Obinutuzumab Outperforms Rituximab in Older Patients with CLL
The anti-CD20 antibody rituximab (Rituxan), combined with chemotherapy agents, had been shown to prolong overall survival (OS) in physically fit patients with previously untreated chronic lymphocytic leukemia (CLL), but not in those with comorbidities. In a recent head-to-head, randomized, phase 3 trial of older patients, researchers investigated the benefit of the anti-CD20 antibody obinutuzumab (Gazyva) plus chlorambucil (Leukeran) compared with rituximab plus chlorambucil in patients with previously untreated CLL and coexisting conditions (Goede V, et al. N Engl J Med.2014 Jan 8. [Epub ahead of print]).
In this open-label study, 781 patients were randomized in a 2:1:2 ratio to receive six 28-day cycles of obinutuzumab plus chlorambucil (N = 333), chlorambucil alone (N = 118), or to rituximab plus chlorambucil (N = 330). Patients were required to have a Cumulative Illness Rating Scale (CIRS) score of >6 and/or a creatinine clearance (CrCl) of 30 mL/min to 69 mL/min. The obinutuzumab and rituximab groups were well balanced. The patients had a median age of 73 years, a CrCl of 62 mL/min, and a CIRS score of 8 at baseline. Most of the patients (83%) had 3 or more coexisting conditions, such as hypertension, coronary artery disease, and diabetes. Chlorambucil was administered orally at 5 mg/kg of body weight on days 1 and 15 of each cycle. Obinutuzumab was administered intravenously at a dose of 1000 mg on days 1, 8, and 15 of cycle 1, and on day 1 of cycles 2 to 6. Rituximab was administered intravenously at a dose of 375 mg/m2 on day 1 of cycle 1, and 500 mg/m2 on day 1 of cycles 2 to 6.
Patients in the obinutuzumab plus chlorambucil group had a significant increase in median prolonged progression-free survival (PFS) and a higher response rate than the rituximab plus chlorambucil group. The median PFS was 26.7 months in the obinutuzumab group and 15.2 months in the rituximab group (hazard ratio [HR], 0.39; 95% confidence interval (CI), 0.31-0.49; P <.001). The complete response rates were 20.7% and 7%, respectively. The median PFS in patients receiving chlorambucil monotherapy was 11.1 months, which was shorter than the obinutuzumab plus chlorambucil group (HR, 0.18) or the rituximab plus chlorambucil group (HR, 0.44).
Grades 3 to 5 adverse events (AEs) ranged from 11% to 14% and did not differ significantly among treatment groups. The main difference was in
infusion-related AEs. In the obinutuzumab plus chlorambucil group, 20% of the patients experienced infusion-related reactions compared with 4% of patients in the rituximab plus chlorambucil group. In the obinutuzumab plus chlorambucil group, the researchers noted that the reaction occurred during the first infusion, and no deaths were associated with infusion-related AEs.
The researchers concluded that the combination of obinutuzumab or rituximab with chlorambucil improves outcomes in patients with previously untreated CLL and coexisting conditions. In this patient population, obinutuzumab plus chlorambucil showed an OS advantage over chlorambucil monotherapy. Furthermore, obinutuzumab plus chlorambucil induced prolonged PFS and a higher complete response rate than rituximab plus chlorambucil.