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Ofatumumab in the treatment of patients with chronic lymphocytic leukemia
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Despite advances in the treatment of chronic lymphocytic leukemia that have increased response rates as well as PFS, it remains a largely incurable malignancy. Purine analogues combined with monoclonal antibodies form the backbone of highly effective therapy for CLL. The FCR regimen, containing fludarabine, cyclophosphamide and rituximab (Rituxan, Genentech), has become the standard of care for CLL patients with good performance status.
Unfortunately, challenges remain because many patients develop disease refractory to fludarabine. Therapy with alemtuzumab (Campath, Genzyme) yields responses in less than half of patients with leukemia resistant to fludarabine. Therefore, there is a great need for therapy effective in patients with disease refractory to fludarabine and alemtuzumab.
Ofatumumab (Arzerra, GlaxoSmithKline), also known as HuMax-CD20, is a newly developed monoclonal antibody in the treatment of CLL. It is a human monoclonal antibody that binds to the CD20 molecule on B-cell CLL cells as well as normal B cells. It binds to a different antigenic determinant than that of rituximab, and it appears to bind more tightly to CD20 than rituximab. Ofatumumab exerts its antitumor effect by activating complement-dependent cytotoxicity, as well as antibody-dependent cellular cytotoxicity, resulting in B-cell lysis. It was thought that because of this binding advantage, ofatumumab would have activity in CLL refractory to rituximab therapy.
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Ofatumumab was studied in a pivotal trial by Osterborg and colleagues. The study included 138 patients with CLL that was refractory to fludarabine/alemtuzumab (double-refractory disease; n=59) or CLL that was refractory to fludarabine with bulky adenopathy (n=79). The median age of enrolled patients was about 63 years. Patients had taken a median of four to five prior treatment regimens. Ofatumumab therapy consisted of an initial 300-mg IV dose, followed by seven weekly doses of 2 g, and then by four monthly doses of 2 g. The table shows the major efficacy and toxicity results from this trial.
The researchers concluded that ofatumumab offers an active treatment option for patients with refractory CLL, in whom other treatments have failed. They encouraged the testing of ofatumumab in other patient groups.
Dose recommendations
The recommended dose of ofatumumab begins with a single IV dose of 300 mg. This should be infused at a rate of 3.6 mg per hour. The infusion rate can be increased every 30 minutes to a maximum of 200 mg per hour. Each dose should be diluted with normal saline to a total volume of 1,000 mL.
The second dose is 2 g IV infused at a rate of 24 mg per hour. The infusion rate of the second dose can be increased every 30 minutes to a maximum of 200 mg per hour. Doses three through eight of 2 g weekly should be infused at 50 mg per hour. The infusion rate of these doses can be increased every 30 minutes to a maximum of 400 mg per hour. Doses nine through 12 are given as 2 g monthly, infused at 50 mg per hour. Doses nine through 12 can be increased every 30 minutes to a maximum rate of 400 mg per hour.
To reduce the risk of infusion-related adverse effects, it is recommended to premedicate the patient with acetaminophen, an antihistamine and a glucocorticoid equivalent to 100 mg of prednisolone (ie, methylprednisolone 80 mg or dexamethasone 15 mg). The dose of the corticosteroid can be decreased gradually starting with dose three, if no grade-3 or -4 infusion-related adverse effects were experienced.
Adverse effects
Some of the most frequent adverse effects seen with ofatumumab are infusion-related effects. These include respiratory symptoms such as dyspnea, bronchospasm, pulmonary edema and laryngeal edema. Other adverse effects seen are hypertension, hypotension, syncope, cardiac ischemia, rash, urticaria or fever. These adverse effects are more common with the first infusion (44%) and the second infusion (29%).
Other common adverse effects include hematologic effects such as anemia (16%-17%), and neutropenia (42%). Infectious complications (70%), including fever, sepsis, pneumonia, bronchitis and cough are common. Other common adverse effects include diarrhea, nausea, bowel obstruction, and viral hepatitis. Rarely, progressive multifocal leukoencephalopathy has been reported.
In summary, ofatumumab is a new monoclonal antibody that shows activity in the treatment of patients with refractory CLL. Infusion-related adverse effects are common, especially with the first two doses. Cytopenias and infectious complications are also commonly seen. Ofatumumab has also been studied in the treatment of lymphoma, rheumatoid arthritis and multiple sclerosis. More research is needed to fully define the role of ofatumumab.
Lisa Lohr, PharmD, BCPS, BCOP, is Clinical Pharmacist in Oncology and Bone Marrow Transplantation the Department of Pharmacy Services at the University of Minnesota Medical Center and HemOnc Today Editorial Board member.
For more information:
- Osterborg A. #328. Presented at: 50th Annual Meeting of the American Society of Hematology; Dec. 5-9, 2008; San Francisco.