Standard therapy options are limited for patients with refractory chronic lymphocytic leukemia, with or without lymphadenopathy, and the results are generally poor. Ofatumumab (Arzerra), a novel human CD20 monoclonal antibody, could be the answer for improving outcomes in this patient population, according to an ongoing international study.
"Ofatumumab demonstrates significant activity and a favorable safety profile, providing meaningful clinical improvements in poor-risk patients with heavily pretreated FA-ref and BF-ref CLL. Results are especially encouraging for a single-agent monoclonal antibody in such heavily pretreated patients as in this salvage setting," wrote the authors (J Clin Oncol 28:1749-1758, 2010).
WILLIAM G. WIERDA, MD, PHD
William G. Wierda, MD, PhD, and colleagues looked at patients with chronic lymphocytic leukemia (CLL) refractory to both fludarabine and alemtuzumab(Drug information on alemtuzumab) (Campath) (FA-ref) and patients with CLL refractory to fludarabine with bulky (> 5 cm) lymph nodes (BF-ref). Dr. Wierda is from Houston's M.D. Anderson Cancer Center, while his coauthors are from numerous institutions in the U.S., Sweden, the UK, Poland, and the Czech Republic.
Ofatumumab is distinct from rituximab(Drug information on rituximab) (Rituxan), the CD20 monoclonal antibody recently approved by the FDA to be used in combination with chemotherapy for CLL, because it is a fully human antibody that targets a unique part of the CD20 molecule. This area encompasses an epitope comprising both small-loop and large-loop domains, Dr. Wierda explained. The epitope is closer in proximity to the cell membrane than the epitope targeted by rituximab, and, as a result, ofatumumab is more effective than rituximab in mediating in vitro complement-dependent cytotoxicity against CD20-positive cell lines and primary leukemia cells.
Ofatumumab also mediates antibody-dependent cellular cytotoxicity, and, to a lesser extent, direct induction of apoptosis of malignant CD20-positive cells. The CD20 molecule is expressed in most B-cell malignancies. Ofatumumab was approved by the FDA in October 2009 for patients with FA-ref chronic lymphocytic leukemia.
| • | 59 patients had FA-ref CLL |
| • | 79 patients had BF-ref CLL |
| • | Median age was 63 years |
| • | More than 70% were male |
| • | Median number of prior treatments was approximately five |
| • | Median duration of CLL was six years |
The published study reports results of a planned interim analysis for 138 treated patients (59 with FA-ref CLL and 79 with BF-ref CLL), representing two-thirds of planned enrollment. Subjects were recruited from 41 centers in 10 countries (see Table). Patients were treated with eight weekly infusions of ofatumumab, followed by four monthly infusions over a 24-week period. Response was assessed independently every four weeks until week 24 and then every three months until month 24.
Overall response rates were 58% for the FA-ref group and 47% for the BF-ref group. The median time to response was 1.8 months and the median duration of response was six months for both groups. Disease-related constitutional symptoms and performance status were considerably improved by ofatumumab treatment even in patients who did not fully respond to treatment according to NCI-Working Group criteria. Complete resolution of constitutional symptoms after a minimum of two months of treatment was reported in 48% of the FA-ref group and 63% of the BF-ref patients. Complete resolution of splenomegaly occurred in 47% and 35%, respectively, and complete resolution of hepatomegaly in 50% and 52%, respectively.
"Patients with thrombocytopenia or anemia at baseline experienced improvements in hematologic parameters," Dr. Wierda said. "These outcomes in hematologic parameters are notable, considering the extent of disease in this patient population and the lack of blood count limits for trial enrollment."
Ofatumumab was generally well-tolerated, with no unexpected toxicities and no formation of human anti-human antibodies. The most common side effects were infusion reactions and infections. Dr. Wierda's group was encouraged by response rates and duration of response in this study irrespective of exposure to prior standard regimens in earlier lines of CLL therapy. Further trials are needed to study ofatumumab's efficacy in combination with other drugs in patients with CLL and earlier in the course of disease, they said (ASH 2010 abstract 921).
KANTI RAI, MD
Dr. Wierda and colleagues offer welcome news for patients with CLL, said Dr. Rai, chief of the department of hematology/oncology at Long Island Jewish Hospital in New Hyde Park, N.Y. Despite all the advances in treatment over the past few years, Dr. Rai said, there are not many good therapeutic options to offer CLL patients who have already received multiple regimens and been classified as having refractory disease.
"Ofatumumab has now emerged as a clear choice for this group of patients and brings some new hope for them," he said. Now that ofatumumab is FDA-approved, it will surely be tested in combination with chemotherapy drugs, he added.
Dr. Rai pointed out that single-agent rituximab has not shown optimum efficacy for CLL patients, "but the same rituximab became a highly effective agent when it was combined with chemotherapy agents."
He predicted that combination therapy with ofatumumab and other chemotherapy drugs will have an impact on patients with advanced and refractory CLL. "Ofatumumab might turn out to be the start of a virtually new era for CLL therapy," Dr. Rai said.
