Rituximab Maintenenance Therapy in CD20+ B-Cell Non-Hodgkin-Lymphoma – Final Results of 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 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 event free survival (EFS), secondary endpoints were relapse rate (RR), relapse free survival (RFS) and overall survival (OS). EFS and OS were analysed using an asymptotic logrank test, RFS using a competing risk model and RR using Fisher's exact test.

After recruitment of 171 pts the planned final analysis was performed on an intention to treat basis. Complete data sets of 163 pts were evaluable. 91 (62%) pts were male, median age was 58 years, 130 pts (80%) hat one previous therapy, 27 pts (17%) 2 previous therapies, 4 pts (2%) 3 previous therapies and 1 pt (1%) 4 previous therapies. At study entry, 120 pts (74%) were in CR, 2 pts (2%) in unconfirmed CR and 41 pts (25%) in PR. Histological subtypes included diffuse large cell lymphoma (67 pts), follicular lymphoma (35 pts), mantle cell lymphoma (18 pts), primary mediastinal lymphoma (16 pts), marginal zone lymphoma (7 pts), Burkitt's lymphoma (5 pts), and other lymphomas (15 pts). Age, sex, number of previous therapies, remission state and diagnoses were well balanced between the rituximab maintenance and the observation group (p>0.05). After a median follow up of 28 months, EFS (HR 0.50, 95% CI 0.23-1.09, p=0.037,) and RFS (HR 2.52, 95% CI 1.11-5.70 p=0.03) were superior for the maintenance group. In regards to diagnostic subgroups, EFS was in particular prolonged in pts with mantle cell lymphoma (p=0.055, one sided logrank test) and to a lesser extent in pts with follicular lymphoma (p=0.16) and diffuse large cell B cell lymphoma (p=0.18). Relapse occurred more often in the observation group than in the treatment group, however this effect was not significant (relapse rate observation group/treatment group = 2.31, 95% CI 0.86-6.75, p=0.08). There was no difference in OS between the two groups (p=0.74). Maintenance therapy was generally well tolerated: in 5 pts a WHO Grade 3 toxicity event occurred, which were arrhythmia, neuropathy, leucopenia (n=1 each) and infections (n=2). In one pt two WHO Grade 3 toxicities were observed (pain and infection).

Rituximab maintenance therapy is feasible, safe and well tolerated and improves EFS in patients with CD20+ B-cell lymphoma. In this analysis, the benefit of rituximab maintenance was particularly striking in patients with mantle cell lymphoma. This study has been continued with an amendment including additional pts with mantle cell and diffuse large cell lymphoma.

No relevant conflicts of interest to declare.