A Phase II Study of Ofatumumab in Combination with ICE or DHAP Chemotherapy in Relapsed or Refractory Aggressive B-Cell Lymphoma Prior to Autologous Stem Cell Transplantation (ASCT)

For patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), standard-of-care second-line therapy in patients eligible for consolidative high-dose therapy with autologous stem cell rescue (HDT/ASCR) is rituximab (R) combined with a platinum-containing regimen such as ifosfamide, carboplatin, and etoposide (ICE) or dexamethasone, cytarabine, and cisplatin (DHAP). In patients with early relapse or refractory disease following first-line treatment, the efficacy of second-line rituximab combined with salvage chemotherapy is lower in patients previously treated with rituximab combined with chemotherapy compared to patients treated with chemotherapy alone (Gisselbrecht et al. J Clin Oncol 2010). Ofatumumab (OFA), a fully human monoclonal antibody against CD20, uses an alternate binding site from that of rituximab, and demonstrates more potent complement-dependent cytotoxicity in vitro than does rituximab (Teeling et al. J Immunol 2006). We hypothesize that the inclusion of ofatumumab in second-line therapy could improve response rates for aggressive B-cell non-Hodgkin's lymphoma (NHL) relapsing after, or refractory to, rituximab-containing initial therapy.

Between May 2009 and April 2011, 61 patients (pts) were enrolled with relapsed or refractory CD20 positive aggressive B-cell NHL (DLBCL, transformed low grade lymphoma or grade 3B follicular lymphoma). Pts were transplant eligible with either pathologically confirmed relapse after first-line therapy or primary refractory disease. Initial therapy must have included rituximab combined with anthracycline/anthracenedione chemotherapy. Sites elected to treat all of their pts with either ICE or DHAP. Chemotherapy was dosed every 21 days for 3 cycles. OFA was dosed on D1 and D8 of cycle 1, then D1 of cycles 2 and 3. Initially, the first dose of OFA was 300mg, but the study was amended to increase the first dose to 1000mg. All other doses of OFA were 1000mg. Response was assessed after cycles 2 (CT) and 3 (CT + PET). The primary endpoint was overall response rate (ORR) using modified RRCML criteria (Cheson et al. J Clin Oncol 2007).

61 pts were enrolled; 35 pts were treated with ICE and 26 pts with DHAP. 21 pts received an initial OFA dose of 300mg and 40 pts received 1000mg. High risk disease was well represented, with 80% having disease that was either primary refractory (47%), relapsed within 12 months of diagnosis (30%), or progressed from unknown response within 12 months of diagnosis (3%); 48% of pts had a second-line age-adjusted IPI (sAAIPI) of 2 (41%) or 3 (7%) risk factors. 9 (15%) pts were prematurely withdrawn from treatment due to investigator decision (n=5, usually due to stable disease deemed an inadequate response), AEs (n=3) or pt decision (n=1). 2 pts were CD20 negative and excluded from the efficacy analysis. The ORR in the 59 evaluable pts was 61% (95% CI: 47%–74%), with CR in 37% (95% CI: 25%–51%). For OFA+DHAP, the ORR was 69% (95% CI: 48%–86%), with CR in 42% (95% CI: 23%–63%), and for OFA+ICE, was 55% (95% CI: 36%–72%), with CR in 33% (95% CI: 18%–52%). For patients with sAAIPI of 2 or 3 (29 pts), the ORR was 59% (95% CI: 39%–77%), with CR in 31% (95% CI: 15%–51%). For pts with primary refractory or early relapsing disease, the ORR was 55% (95% CI: 40%–70%), with CR in 30% (95% CI: 17%–45%). 45 pts underwent peripheral blood stem cell mobilization, and 43 (96%) mobilized ≥2×10⁶ CD34⁺ cells/kg (median, 5.8×10⁶ CD34⁺ cells/kg). Grade ≥3 AEs occurred in 47 pts (77%); the most common were thrombocytopenia (59% pts), anemia (36%), neutropenia (26%), lymphopenia (23%), leukopenia (18%), febrile neutropenia (13%), and hypokalemia (13%). 3 pts (12%) treated with OFA+DHAP had grade ≥3 nephrotoxicity. 3 pts discontinued treatment due to chemotherapy related AEs: mental status change (2 pts), respiratory distress (1 pt), and elevated creatinine (1 pt). No treatment related deaths were reported.

OFA combined with salvage ICE or DHAP showed promising activity with an ORR of 61%. Treatment was adequately tolerated, with no unexpected toxicity, and stem cell mobilization was not adversely affected. Furthermore, the results are particularly promising in patients with primary refractory or early-relapsing disease, a group that has been reported to have extremely adverse outcomes. In order to compare rituximab to OFA in the salvage setting, a phase III randomized trial of OFA+DHAP and R+DHAP is ongoing.

Matasar:GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Ofatumumab is an anti-CD20 monoclonal antibody approved for the treatment of fludarabine- and alemtuzumab-refractory chronic lymphocytic leukemia, and is 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). Czuczman:Ortho Biotech: Research Funding; Centocor: Research Funding; Novartis: Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Abbott: Research Funding; Sanofi-Aventis: Consultancy; Genentech: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Cephalon: Consultancy, Research Funding. Rodriguez:Genentech: Research Funding; Pfizer Pharmaceuticals: Research Funding; Ortho Biotech: Research Funding. Fennessy:Glaxo Smith-Kline: Employment, Equity Ownership. Shea:Otsuka: Research Funding; Millenium: Research Funding; Genzyme: Research Funding; Novartis: Research Funding; GlaxoSmithKline: Research Funding; Bristol-Myers Squibb: Research Funding. Spitzer:Amgen: Equity Ownership; Celgene: Speakers Bureau; Millenium: Honoraria, Speakers Bureau; Cephalon: Honoraria, Speakers Bureau; Merck: Honoraria, Speakers Bureau; GSK: Honoraria, Speakers Bureau. Fayad:GSK: Research Funding. Liao:GlaxoSmithKline: Employment. Edvardsen:GlaxoSmithKline: Employment. Lisby:Genmab: Employment.