Optimal Rituximab Dose in Lymphoma

Since its approval in the late 1990s, rituximab (R, Rituxan, MabThera) has been the backbone of chemo-immunotherapy in diffuse large B cell lymphoma (DLBCL). The addition of R has consistently shown improvement in progression-free survival and overall survival compared to CHOP (cyclophosphamide, vincristine, Doxorubicin and Prednisone) without R. Now, there are ongoing efforts to improve response rate and survival outcomes by adding biologic agent (X) to the R-CHOP backbone.

Interestingly, the R in R-CHOP was scheduled based on convenience and not on pharmacokinetics. Pfreundschuh and colleagues from Germany have shown that in elderly women rituximab clearance is lower, leading to increased serum rituximab levels and prolonged exposure of R compared with elderly men.¹ Because of the increased clearance of rituximab in elderly men, they had less benefit from rituximab for treatment of DLBCL. Interestingly, young men had similar clearance compared with young women.

Pfreundschuh and colleagues recently published a phase II clinical trial with a different R schedule in elderly patients with DLBCL (Pfreundschuh et al, JCO. November 17, 2014). In this study, like in the RICOVER-60 trial, elderly (>60 years old) patients with DLBCL were enrolled. These patients were treated with CHOP chemotherapy every 2 weeks (CHOP-14 on days 1, 15, 29, 43, 57, and 71) while rituximab was given at 375 mg/m² on days -4, 0, 10, 29, 57, 99, 155, and 239. Compared with RICOVER-60, elderly male patients with poor IPI scores did better with this regimen of extended R. In this subgroup, early relapses were less compared with DENSE-R-CHOP-14, probably because of day 155 and 239 of R.

The OPTIMAL >60 study is currently evaluating two different dose schedules of R (DENSE-R: 12 R applications, including 4 in the first 3 weeks vs SMARTE-R: 8 two weekly application of R including two late doses on days 155 and 239) in a prospective trial.

We have learned from our bone marrow transplant colleagues that pharmacokinetic based approaches are better for individual patients for optimal dosage and less toxicity. As an example, Busulfan is currently dosed in a majority of transplant centers based on individual pharmacokinetics in each patient, which is recognized after the first dose of Busulfan. This way we can not only avoid toxic side effects of the chemotherapy but also get the maximum antitumor activity.

Personalized medicine that broadly defines tumor characteristics is advancing rapidly. Based on these characteristics, a particular targeted therapy can be selected. Based on the evidence from rituximab clearance studies, individual dosing might be equally important and should be part of personalized medicine.

1. Pfreundschuh M, Poeschel V, Zeynalova S et al. Optimization of Rituximab for the Treatment of Diffuse Large B-Cell Lymphoma (II): Extended Rituximab Exposure Time in the SMARTE-R-CHOP-14 Trial of the German High-Grade Non-Hodgkin Lymphoma Study Group. J Clin Oncol, 32(36), 4127-4133 (2014).