The US Food and Drug Administration (FDA) has granted full approval to ofatumumab (Arzerra Injection, for intravenous infusion; GlaxoSmithKline) for chronic lymphocytic leukemia (CLL). The indication is for use in combination with chlorambucil, for previously untreated patients who are not candidates for fludarabine (Fludara)-based therapy. The drug has a breakthrough therapy designation for this indication
Ofatumumab is already marketed in the United States. It was granted accelerated approval in 2009 for the treatment of patients with CLL refractory to fludarabine and alemtuzumab (Campath).
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 an attack from the immune system.
The full approval now was based on the results of a multicenter, randomized, open-label trial that compared ofatumumab in combination with chlorambucil to single-agent chlorambucil. The cohort included 447 patients who were not eligible for fludarabine-based therapy, for reasons that included advanced age or presence of comorbidities.
The median age of participants was 69 years; 72% had 2 or more comorbidities and 48% of patients had a creatinine clearance of < 70 mL/min. Ofatumumab was given as an intravenous infusion according to the following schedule: 300 mg administered on cycle 1 day 1, 1000 mg administered on cycle 1 day 8, and 1000 mg administered on day 1 of all subsequent 28-day cycles.
In both arms, chlorambucil was given at a dose of 10 mg/m2 orally on days 1 to 7 every 28 days. Prior to each infusion of ofatumumab, patients received premedication with acetaminophen, an antihistamine, and a glucocorticoid.
Median progression free survival, the study's primary endpoint, was 22.4 months for patients receiving ofatumumab in combination with chlorambucil, compared with 13.1 months for patients receiving single-agent chlorambucil (hazard ratio, 0.57; stratified log-rank P value < .001).
The results of this trial were adequate to fulfill the postmarketing requirement for GlaxoSmithKline to verify the clinical benefit of ofatumumab, says the FDA in their approval announcement, and thus the conversion from accelerated approval to regular approval.
The most common adverse reactions (greater than or equal to 5%) with ofatumumab in combination with chlorambucil (greater than or equal to 2% more than in the control arm) were infusion reactions, neutropenia, asthenia, headache, leukopenia, herpes simplex, lower respiratory tract infection, arthralgia, and upper abdominal pain.
Overall, about two thirds (67%) of patients who received ofatumumab experienced one or more symptoms of infusion reaction, and 10% of patients experienced a grade 3 or greater infusion reaction.
Ofatumumab carries a boxed warning, in that it 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. In addition, progressive multifocal leukoencephalopathy resulting in death can occur in patients receiving CD20-directed cytolytic antibodies.
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Cite this: FDA Grants Full Approval to Ofatumumab (Arzerra) for CLL - Medscape - Apr 17, 2014.