June 11, 2009 (Berlin, Germany) — The novel CD20 monoclonal antibody ofatumumab (Arzerra) has demonstrated superior response rates in 2 challenging groups of chronic lymphocytic leukemia (CLL) patients: those refractory to fludarabine and alemtuzumab; and those refractory to fludarabine and considered inappropriate candidates for alemtuzumab because of bulky tumor masses in their lymph nodes. Updated results in both patient groups were presented here at the 14th Congress of the European Hematology Association.
Ofatumumab is not marketed yet, but could be soon. Recently, on the basis of these results, the drug received a favorable recommendation from the US Food and Drug Administration's Oncologic Drugs Advisory Committee (ODAC) for use in CLL patients refractory to other therapies.
The data come from an interim analysis of 59 patients who were refractory to fludarabine and alemtuzumab and 79 patients who were refractory to fludarabine and considered inappropriate candidates for alemtuzumab because of bulky tumor masses in their lymph nodes. Over the 24 months of the study, patients received 8 weekly intravenous infusions of ofatumumab, followed by 4 monthly infusions. Patients received 300 mg of ofatumumab at the first infusion and 2000 mg at each subsequent infusion. Disease status was assessed every 4 weeks until week 28, and every 3 months thereafter until disease progression or month 24.
Responses were assessed by the ODAC according to the National Cancer Institute Working Group guidelines. An overall response rate of 58% was achieved in the double-refractory group and of 47% in the group refractory to fludarabine with bulky tumor masses (>5 cm). Responses lasted for a median of 6 months in both groups.
In the double-refractory group, median progression-free survival was 5.7 months and overall survival was 13.7 months; in the group refractory to fludarabine with bulky tumor masses, median progression-free survival was 5.9 months and median overall survival was 15.4 months.
"With our data from MD Anderson Cancer Center, we found that a variety of salvage therapies in similar patients gave an overall response rate of 23%, with average patient survival of 9 months," said lead investigator William Wierda, MD, associate professor of medicine at the University of Texas MD Anderson Cancer Center in Houston. Thus, with ofatumumab, "survival is improved in responders by a landmark analysis," he said.
Adverse effects seen with ofatumumab were not beyond the range expected for this patient population. Infusion reactions occurred in 38% of patients and were more common at the first 3 treatments. Infections and neutropenia were the most common grade 3 or 4 adverse events. Dr. Wierda noted that these patients experienced infections because they had previously received 2 lines of immunosuppressive standard therapy. "They had very little immunity when they entered the study and, by virtue of them being refractory, they were at very high risk of infection."
Different Binding Site to Rituximab
Ofatumumab is an investigational monoclonal antibody that is fully human-derived. It binds to a specific part of the CD20 protein on the surface of B cells, known as the small loop epitope, and then recruits complement to aid in cell destruction. Because this binding site is different than that used by rituximab, another CD20 monoclonal antibody used to treat CLL patients, the investigators looked at response to ofatumumab in patients who had previously received rituximab.
This second analysis was based on the premise that previous rituximab therapy might affect response to later treatment with another CD20 monoclonal antibody. "We found that patients treated with rituximab and then ofatumumab showed no statistical difference in response rate to those patients who had not had prior rituximab," said Dr. Wierda.
He added that direct in vitro comparisons showed that ofatumumab might be more effective at killing leukemia cells than rituximab, but this is difficult to show in patients. "This is a major question in people's minds. They both bind to CD20, but which is the better or more effective?"
Paolo Ghia, MD, assistant professor of internal medicine at the Università Vita-Salute San Raffaele in Milan, Italy, told Medscape Oncology that refractory CLL patients desperately need novel treatments to extend life expectancy. "This drug belongs to an interesting new category of anti-CD20 compounds, which should demonstrate good results in patients in the next few years, especially in combination. Older agents such as rituximab are ineffective as monotherapy, but these new ones prove efficacious when used alone and may be even more promising in combination with chemotherapy. It would be good to use this first-line in all CLL patients."
The study was funded by GlaxoSmithKline and Genmab. Dr. Wierda and Dr. Ghia have disclosed no relevant financial relationships.
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