February 2014, Vol 3, No 1
Anti-CD20 Agent Improves Outcomes in Elderly/Unfit Patients With Chronic Lymphocytic Leukemia
Elderly and unfit patients constitute the majority of patients with chronic lymphocytic leukemia (CLL), but unfortunately these groups have limited treatment options. A second-generation fully humanized monoclonal antibody against the CD20 protein, ofatumumab, added to chlorambucil improves clinical outcomes and is tolerable irrespective of age and fitness in patients with previously untreated CLL who are considered inappropriate for fludarabine, according to the results of a phase 3 study.
In older CLL patients who are unfit for the gold standard therapy of fludarabine-cyclophosphamide-rituximab, chlorambucil using various dosing schedules remains a treatment option, said Peter Hillmen, MD, PhD, lead investigator of the study and consultant hematologist, Leeds Teaching Hospitals NHS Trust, St. James University Hospital, Leeds, UK.
Ofatumumab has a discrete epitope that targets both the small and large extracellular loops of CD20. In vitro, it displays more activity through complement and through antibody-dependent cellular cytotoxicity than rituximab.
In the phase 3 study, known as COMPLEMENT 1, 447 patients with previously untreated CLL who were considered inappropriate for fludarabine-based therapy based on advanced age and/or comorbidities were randomized to chlorambucil or ofatumumab plus chlorambucil until best response. Ofatumumab was given as an intravenous infusion for a maximum 12 cycles. Chlorambucil was dosed orally at 10 mg/m2 on days 1 through 7 of each 28-day cycle.
About one-fourth of the patients were older than 75 years; 87% in each group were either ?65 years or had ?2 comorbidities or a creatinine clearance <70 mL/min and thus ineligible for fludarabine, said Hillmen.
Nineteen percent of patients in each arm required chlorambucil dose reduction as a result of experiencing neutropenia. After a median follow-up of 28.9 months, progression-free survival, as assessed by an Independent Review Committee, was 22.4 months in the ofatumumab-chlorambucil arm compared with 13.1 months in the chlorambucil alone arm, corresponding to a 43% improvement with ofatumumab (P=.001). Overall survival (OS) was also significantly superior in the ofatumumab arm (82% vs 69%; P<.001), as was the rate of complete response (14% vs 1%). The median OS was not reached in either arm.
Twelve percent in the ofatumumab-chlorambucil arm were negative for minimal residual disease compared with 4% in the chlorambucil alone arm.
There was a trend toward a shorter time to response in the ofatumumab-chlorambucil arm versus the chlorambucil alone arm (median: 1.1 vs 1.9 month; P=.084). The median duration of response was longer in the ofatumumab-chlorambucil arm at 22.1 versus 13.1 months (P<.001) in the chlorambucil alone arm. The time to next treatment was also significantly longer in the ofatumumab-chlorambucil arm versus chlorambucil alone, with a median 39.8 versus 24.7 months (P<.001).
More than 80% of patients completed at least 6 cycles. Combination treatment was well tolerated. The rate of withdrawal from treatment due to adverse events was 13% in each arm. The rate of grade ?3 adverse events was 50% with ofatumumab-chlorambucil versus 43% with chlorambucil alone; 10% in the ofatumumab-chlorambucil arm had grade ?3 infusion reactions. There was a higher rate of grade ?3 neutropenia in patients assigned to ofatumumab-chlorambucil compared with chlorambucil alone (26% vs 14%), but this difference did not translate into a higher risk of infection, said Hillmen.
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