Bendamustine Plus Rituximab Versus CHOP Plus Rituximab in the First-Line Treatment of Patients with Indolent and Mantle Cell Lymphomas - First Interim Results of a Randomized Phase III Study of the StiL (Study Group Indolent Lymphomas, Germany).

Background: Promising results have been observed in our previous phase-II study evaluating the combination of Bendamustine plus Rituximab (B-R) in patients with relapsed/refractory indolent or mantle cell lymphomas. An overall response rate (ORR) of 90%, including a 60% rate of complete remissions (CR) was documented.

Objective: In October 2003 we initiated a multicenter randomized phase-III study to compare efficacy and safety of the combination B-R versus CHOP plus Rituximab (CHOP-R) as first-line therapy for follicular, indolent and mantle cell lymphomas.

Methods: Patients (pts) were randomized to receive Rituximab 375 mg/qm (day 1) plus either Bendamustine 90 mg/qm (days 1+2) every 28 days or the standard CHOP regimen every 21 days for a maximum of 6 cycles. The primary endpoint was event-free survival (EFS). A sample size of 474 pts were calculated to power the study sufficiently to demonstrate a non-inferior EFS associated with B-R treatment, as defined by a difference in EFS between the two regimes of less than 10% after 3 years. An event was defined by a response less than a partial response, disease progression, relapse, or death from any cause.

Results: So far 439 patients have been randomized. 273 patients are evaluable for response for this first interim analysis (B-R: n=139; CHOP-R: n=134). Median patient age is 63 years. Histologies are equally distributed between arms: follicular 52%, mantle cell 20%, and other indolent lymphomas 28% in both treatment groups, each. The ORR for pts treated with B-R was similar to that associated with CHOP-R (94% vs 93%, respectively). CR was also similar at 51% for B-R compared to 40% for CHOP-R. The median observation time for both groups is 17 months. Thus far, 15 deaths have been observed (B-R: 7; CHOP-R: 8). Progressive or relapsed disease has been documented during the follow-up period: 27 in pts treated with B-R and 32 in the CHOP-R group. The B-R regimen appears to have a better toxicity profile, as evidenced by a lower rate of total alopecia (40% CHOP-R vs. 0% with B-R) and a lower number of infectious complications (41 in CHOP-R pts vs. 19 in the B-R group). Correlating, the CHOP-R regimen was more hematotoxic: WHO grade 3/4 leukocytopenia was reported in 41% CHOP-R treated pts compared with 12% in pts treated with B-R.

Conclusions: In this first interim analysis the combination of Bendamustine plus Rituximab appears to be non-inferior to the standard CHOP-R while showing a better tolerability profile. The study will be closed in December 2007 according to the planned patient recruitement schedule. Updated results will be presented at this time.