Results of a Phase II Study with Bendamustine and Ofatumumab in Untreated Indolent B-Cell Non-Hodgkin's Lymphoma

Combination chemo-immunotherapy regimens are used in the majority of patients with advanced stage indolent lymphoma who require treatment. Despite high overall response rates following frontline therapy, nearly all patients relapse and many die of their disease. Bendamustine in combination with anti-CD20 monoclonal antibody therapy has been shown to be highly active and well tolerated. Ofatumumab is a fully humanized (IgG1) monoclonal antibody that binds specifically to a unique epitope on CD20, and is active in indolent B-cell non-Hodgkin's lymphoma (NHL). The efficacy and safety of both agents in combination has not been described. The purpose of this phase 2, multicenter study was to determine the efficacy and safety of bendamustine in combination with ofatumumab in first-line treatment of patients with indolent B-cell NHL.

Untreated patients with follicular lymphoma (FL) (grade 1–3a), marginal zone lymphoma (MZL), or lymphoplasmacytic lymphoma (LPL) who met predefined need-for-treatment criteria and had adequate hematologic function, ≥ stage 2 disease, and measurable disease (> 1.5cm) were eligible for study entry. Patients were scheduled to receive 6–8 28 day cycles of bendamustine (90 mg/m² on days 1 and 2) and ofatumumab (300 mg on day 1 of cycle 1, 1000 mg on day 8 of cycle 1, and 1000 mg on day 1 of subsequent cycles). The primary objective of the study was to determine the overall response rate (ORR) based on 2007 International Working Group criteria. The secondary objectives were safety and complete response (CR) rate following treatment.

Fifty patients were enrolled and 49 received treatment between May and December 2010. Forty-five patients were eligible for efficacy analysis (4 pts withdrew prior to first post-baseline response assessment). Thirty-six patients had FL; 13 had MZL or LPL. Fifty-five percent had bone marrow involvement, and 94% had stage III/IV disease. In general, the combination of bendamustine and ofatumumab was well-tolerated. Forty-one of the 49 patients received at least 6 cycles of bendamustine/ofatumumab (4 received 7–8 cycles; median = 6). Seven patients withdrew from the study due to adverse events. Ongoing safety analysis showed the most commonly observed treatment-emergent adverse events (≥25% patients) were constipation (35%), diarrhea (27%), nausea (61%), fatigue (51%), and infusion related reaction (47%). Nausea and fatigue were more often attributed to bendamustine. Infusion-related reaction was more often attributed to ofatumumab. The most common (≥ 3 patients) grade 3/4 adverse events were neutropenia and fatigue. Serious adverse events (SAEs) occurred in 13 (27%) patients. The most common SAEs were sepsis (3 patients), dehydration (3), febrile neutropenia (2), fever (2), and infusion reaction (2). One patient died following a diagnosis with non-small cell lung cancer, which was deemed unrelated to study treatment. An objective response was attained in 98% (60% CR) of patients, 1 patient (2%) had stable disease. To date, no patients have progressed through 3 months of post-treatment follow-up. Further analysis on the safety of the combination is ongoing.

Bendamustine and ofatumumab was well tolerated and active in patients with previously untreated indolent NHL. The ORR of 98% and CR of 60% in the evaluable population compare favorably with previously reported response rates observed in patients with indolent lymphoma. Phase II studies in other histologies are underway and the results of this study support further evaluation of the combination in randomized trials.

This study was sponsored by Cephalon. Ofatumumab was provided by GlaxoSmithKline.

Fowler:Cephalon, Inc.: Research Funding, Scientific advisory board. Off Label Use: Bendamustine is FDA-approved for adults with chronic lymphocytic leukemia or indolent B-cell non-Hodgkin's lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. Forero:Cephalon, Inc.: Research Funding. Munteanu:Cephalon, Inc.: Employment. Davis:Cephalon, Inc.: Employment. Brown:Cephalon, Inc.: Employment. Czuczman:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cephalon, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; MorphoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees.