Bendamustine and Rituximab Combination In Untreated Indolent Non Follicular B-Cell Non-Hodgkin's Lymphomas. A Phase II Study From The Fondazione Italiana Linfomi (INFL09)

Indolent non follicular B-Cell Lymphomas (INFL) are a heterogeneous group of lymphomas and include small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphomas (LPL), and marginal zone lymphomas (MZL). Combination chemo-immunotherapy regimens are used in the majority of patients (pts) with advanced stage INFL who require treatment. Bendamustine in combination with anti-CD20 monoclonal antibody therapy has been shown to be highly active and well tolerated. The purpose of this phase 2, multicenter study was to determine the activity and safety of bendamustine in combination with rituximab in first-line treatment of patients with INFL.

Untreated patients with SLL, nodal MZL and LPL who met predefined need-for-treatment criteria, had adequate hematologic function and stage II-IV disease, were eligible for study entry. Patients were scheduled to receive 6 cycles BR: bendamustine (90 mg/m2 on days 1 and 2 every 28 days) and 6 rituximab doses (375 mg/m2 on day 8 of cycle 1, and on day 1 of subsequent cycles) + 2 rituximab doses every 2 weeks. The primary endpoint of the study was the complete response rate (CRR) based on 2007 International Working Group criteria (Cheson 2007). The secondary endpoints were the rate of adverse events, the overall response rate (ORR), the progression free survival (PFS) and the overall survival (OS). Sample size was defined at 67 patients evaluable for response assuming a CR rate of 60%, a power of 80% and p value of 5%.

The study was conducted from February 2011 to march 2012. Seventy-two patients were enrolled, and 3 patients were excluded from the study due to violation of inclusion criteria (1 patient) and due to treatment interruption before completion of cycle one (2 patients). Based on local pathology report 17 patients had SLL, 20 had nodal MZL, and 32 had LPL. Median age was 65 years (45-75) and 65% were male. LDH value was increased in 17% of pts and β2-microglobulin in 67%. B-symptoms were present in 16% of pts, 91% percent had bone marrow involvement and 99% had stage III/IV disease. Fifty-nine out of the 69 patients received at least 6 cycles of bendamustine/rituximab (BR, 85,5%). Based on the intention to treat analysis and on local assessment of response, ORR was 84% including 40 patients in CR in (58%), and 18 in PR (26%); 1 patients had stable disease and 5 patients had lymphoma progression; in 5 patients response was not assessed due to adverse event or early withdrawal. Safety analysis was available for all 69 patients and for 472 cycles. Overall, the combination of BR was well-tolerated. The most common grade 3/4 adverse events were neutropenia (43% of pts), febrile neutropenia (3%), thrombocytopenia (9%), gastrointestinal disorders (3%), and skin reaction (3%). One patient died during treatment due to a severe infection after cycle 2. At time of current analysis after a median follow-up of 15.6 months (range 1 to 25 months), 2 disease progressions and 2 deaths (due to lymphoma) were observed. As a result 1 year PFS was 90% (CI95% 80-95%) and 1 year OS was 95% (CI95% 87-98%).

Based on this preliminary analysis of the INFL09 study, BR combination is active and well tolerated in patients with previously untreated INFL. The ORR of 85% and CRR of 58% compare favorably with previously reported response rates observed in patients with indolent lymphoma.

Federico:MedImmune: Research Funding.