Credit: Linda Bartlett
The US Food and Drug Administration (FDA) has approved ofatumumab (Arzerra) in combination with chlorambucil for previously untreated patients with chronic lymphocytic leukemia (CLL) who should not receive fludarabine-based therapy.
Ofatumumab, a CD20-directed monoclonal antibody, is already FDA-approved as monotherapy for CLL patients who are refractory to fludarabine and alemtuzumab.
The latest approval was based on results of the phase 3 COMPLEMENT 1 trial.
In this randomized trial, researchers compared single-agent chlorambucil to chlorambucil plus ofatumumab. They enrolled 447 patients for whom fludarabine-based therapy was considered inappropriate (due to factors such as advanced age or comorbidities).
In the overall trial population, the median age was 69 years (range, 35 to 92). Seventy-two percent of patients had 2 or more comorbidities, and 48% of patients had a creatinine clearance of less than 70 mL/min.
The researchers randomized 221 patients to receive chlorambucil plus ofatumumab and 226 patients to receive chlorambucil alone.
Patients in the ofatumumab arm received the drug as an intravenous infusion according to the following schedule: 300 mg in cycle 1 on day 1, 1000 mg in cycle 1 on day 8, and 1000 mg administered on day 1 of all subsequent 28-day cycles.
In both arms, patients received chlorambucil at a dose of 10 mg/m2 orally on days 1 to 7, every 28 days.
Prior to each infusion of ofatumumab, patients received acetaminophen, an antihistamine, and a glucocorticoid.
The primary endpoint of the trial was progression-free survival, as assessed by a blinded independent review committee using the 2008 International Workshop on Chronic Lymphocytic Leukemia update of the National Cancer Institute Working Group guidelines.
The median progression-free survival was 22.4 months for patients receiving ofatumumab and chlorambucil, compared to 13.1 months for patients receiving chlorambucil alone. The hazard ratio was 0.57 (P<0.001).
The most common adverse reactions observed in patients receiving ofatumumab and chlorambucil (at least 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, 67% of patients who received ofatumumab experienced 1 or more symptoms of infusion reaction. Ten percent of patients experienced a grade 3 or greater infusion reaction.
The drug’s label carries a boxed warning detailing the risk of hepatitis B virus reactivation—which can result in fulminant hepatitis, hepatic failure, and death—as well as the risk of progressive multifocal leukoencephalopathy—which can result in death.
The recommended dose and schedule for ofatumumab in previously untreated CLL is 300 mg on day 1, followed 1 week later by 1000 mg on day 8 (cycle 1), followed by 1000 mg on day 1 of subsequent 28-day cycles, for a minimum of 3 cycles until best response or a maximum of 12 cycles.
Ofatumumab is under development by GlaxoSmithKline and GenMab. For more details on the drug, see the full prescribing information.
