FDA Approves Ofatumumab for Refractory Chronic Lymphocytic Leukemia

Yael Waknine

October 28, 2009

October 28, 2009 — The US Food and Drug Administration (FDA) has granted accelerated approval of ofatumumab intravenous infusion (Arzerra, GlaxoSmithKline) for the treatment of patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab.

"The approval of Arzerra illustrates FDA's commitment to using the accelerated approval process to approve drugs for patients who have limited therapeutic options," said Richard Pazdur, MD, director of the Office of Oncology Drug Products in the FDA's Center for Drug Evaluation and Research, in an agency news release. Approximately 16,000 patients are diagnosed and about 4400 die from CLL each year.

Ofatumumab is a cytolytic monoclonal antibody that binds specifically to the CD20 molecule expressed on the surface of normal and malignant B lymphocytes, making them more susceptible to immune system attack.

The approval of the drug was based primarily on data from a single-arm, multicenter study of 154 patients, of whom 93% had received prior treatment with alkylating agents and 59% had received rituximab therapy; all had received fludarabine and alemtuzumab.

Results demonstrated that treatment with ofatumumab yielded an investigator-determined overall response rate of 42% (99% confidence interval [CI], 26 – 60), with a median duration of response of 6.5 months (95% CI, 5.8 – 8.3); no complete responses were observed.

Although there are currently no data demonstrating an improvement in disease-related symptoms or increased survival, ongoing clinical studies are expected to confirm that the addition of ofatumumab to standard chemotherapy delays CLL progression.

The recommended regimen for ofatumumab consists of a 12-dose cycle: a 300-mg initial dose followed 1 week later by 2000 mg weekly for 7 doses, which is then followed 4 weeks later by 2000 mg given every 4 weeks for 4 doses. Patients should be premedicated with an intravenous corticosteroid, oral analgesic, and oral or intravenous antihistamine to reduce the risk for infusion reactions. In the study, 88% of patients received at least 8 infusions, and 54% were able to tolerate all 12.

Adverse reactions reported in 10% or more of patients receiving ofatumumab therapy include neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections.

Prolonged (≥1 week) severe neutropenia and thrombocytopenia can occur during treatment with ofatumumab, and complete blood and platelet counts should be monitored regularly.

As with other monoclonal antibodies, ofatumumab is linked to a risk for potentially fatal progressive multifocal leukoencephalopathy, which should be considered in patients who present with new onset or changes in preexisting neurologic signs and symptoms.

Ofatumumab may also cause hepatitis B virus reactivation, and high-risk patients should be screened for infection before initiation of therapy. Hepatitis B virus carriers should be closely monitored for signs of active infection during treatment and for 6 to 12 months after discontinuation of therapy.

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