oncotarget. 2017;8:105211–21.

    Article  Google Scholar 

  19. 19.

    Candelaria M, Gonzalez D, Fernandez Gomez FJ, Paravisini A, Del Campo Garcia A, Perez L, et al. Comparative assessment of pharmacokinetics, and pharmacodynamics between RTXM83, a rituximab biosimilar, and rituximab in diffuse large B-cell lymphoma patients: a population PK model approach. Cancer Chemother Pharmacol. 2018;81:515–27.

    CAS  Article  Google Scholar 

  20. 20.

    Brendel K, Comets E, Laffont C, Laveille C, Mentre F. Metrics for external model evaluation with an application to the population pharmacokinetics of gliclazide. Pharmacol Res. 2006;23:2036–49.

    CAS  Article  Google Scholar 

  21. 21.

    Koletsi D, Pandis N. Conditional logistic regression. Am J Orthod Dentofac Orthop. 2017;151:1191–2.

    Article  Google Scholar 

  22. 22.

    Tobinai K, Igarashi T, Itoh K, Kobayashi Y, Taniwaki M, Ogura M, et al. Japanese multicenter phase II and pharmacokinetic study of rituximab in relapsed or refractory patients with aggressive B-cell lymphoma. Ann Oncol. 2004;15:821–30.

    CAS  Article  Google Scholar 

  23. 23.

    Li J, Zhi J, Wenger M, Valente N, Dmoszynska A, Robak T, et al. Population pharmacokinetics of rituximab in patients with chronic lymphocytic leukemia. J Clin Pharmacol. 2012;52:1918–26.

    CAS  Article  Google Scholar 

  24. 24.

    Bologna L, Gotti E, Da Roit F, Intermesoli T, Rambaldi A, Introna M, et al. Ofatumumab is more efficient than rituximab in lysing B chronic lymphocytic leukemia cells in whole blood and in combination with chemotherapy. J Immunol. 2013;190:231–9.

    CAS  Article  Google Scholar 

  25. 25.

    Bologna L, Gotti E, Manganini M, Rambaldi A, Intermesoli T, Introna M, et al. Mechanism of action of type II, glycoengineered, anti-CD20 monoclonal antibody GA101 in B-chronic lymphocytic leukemia whole blood assays in comparison with rituximab and alemtuzumab. J Immunol. 2011;186:3762–9.

    CAS  Article  Google Scholar 

  26. 26.

    Cheah CY, Chihara D, Ahmed M, Davis RE, Nastoupil LJ, Phansalkar K, et al. Factors influencing outcome in advanced stage, low-grade follicular lymphoma treated at MD Anderson Cancer Center in the rituximab era. Ann Oncol. 2016;27:895–901.

    CAS  Article  Google Scholar 

  27. 27.

    Dirks NL, Meibohm B. Population pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49:633–59.

    CAS  Article  Google Scholar 

  28. 28.

    O’Brien SM, Kantarjian H, Thomas DA, Giles FJ, Freireich EJ, Cortes J, et al. Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol. 2001;19:2165–70.

    Article  Google Scholar 

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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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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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The authors declare no competing interests.

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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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