Dose-Dense Rituximab Improves Outcome of Elderly Patients with Poor-Prognosis Diffuse Large B-Cell Lymphoma (DLBCL): Results of the DENSE-R-CHOP-14 Trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL).

Background: While 6 to 8 cycles of CHOP in combination with rituximab are widely accepted as standard regimen of care for aggressive lymphomas, the optimal dose and number of rituximab application have not been determined to date. In a previous pharmacokinetic study we had shown that the concomitant application of CHOP and rituximab does not achieve a plateau of rituximab trough levels until cycle 5 (Reiser, Blood 108, 778a, 2006). In order to achieve high rituximab levels early, we increased the number of rituximab applications.

Methods: 100 elderly patients with aggressive CD20⁺ B-cell lymphoma received 6 cycles of biweekly CHOP-14 combined with 12x rituximab (375 mg/m²) on days 0, 1, 4, 8, 15, 22, 29, 43, 57, 71, 85, and 99. Radiotherapy was planned to sites of initial bulk and/or extranodal involvement. The primary endpoint was event-free survival (EFS). 306 patients treated within the RICOVER-60 trial (Pfreundschuh et al., Blood 64a, 2006) with 6xCHOP-14 and 8 applications of rituximab served as control.

Results: 97/100 patients are evaluable for response. Dose-dense rituximab resulted in plateau trough serum levels of rituximab as early as day 1 of the first chemotherapy cycle and higher rituximab levels were maintained throughout the treatment compared to 8 bi-weekly applications. Because 3 therapy-associated deaths were observed among the first 20 patients treated, prophylaxis with levofloxacin, acyclovir and cotrimoxazol became mandatory for the following patients. Despite a less favorable study population DENSE-R-CHOP-14 resulted in a somewhat higher complete remission (83% vs. 78%) and lower progression under therapy rate (5% vs. 7%) rate, but event free and overall survival were not different compared to 8 biweekly applications of rituximab. However, a subgroup analysis of patients according to IPI risk group showed that DENSER-R-CHOP-14 resulted in a higher complete response rate of patients with poor-prognosis (IPI:3–5) disease (81% vs. 68%). This advantage translated into a better 1-year event-free survival rate (74% vs. 65%) of these patients.

Conclusion: In combination with 6 cycles of CHOP-14 densification of rituximab achieves higher rituximab serum levels and results in higher complete remission and event-free survival rates in elderly patients with poor-prognosis DLBCL. These observations from a phase-II trial must be confirmed in a randomized study.