Male Sex Is Associated with Lower Rituximab Trough Serum Levels and Evolves as a Significant Prognostic Factor in Elderly Patients with DLBCL Treated with R-CHOP: Results From 4 Prospective Trials of the German High-Grade Non-Hodgkin-Lymphoma Study Group (DSHNHL).

In the RICOVER-60 trial, where 1222 elderly (61-80 year-old) patients with untreated CD20-positive aggressive NHL were randomized to receive 6 or 8 cycles of CHOP-14 with or without 8 applications of rituximab, best results were obtained with 6xR-CHOP-14 plus 2 R in all subgroups of patients. To study the impact of sex on treatment outcome and pharmacokinetics, serum levels, patient characteristics and results were analyzed according to the patients' sex.

The results of 4 prospective DSHNHL trials (RICOVER-60: 1222 pts.; RICOVER-no-Rx: 164 pts; Pegfilgrastim trial: 103 pts., NHL-B2 trial: 241 pts.) in elderly patients with DLBCL who received CHOP-14 with or without rituximab were analyzed to compare the outcome of female and male patients. In addition, a pharmacokinetic study of rituximab was performed in 20 patients.

Female patients in the RICOVER-60 trial presented with a significantly higher LDH and lower performance status compared to the male counterparts (elevated LDH: 53.7% vs. 45.7 %, p=0.005; ECOG >1: 17.3% vs. 11.8%, p=0.007). Nevertheless, female patients had a higher 3-year PFS (67.5% vs. 61.0%; p=0.062) and OS (74.2% vs. 68.4% p=0.086). The differences in outcome between female and male patients were largely due to a greater improvement of outcome achieved by the addition of rituximab in females: while the difference in 3-year PFS between female and male patients was 5.2% (p=0.448) in patients receiving CHOP-14 only, this increased to 7.6% (p=0.053) when rituximab was added. In a multivariate analysis adjusting for the IPI-relevant risk factors LDH, ECOG performance status, advanced stage and >1 extranodal involvement, the relative risk for progression in male compared to female patients was not significantly elevated after CHOP-14 only (1.1 p=0.348), but was significantly higher when rituximab was added (1.6 ; p=0.004). The different outcome of male and female patients was confirmed in the Pegfilgrastim trial, where the relative risk for males was 0.7 without and 3.3 (p=0.047) with rituximab in EFS. In the RICOVER-no-Rx study (164 pts) where all pts. received R-CHOP-14, the relative risk for males was 1.6, whereas in the NHL-B2 trial (241 pts.) where no rituximab was given, it was 1.3 for EFS. A pharmacokinetic study of the rituximab trough serum levels revealed that male patients had trough serum levels that were about one third lower in males than in females.

Rituximab improves outcome both in elderly female and male patients treated with CHOP-14; however, the positive effect of rituximab was more pronounced in female patients and renders male sex a significant risk factor under rituximab. In 4 prospective DSHNHL trials, the relative risk of male patients was consistently higher in males than in females when rituximab was given compared to treatment results obtained with CHOP-14 without rituximab. Our pharmacokinetic studies suggest that the increased relative risk of males might be due to lower rituximab serum levels which are probably due to the lower intrinsic clearance in female patients. These results together with the low toxicity of rituximab justify a trial with higher rituximab doses, which has recently been initiated by the DSHNHL. Supported by Deutsche Krebshilfe.

Pfreundschuh:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Travel Grants; Celgene: Consultancy; Lilly: Consultancy. Murawski:Roche: Travel grants. Schubert:Roche: Honoraria. Schmitz:Roche: Honoraria, Research Funding, travel grants.