Mira Tout (1), Anne-Laure Gagez (2), Stéphane Leprêtre (3), Nicolas Azzopardi (1), Caroline Dartigeas (4), Béatrice Mahé (5), Emmanuelle Ferrand (6), Hervé Maisonneuve (7), Thérèse Aurran (8), Gilles Paintaud (1,9), Guillaume Cartron (2,10), David Ternant (1,9)
(1) CNRS UMR 7292, Université François Rabelais, Tours, France, (2) CNRS UMR 5235, Université de Montpellier, Montpellier, France, (3) Hematology, Henri Becquerel Center, Rouen, France, (4) Hématologie et thérapie cellulaire, CHRU Tours, Tours, France, (5) Hematology, CHRU Nantes, Nantes, France, (6) Hematology, CHRU Dijon, Dijon, France, (7) Hematology, CHD La Roche sur Yon, La Roche Sur Yon, France, (8) Hematology, Institut Paoli Calmette, Marseille, France, (9) Laboratoire de Pharmacologie-Toxicologie, CHRU Tours, Tours, France, (10) Hematology, CHRU Montpellier, Montpellier France
Objectives: The anti-CD20 monoclonal antibody rituximab is indicated as first-line treatment in chronic lymphocytic leukemia (CLL). Rituximab exhibits time-dependent clearance in CLL [1], possibly because of treatment-related decrease in B-cell burden over time. However, the influence of CD20 antigenic mass on rituximab pharmacokinetics (PK) has never been investigated in CLL. Our study aimed to quantify the effect of both antigenic mass and FcγRIIIA (FCGR3A) genetic polymorphism on rituximab PK in CLL patients.
Methods: Patients included in the CLL 2010 FMP trial were randomly assigned to receive 6 FCR (fludarabine, cyclophosphamide, rituximab) cycles every 28 days, with rituximab IV doses of 375 mg/m2 in cycle 1 and 500 mg/m2 in cycles 2-6 (standard FCR) or a prephase of intensified rituximab course (500 mg on day 0, and 2000 mg on days 1, 8, and 15) followed by 6 FCR cycles every 28 days with 500 mg/m2 rituximab infusions (dense FCR). Population modeling was applied using Monolix® 4.3.3, where PK was described by a two-compartment model linked to latent B-cell growth. Baseline total burden of CD20 in the circulation (CD20cir) and in the lymph nodes (CD20LN), as well as FCGR3A-V158F polymorphism were tested as covariates on the PK parameters.
Results: A total of 118 patients (55 standard FCR, 63 dense FCR) were included in the analysis. Our model adequately described rituximab serum concentrations, and allowed the quantification of both rituximab endogenous clearance (CL) and target-mediated elimination (kdeg). In the final model, kdeg increased significantly with CD20cir (p = 8.1×10-5), and was 13-fold greater between extreme CD20cir values ranging from 0.12 x1014 to 402.4 x1014. Patients with the FCGR3A-V/V genotype had a 4-fold higher kdeg than F carriers (V/F and F/F) (p = 8.6×10-5).
Conclusions: This is the first study showing that B-cell burden and FCGR3A genotype influence rituximab elimination. The increase in target-mediated elimination with circulating CD20 antigen suggests that patients with high CD20 antigenic burden may benefit from an increase in rituximab doses.
References:
[1] Li J. et al. Population pharmacokinetics of rituximab in patients with chronic lymphocytic leukemia. J Clin Pharmacol (2012) 52, 1918–1926
Reference: PAGE 25 () Abstr 5965 [www.page-meeting.org/?abstract=5965]
Poster: Drug/Disease modeling - Oncology