Adding ofatumumab to chlorambucil in patients with previously untreated chronic lymphocytic leukemia who are considered inappropriate for fludarabine improves clinical outcomes and is tolerable irrespective of patient age or fitness.
Peter Hillmen, MD, PhD
Adding ofatumumab to chlorambucil in patients with previously untreated chronic lymphocytic leukemia (CLL) who are considered inappropriate for fludarabine improves clinical outcomes and is tolerable irrespective of patient age or fitness.
Median progression-free survival (PFS), overall response (OR) rate, complete response (CR) rate, and the treatment-free period were all superior with the addition of ofatumumab to chlorambucil compared with chlorambucil alone, reported Peter Hillmen, MD, PhD, at the 55th Annual Meeting of the American Society of Hematology.
In older CLL patients who are unfit for the gold-standard therapy of fludarabine-cyclophosphamide-rituximab, chlorambucil using a variety of dosing schedules remains a treatment option, said Hillmen, consultant hematologist, Leeds Teaching Hospitals NHS Trust, St. James University Hospital, Leeds, UK.
Phase II data on the combination of an anti-CD20 monoclonal antibody, mainly rituximab, with chlorambucil show superior efficacy than chlorambucil alone as front-line therapy in elderly/unfit patients with CLL.
Ofatumumab is a novel second-generation fully humanized monoclonal antibody against the CD20 protein, which is expressed on the surface of malignant B cells. It has a discrete epitope that targets both the small and large extracellular loops of CD20. In vitro, ofatumumab has more activity through complement and through antibody-dependent cellular cytotoxicity than rituximab. Ofatumumab has been shown to be effective as monotherapy in CLL patients who are refractory to rituximab.
In the study known as COMPLEMENT 1, 447 patients with previously untreated CLL who were considered inappropriate for fludarabine-based therapy due to advanced age and/or comorbidities were randomized to a minimum of 3 cycles until best response, up to a maximum of 12 cycles, of chlorambucil or ofatumumab plus chlorambucil. The median duration of therapy was six cycles in both arms.
Ofatumumab was given as an intravenous infusion, 300 mg on day 1 and 1,000 mg on day 8 of the first cycle, and then 1,000 mg every 28 days during cycles 2 through 12. Chlorambucil was dosed orally at 10 mg/m2 on days 1 through 7 of each 28 day-cycle. According to Hillmen, the 7-day duration of chlorambucil therapy during each cycle may be responsible for higher response rates achieved with the combination regimen compared with once every 15 days often used in clinical trials.
Baseline characteristics were similar between the two treatment groups. The median age was 69 years, 91% of patients overall were classified within European Cooperative Oncology Group performance status 0 or 1, and the median number of comorbidities was three in each group. About one-fourth of the patients were older than 75 years. Eighty-seven percent in each group were either 65 years of age or older or had ≥2 comorbidities or a creatinine clearance <70 mL/min, and thus were ineligible for fludarabine.
The primary endpoint was PFS as assessed by an Independent Review Committee. After a median follow-up of 28.9 months, PFS was 22.4 months in the ofatumumab plus chlorambucil arm compared with 13.1 months in the chlorambucil alone arm (hazard ratio [HR] = 0.57; P = .001), with a superior OR rate (82% vs 69%; P < .001) and a superior CR rate (14% vs 1%).
The median duration of response was 22.1 months vs 13.1 months (P < .001) in the ofatumumab/chlorambucil and chlorambucil alone arms, respectively, and the time to next treatment was also significantly longer in the ofatumumab/chlorambucil arm (median: 39.8 months vs 24.7 months [P < .001]).
Median OS was not reached for either arm. At 2 years, 88.7% of patients in the ofatumumab/chlorambucil arm were alive compared with 86.7% in the chlorambucil alone arm, and at 3 years, these percentages were 85.1% and 83.2%, respectively.
Combination treatment was well tolerated. Withdrawal from treatment due to adverse events was 13% in each arm. Ten percent 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. Nineteen percent of patients in each arm had their chlorambucil dose reduced as a result of experiencing neutropenia.
Hillmen P, Robak T, Janssens A, et al. Ofatumumab + chlorambucil versus chlorambucil alone In patients with untreated chronic lymphocytic leukemia: results of the phase III study Complement 1 (OMB110911). Presented at: the ASH 55th Annual Meeting; December 7-10, 2013; New Orleans, LA. Abstract 528.