Ofatumumab (HuMax-CD20), a Novel CD20 Monoclonal Antibody, Is An Active Treatment for Patients with CLL Refractory to Both Fludarabine and Alemtuzumab or Bulky Fludarabine-Refractory Disease: Results from the Planned Interim Analysis of An International Pivotal Trial

Background: The prognosis for patients with CLL refractory to fludarabine and alemtuzumab (double-refractory, DR) or refractory to fludarabine with bulky (>5cm) lymphadenopathy (bulky fludarabine-refractory, BFR) is poor. The overall response rate (ORR) to salvage therapy for such patients is approximately 20% with a median survival of 9 mo (Tam et al, Leuk Lym, 2007). New effective treatments are needed for these patients. Ofatumumab (HuMax-CD20) is a human monoclonal antibody that targets a unique small-loop epitope on CD20 and elicits potent in vitro complement-dependent cytotoxicity, even in malignant B cells with low CD20 expression levels. We report on a planned interim analysis of an international, multicenter, pivotal study of ofatumumab in patients with DR and BFR CLL. Methods: Patients with DR or BFR CLL received 8 weekly infusions of ofatumumab followed by 4 monthly infusions (Dose 1, 300 mg; Doses 2–12, 2000 mg). Patients were premedicated with paracetamol, antihistamine and glucocorticoid. The primary end point was ORR (1996 NCI-WG response criteria) assessed by an Independent end points Review Committee (IRC) over a 24 wk period. Overall survival (OS) and safety were also evaluated. Results: This interim analysis included all 138 treated patients (DR, n=59; BFR, n=79: Table); 54% received all 12 infusions and 90% received □8 infusions. The ORR (99% CI) based upon IRC assessment was 51% (34, 68%) for the DR group and 44% (30, 59%) for the BFR group; 1 patient had CR. Additionally, a considerable number of patients had stable disease (Table). Median time to next CLL therapy was 9 mo for the DR group and 8 mo for the BFR group (Table); clinical progression was typically due to worsening lymphadenopathy. The median OS was about 14 mo for the DR group and 15 mo for the BFR group (Table); based upon a landmark analysis at wk 12, response was significantly correlated with longer survival for both groups. Updated efficacy results will be presented at the meeting. Ofatumumab was associated with infusion-related adverse events on the first infusion day in 46% of patients in the DR group and 38% in the BFR group, which were grade 3 (no grade 4) in 7% and 3%, respectively (only 1 grade 3 event was considered a serious adverse event). These events generally subsided with subsequent infusions. The most common grade 3 or 4 toxicities were infections (25% in DR; 27% in BFR group) and hematologic events including neutropenia (12% in DR; 10% in BFR group) and anemia (8% in DR; 4% in BFR group). Early death (within 8 wks from start of treatment) occurred in 2 patients (3%) in the DR group (sepsis, n=1; fungal pneumonia, n=1) and 3 patients (4%) in the BFR group (PD, n=1; sepsis, n=1; myocardial infarction, n=1). No patient tested developed antibodies to ofatumumab. Conclusions: These results demonstrate the effectiveness of ofatumumab in patients with double-refractory CLL or bulky fludarabine-refractory disease. Ofatumumab was well tolerated with no unexpected toxicities. This monoclonal antibody potentially represents an active treatment option with clinical benefit for patients with very poor prognosis who have exhausted standard treatment options. The encouraging single-agent activity in patients with refractory CLL warrants further investigation of ofatumumab in earlier disease settings, in combination with other agents, as maintenance, and in other B-cell malignancies. Table