Model-based optimization of rituximab dosing regimen in follicular non-Hogdkin lymphoma
David Ternant (1,2), Emilie Hénin (1), Guillaume Cartron (3), Michel Tod (1), Gilles Paintaud (1), Pascal Girard (1)
(1) Tours University Hospital, Tours, France. (2) Lyon-1 university, Oullins, France. (3) Lapeyronie University Hospital, Montpellier, France.
Objectives: Rituximab has dramatically improved the survival of patients with non-Hodgkin lymphomas (NHL) but currently used dosing regimen should be optimised. However, the concentration-effect relationship of rituximab has never been described by pharmacokinetic-pharmacodynamic (PK-PD) modeling, precluding the use of simulation to test new dosing regimens. The aims of this study were to:
- develop a PK-PD simulation model of rituximab in follicular NHL (FL);
- quantify the benefit of new dosing strategies of rituximab in FL patients for rituximab monotherapy and R-CHOP treatments;
- design clinical trials where the optimal dosage for rituximab would be investigated.
Methods: A model describing the relationship between rituximab concentrations and progression-free survival (PFS) was developed using data extracted from the pivotal study, which evaluated 151 relapsed/resistant FL patients. The influence of FCGR3A genetic polymorphism onthe efficacy of rituximab in FL, which was quantified using data from 87 relapsed/resistant FL patients [1,2]. The predictive performance of the model was analysed using two independent data sets: a study which evaluated rituximab combined with chemotherapy (R-CHOP) in 334 relapsed/resistant FL patients [3] and a study which evaluated rituximab monotherapy in 47 asymptomatic FL patients with known FCGR3A genotype [4]. Several dosage strategies, including rituximab maintenance, were tested for rituximab monotherapy and R-CHOP. The benefit of a rituximab dose adjustment according to FCGR3A was investigated.
Results: For R-CHOP, observed and model-predicted PFS at 24 months were 0.50 and 0.48, respectively for the observation arm, and 0.62 and 0.59, respectively for the rituximab maintenance arm [3]; for rituximab monotherapy, observed and predicted PFS at 24 months were 0.67 and 0.63, respectively for FCGR3A-V/V patients, and 0.41 and 0.36, respectively for FCGR3A-F carriers [4]. The optimal dosage was 1500 mg/m2 in cure period and 2250 mg/m2 for maintenance. Because of a high difference in PFS between VV patients and F carriers, a dosage adjustement for rituximab according to the FCGR3A genotype is not feasible.
Conclusions: Our model provides a satisfactory prediction of PFS at 24 months. The results support the benefit of a dose increase of rituximab in FL, which should be confirmed in controlled clinical trials. In these trials, 230 to 470 patients should be included.
References:
[1] Berinstein NL et al. Ann Oncol, 1998
[2] McLaughlin P et al. J Clin Oncol, 1998
[3] van Oers et al. Blood, 2006
[4] Cartron et al. Blood, 2002
