On January 19, 2016, ofatumumab (Arzerra) was approved for extended treatment of patients in complete or partial response after at least two lines of therapy for recurrent or progressive chronic lymphocytic leukemia (CLL).1,2 Ofatumumab was previously approved for treatment of untreated patients with CLL for whom fludarabine-based therapy was considered inappropriate and patients with CLL refractory to fludarabine and alemtuzumab (Campath).
Supporting Efficacy Data
The new approval was based on demonstration of improved progression-free survival in an open-label phase III trial in which 474 patients with complete or partial response after at least two lines of prior therapy were randomized to receive ofatumumab infusion every 8 weeks (n = 238) or observation (n = 236).2,3 Ofatumumab was given via intravenous (IV) infusion at 300 mg on day 1, 1,000 mg on day 8, and 1,000 mg 7 weeks later and every 8 weeks thereafter, for up to 2 years.
Patients had a median age of 65 years (range = 33–87 years), 68% were male, and 96% were white. Most patients were in partial remission (81%), had had two prior treatments (70%, range = 2–5), and had received chemoimmunotherapy (80%) as prior therapy. The main efficacy outcome was investigator-assessed progression-free survival.
Median follow-up was 19.4 months in the ofatumumab group and 18.7 months in the observation group. Investigator-assessed median progression-free survival was 29.4 months (95% confidence interval [CI] = 26.2–34.2 months) vs 15.2 months (95% CI = 11.8–18.8 months), yielding a hazard ratio of 0.50 (P < .0001).
How It Works
Ofatumumab is a CD20-directed cytolytic monoclonal antibody that binds specifically to both the small and large extracellular loops of the CD20 molecule. The CD20 molecule is expressed on normal B lymphocytes (pre-B to mature B lymphocytes) and on B-cell CLL and is neither shed from the cell surface nor internalized following antibody binding. The Fab domain of ofatumumab binds to the CD20 molecule, and the Fc domain mediates immune effector functions, resulting in B-cell lysis in vitro. The potential mechanisms of cell lysis include complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity.
How It Is Used
The recommended dose of ofatumumab as single-agent extended treatment in CLL is 300 mg on day 1, followed by 1,000 mg 1 week later on day 8, followed by 1,000 mg 7 weeks later and every 8 weeks thereafter, for a maximum of 2 years.
Patients should receive premedication with IV corticosteroid at 50 mg (prednisolone or equivalent), oral acetaminophen at 1,000 mg, and oral or IV antihistamine (diphenhydramine at 50 mg, cetirizine at 10 mg, or equivalent) prior to the first and second infusions. For subsequent infusions, corticosteroid may be given at 0 to 50 mg (omitted or reduced in the absence of grade ≥ 3 reaction during the previous infusion), and acetaminophen and antihistamine doses should remain the same.
In the absence of an infusion reaction, infusion rates for the first 300-mg infusion should be 12, 25, 50, 100, 200, 300, and 400 mL/hour over the first 0–30, 31–60, 61–90, 91–120, 121–150, 151–180, and > 180 minutes. Rates for subsequent 1,000-mg infusions during these time intervals should be 25, 50, 100, 200, 400, 400, and 400 mL/hour. For these infusions, the infusion rate should start at 12 mL/hour if an infusion-related event of grade ≥ 3 occurred during the previous infusion.
Infusion should be interrupted for infusion reactions of any severity, with treatment resumed at the physician’s discretion. For reactions resolving to or remaining at grade ≤ 2, infusion can be resumed at one-half the previous infusion rate for grade 1 or 2 reactions and at 12 mL/hour for grade 3 or 4 reactions. Based on patient tolerance, the rate can be increased according to the above guideline. Permanent treatment discontinuation should be considered if the severity of the reaction does not resolve to ≤ grade 2 despite adequate clinical intervention. Treatment should be permanently discontinued for an anaphylactic reaction.
In the phase III trial, the most common adverse events of any grade in the ofatumumab group with an incidence ≥ 2% higher vs the observation group were infusion reactions (46% vs 0%), neutropenia (24% vs 9%), and upper respiratory tract infection (19% vs 9%). Adverse events ≥ grade 3 that were more common in the ofatumumab group included neutropenia (22% vs 8%), pneumonia (5% vs 3%), and infusion reactions (4% vs 0%). Serious adverse events occurred in 33% of the ofatumumab group, with the most common being pneumonia, pyrexia, and neutropenia (including febrile neutropenia).
Infusion reactions occurred in 25% of patients during the first infusion, with the frequency (between 2% and 10%) decreasing thereafter. Overall, 65% vs 51% of patients experienced bacterial, viral, or fungal infections, with infections being serious in 20% vs 18% and fatal in 2% vs 3%. No cases of neutropenic sepsis were observed in ofatumumab patients. Prolonged neutropenia was observed in 5% vs 2% of patients, and late-onset neutropenia was observed in two ofatumumab patients (< 1%) and one observation patient (< 1%). Death due to adverse events occurred in two ofatumumab patients (1%) and five observation patients (2%) within 60 days of the last dose of study medication/last visit in the observation group.
Ofatumumab carries boxed warnings for hepatitis B virus reactivation and progressive multifocal leukoencephalopathy, which can occur in patients receiving CD20-directed cytolytic antibodies, including ofatumumab. Hepatitis B reactivation has resulted in fulminant hepatitis, hepatic failure, and death, and progressive multifocal leukoencephalopathy has resulted in death.
Ofatumumab also carries warnings/precautions for infusion reactions, tumor lysis syndrome, and cytopenias. Tumor lysis syndrome should be anticipated in high-risk patients, and premedication with antihyperuricemic agents and hydration should be performed. Cases of late-onset and prolonged neutropenia have been observed. Complete blood cell counts should be monitored at regular intervals. ■
1. U.S. Food and Drug Administration: Ofatumumab (Arzerra Injection). Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm482308.htm. Accessed February 4, 2016.
2. Arzerra (ofatumumab) injection, for intravenous use prescribing information, Novartis Pharmaceuticals Corporation, January 2016. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125326s062lbl.pdf. Accessed February 4, 2016.
3. van Oers MH, Kuliczkowski K, Smolej L, et al: Ofatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): An open-label, multicentre, randomised phase 3 study. Lancet Oncol 16:1370-1379, 2015.