Ofatumumab Combined with Fludarabine and Cyclophosphamide (O-FC) Shows High Activity in Patients with Previously Untreated Chronic Lymphocytic Leukemia (CLL): Results From a Randomized, Multicenter, International, Two-Dose, Parallel Group, Phase II Trial.

Chemoimmunotherapy regimens have become the treatment standard for patients with CLL. Ofatumumab is a human monoclonal antibody that targets a unique small-loop epitope on CD20 and elicits rapid and efficient in vitro complement-dependent cytotoxicity, as well as antibody-dependent cellular cytotoxicity. Recent studies demonstrated single-agent ofatumumab activity, with high overall response rates (ORR) in patients with refractory CLL. We conducted an international, randomized, parallel group, Phase II trial with two doses of ofatumumab combined with fludarabine and cyclophosphamide (FC) in previously untreated patients with CLL to evaluate the efficacy and tolerability of this chemoimmunotherapy regimen.

Previously untreated patients (N=61) with active CLL (by NCI-WG guidelines) were randomized to receive ofatumumab 500 mg (Group A) or 1000 mg (Group B) on day 1, combined with fludarabine (25 mg/m² IV daily; days 1–3) and cyclophosphamide (250 mg/m² IV daily; days 1–3) every 4 weeks for a total of 6 courses. In both Groups, the first dose of ofatumumab was 300 mg. Dose reduction of FC, but not ofatumumab, was allowed. Premedication for ofatumumab was paracetamol and antihistamine prior to each infusion, and glucocorticoid prior to infusions 1 and 2. Neutrophil growth factor and anti-infective prophylaxis were not mandated. The primary endpoint was complete response (CR) rate (1996 NCI-WG criteria) assessed by an Independent Review Committee (IRC), measured from the start of treatment until 3 months after the last infusion. Safety evaluations included investigator-reported adverse events (AEs) and deaths. Follow-up continues for collection of time-to-event endpoints.

Data from all 61 patients were available for response assessment (primary endpoint). Pretreatment characteristics are shown in the Table. 71% and 57% of patients in Groups A and B, respectively, completed all 6 courses of O-FC treatment. The CR rate (95% CI) by IRC evaluation was 32% (17, 51%) for Group A and 50% (31, 69%) for Group B; the ORR (95% CI) was 77% (59, 90%) and 73% (54, 88%), respectively (Table). The median progression-free survival has not been reached with the short median follow up of 8 months. No CTC grade 3–4 infusion-related reactions on the day of ofatumumab infusion were reported. During treatment and up to 30 days following the last dose, the most common (>10% of patients) grade 3–4 AEs reported by investigators were infections in 11 patients (Group A, n=4; Group B, n=7) including febrile neutropenia in 3 patients in each Group, and hematologic AEs including neutropenia in 29 patients (Group A, n=11; Group B, n=18), anemia in 8 patients (Group A, n=2; Group B, n=6) and thrombocytopenia in 9 patients (Group A, n=2; Group B, n=7); grade 3–4 hemolytic anemia occurred in 2 patients in Group A and 1 in Group B; one patient in Group B died (19 days from last dose) with dyspnea (etiology unknown). Beyond the AE reporting period mentioned above, one patient in Group A died (50 days from last dose) due to febrile neutropenia during the follow up period. Results from additional analysis of data will be presented at the meeting.

The O-FC regimen is highly active in previously untreated patients with CLL at both ofatumumab doses investigated and may offer a new chemoimmunotherapy treatment option in these patients. AEs with the O-FC regimen were manageable with no unexpected toxicities. The 1000 mg dose of ofatumumab is currently being evaluated in combination with chemotherapy in other studies for patients with CLL.

Wierda:Genmab, GlaxoSmithKline: Honoraria, Research Funding. 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). Kipps:Physicians' Education Resource, Educational Concepts: Speakers Bureau; Genmab, Abbott Industries, Celgene, Biogen Idec, Cephalon, sanofi-aventis, Medimmune, Memgem, Genentech: Research Funding. Dürig:GlaxoSmithKline: Honoraria. Griskevicius:GlaxoSmithKline, Genmab: Research Funding. Stilgenbauer:GlaxoSmithKline, Genmab: Consultancy, Honoraria, Research Funding. Mayer:GlaxoSmtihKline: Consultancy. Smolej:Bayer Schering: Honoraria. Padmanabhan:GlaxoSmithKline: Consultancy, Honoraria; Celgene, Genentech: Consultancy. Gorczyca:GlaxoSmithKline: Employment. Chan:GlaxoSmithKline: Employment. Gupta:GlaxoSmithKline: Employment. Andersen:H. Lundbeck A/S: Shares ownership; Novo Nordisk A/S, H. Lundbeck A/S and Genmab A/S: Consultancy. Strange:Genmab: Employment. Nielsen:Genmab: Employment. Russell:Genmab: Employment, Equity Ownership.