ORLANDO, Fla.—Bendamustine plus rituximab (B-R) demonstrated a superior progression-free survival benefit in patients with relapsed follicular, indolent, or mantle cell lymphomas when compared with fludarabine plus rituximab (F-R), final results of a randomized phase 3 study have confirmed.
Progression-free survival was 30.4 months in the B-R group vs 11.2 months in the F-R arm (hazard ratio [HR] 0.50; 95% CI, 0.34-0.68; P<0.0001). Overall response rate was also significantly higher with B-R than with F-R, 82% vs 49%, respectively (P<0.0001), as was the complete response rate, 38.5% vs 16.2% (P=0.0004), reported Mathias J. Rummel, MD, PhD, of Justus-Liebig-Universität Giessen, Giessen, Germany, and colleagues on behalf of StiL (Study Group Indolent Lymphomas, Germany) during the 52nd American Society of Hematology Annual Meeting and Exposition here. Median remission duration did not differ between the two arms, 36.5 months in the B-R arm and 27.5 months in the F-R arm (HR 0.74; 95% CI, 0.45-1.19; P=0.2074). Overall survival was similar between the two arms, with 42 deaths documented in the B-R arm and 46 deaths in the F-R arm. Median overall survival was 63.6 months in the B-R arm and 49.2 months in the F-R arm (HR 0.76; 95% CI, 0.5-1.15; P=0.1932).
The multicenter study, initiated in 2003, randomized 219 patients with relapsed follicular, indolent, or mantle cell lymphoma to rituximab 375 mg/m² day 1 plus either bendamustine 90 mg/m² days 1 and 2 or fludarabine 25 mg/m² (days 1–3) every 28 days for a maximum of 6 cycles. Use of granulocyte colony-stimulating factor was permitted only in cases of severe granulocytopenia. In 2006, following regulatory approval, the protocol was amended to allow rituximab maintenance therapy (rituximab 375 mg/m2 every 3 months for up to 2 years) in both arms. Primary end point was progression-free survival after 1 year.
A total of 208 patients were evaluable for the final analyses, 109 in the B-R arm and 99 in the F-R arm. Baseline characteristics were similar between the treatment arms, including age, stage, LDH, International Prognostic Index (IPI), follicular IPI, bone marrow infiltration, and extranodal involvement. The majority of patients had stage 4 (72% in the bendamustine group and 61% in the fludarabine group). Median age of the patients was 68 years (range, 38-87 years), who had received a median of one prior therapy (range, 1-7). Histological subtypes were distributed equally between the two arms: follicular 45.9% (50/109) in the B-R group and 47.5% (47/99) in the F-R group; mantle cell lymphoma 20.2% (22/109) and 21.2% (21/99); Waldenstrom macroglobulinemia 11.9% (13/109) and 10.1% (11/109); marginal zone 9.2% (10/109) and 7.1% (7/99); and lymphocytic 7.4% (8/109) and 8.1% (8/99).
A median of 6 cycles of chemotherapy was given; 75.2% of patients in the bendamustine group received 6 cycles vs 53.4% of patients in the fludarabine group. As of June 2010, median observation time was 33 months. No significant differences were observed between groups in the rates of alopecia, stomatitis, erythema, allergic reactions, peripheral neuropathy, or infectious episodes. In the B-R group, 14% of patients had grade 3/4 neutropenia vs 14.5% in the F-R group; grade 3/4 leukocytopenia was 13.6% in the bendamustine group and 14.2% in the fludarabine group. Serious adverse events were reported in 17.4% of patients receiving B-R and 22.2% of patients in the F-R group.
When the effect of rituximab maintenance therapy was examined in an unplanned subgroup analysis in patients who had received this treatment (n=40; 23 in the B-R and 17 in the F-R group), overall survival (hazard ratio 0.29; 95% CI, 0.22-0.82; P=0.0104) as well as progression-free survival (hazard ratio 0.37; 95% CI, 0.3-0.74; P=0.0013) was found to be significantly prolonged when compared with those who did not receive maintenance therapy (n=119). Dr. Rummel concludes that “B-R was more effective than F-R in this setting of relapsed indolent lymphoma due to higher response rates and a longer progression-free survival. Additionally, rituximab maintenance [after B-R or F-R] appeared to have additional benefit, but limitations include a potential selection bias, a small sample size, and an unplanned nature of that comparison.”