Ofatumumab Monotherapy for Treatment of Patients with Relapsed/Progressive Diffuse Large B-Cell Lymphoma: Results From a Multicenter Phase II Study

Patients (pts) with relapsed diffuse large B-cell lymphoma (DLBCL) ineligible for autologous stem cell transplant (ASCT) or relapsing after ASCT have a poor prognosis and limited therapeutic options. New treatment options are needed for these pts. Ofatumumab is a human monoclonal antibody that targets a membrane-proximal epitope comprising both the large loop and small loop of CD20, and has shown effective lysis of chemotherapy-refractory DLBCL cells in vitro (Teeling et al. Blood 2004; Cillessen et al. Blood 2007; abstract 2346). We report the first results from an open-label, single-arm, international Phase II trial that evaluated ofatumumab monotherapy in relapsed or progressive DLBCL.

Pts (age ≥18 years) with relapsed or progressive CD20⁺ DLBCL ineligible for ASCT or with relapsed or progressive disease after ASCT were enrolled between December 2007 and August 2009 (N=81). Relapsed or progressive disease was defined as relapse after a complete remission (CR) or disease progression after partial remission (PR). Pts received 8 weekly infusions of ofatumumab (dose 1, 300 mg; doses 2–8, 1000 mg). The primary endpoint was overall response rate (ORR) evaluated during the 6 months from the start of treatment, as assessed by an Independent Endpoint Review Committee according to the revised response criteria (Cheson et al. J Clin Oncol 2007). Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS) and safety.

Baseline characteristics are shown in the Table. Pts were heavily pretreated (median 3 prior systemic therapies), and 32% of pts did not respond to their last prior therapy. Nearly all pts (96%) had received prior rituximab-containing treatment; 54% had received 2 or more courses of prior rituximab therapy (Table). Overall, 58% of pts completed all 8 infusions of ofatumumab, 65% received at least 6 infusions, and 81% received at least 4 infusions. The primary reason for treatment discontinuation was disease progression. The ORR (95% CI) was 11% (4–18%), including 3 CRs (4%) and 6 PRs (7%). Of these 9 responding pts, 8 had responded to their last systemic therapy. The median duration of response (95% CI) was 6.9 months (5.3–6.9) and median PFS (95% CI) was 2.5 months (2.3–2.9). Infusion-related events occurred in 59% of pts, primarily occurred during infusion 1 (40% of pts) and infusion 2 (22%), and subsided during subsequent infusions; these events were predominantly grade 1–2 in severity (96% of pts). The most common (>10% of pts) adverse events (AEs; any grade) were diarrhea (17%), fatigue (15%), peripheral edema (15%), neutropenia (14%), abdominal pain (12%), constipation (12%), nausea (12%), pyrexia (11%), anemia (11%) and leukopenia (11%). Of these, ≥ grade 3 events included neutropenia (10%), leukopenia (6%), anemia (5%) and fatigue (1%). Grade 3 or greater thrombocytopenia and febrile neutropenia were reported in 6% and 4% of pts, respectively. The most common infectious events were upper respiratory tract infections (7% of pts), all of which were grade 1–2 events. In total, 13 pts died during the study; 3 pts died during the treatment period and 10 pts died during post-treatment follow up (until 24 months from study start). Deaths were due to disease progression (n=10), sepsis (n=1), circulatory collapse (no further details; n=1) and multi-organ failure (n=1).

Single-agent ofatumumab was well tolerated with an ORR of 11% in heavily pretreated pts with relapsed or progressive DLBCL, nearly all of whom had received prior rituximab therapy. Response to last systemic treatment appeared to influence response to ofatumumab in this pt population. Further studies of ofatumumab in combination with chemotherapy in relapsed DLBCL are currently underway.

Off Label Use: Ofatumumab is an investigational anti-CD20 monoclonal antibody, currently under development for the treatment of B-cell malignancies (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Waldenstroms macroglobulinemia and follicular lymphoma) as well as autoimmune diseases (rheumatoid arthritis and multiple sclerosis). Davies:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees. Padmanabhan:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gupta:GlaxoSmithKline: Employment. Lin:GlaxoSmithKline: Consultancy, Employment. Davis:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees. Losic:Genmab A/S: Employment, Equity Ownership. Lisby:Genmab A/S: Employment. Radford:GlaxoSmithKline: Equity Ownership; Genmab: Consultancy, Honoraria.