Rituximab Maintenance Therapy in Diffuse Large B-Cell Lymphoma in a Multicenter Prospective Randomised Phase II Study,

Clinical and pharmacokinetic data suggest that the effect of rituximab could be improved by prolonged exposure to the drug. To test for this hypothesis we performed a prospective randomized trial of rituximab maintenance therapy versus observation in patients (pts) with CD20+ B-cell Non-Hodgkin-Lymphoma.

After completion of standard treatment, pts with CD20+ B-cell lymphoma were randomized to either observation or maintenance therapy with rituximab (375 mg/m²) administered every 3 months for 2 years. Both pts after first line therapy and pts after relapse treatment were included in the study. Pts with aggressive lymphoma were enrolled if they had achieved a complete response (CR) after initial treatment. Pts with aggressive lymphoma with residual tumor mass underwent positron emission tomography (PET) and qualified for randomization if this examination showed no signs of tumor activity. Pts with indolent lymphoma were eligible for the study if at least a partial response (PR) was achieved. Primary endpoint of the study was progression free survival (PFS), secondary endpoints were time to progression (TTP), overall survival (OS) and response to treatment. Differences between PFS and OS were analysed using the logrank test and the proportional hazard model of Cox. TTP was analyzed using a competing risk model with death as competing event.

326 pts were included in the trial. Complete data sets of 294 pts were available for analysis on an intention-to-treat basis. We here report on the subset of 145 patients with diffuse large B cell lymphoma (DLBCL). 73 pts were randomized to the treatment group and 72 pts to the observation group. 77 (53%) pts were male and 68 (47%) female, with no significant gender differences between treatment and observation groups (p=0.74, Fisher's exact test). The median age was 58.6 years. 130 pts had received one previous therapy, 12 pts two, and two pts three previous lines of therapy. At study entry, 116 pts were in CR, 15 pts in unconfirmed CR and 14 pts in PR. Age, sex, number of previous therapies and remission status were well balanced between the treatment and the observation group (p≥0.48). After a median follow up of 30 months, PFS was excellent with 91% in the treatment group and 86% in the observation group (p=0.38). There was no difference in OS between the two groups. In a multivariate Cox model, OS and PFS were not different between men and women. The estimated hazard ratio of female vs. male was HR(F:M)=0.90 (p=0.90) for OS and HR(F:M)=0.49 (p=0.20) for PFS. However, interestingly there was a significant interaction (p=0.02) between therapy group and gender in regards to PFS with significant more events in men than in women in the observation group (HR(F:M) = 0.12; 95% confidence interval (CI) =(0.02, 1.00)), and no differences between men and women in the treatment group (HR(F:M) = 2.71; 95%CI=(0.50,14.9)).

In this study, rituximab maintenance therapy did not improve PFS or OS in patients with DLBCL in general. Contrary to the results of the CORAL trial, there was no significant difference in PFS between women and men in the treatment group. However, in male patients a significant better PFS was found in the treatment group compared to the observation group (HR=0.21; p=0.03), suggesting a benefit of rituximab maintenance therapy for male patients with DLBCL.

No relevant conflicts of interest to declare.