Superior Progression-Free Survival With Obinutuzumab/Chlorambucil vs Rituximab/Chlorambucil in Previously Untreated CLL With Coexisting Conditions
Obinutuzumab (Gazyva) is a glycoengineered type 2 anti-CD20 antibody that appears to exhibit increased activity against chronic lymphocytic leukemia cells (CLL), with increased antibody-dependent cellular cytotoxicity and reduced complement-dependent cytotoxicity, compared with rituximab (Rituxan). In an open-label phase III trial reported in The New England Journal of Medicine, Goede et al in the German CLL Study Group compared obinutuzumab/chlorambucil (Leukeran) and rituximab/chlorambucil vs chlorambucil alone and vs each other in patients with previously untreated CLL and coexisting medical conditions. Progression-free survival was significantly greater with the antibody/chlorambucil combinations vs chlorambucil alone and with obinutuzumab/chlorambucil vs rituximab/chlorambucil.
Study Details
In the trial, 781 patients were randomly assigned 1:2:2 between April 2010 and July 2012 to receive chlorambucil alone (n = 118), obinutuzumab/chlorambucil (n = 333), or rituximab/chlorambucil (n = 330). After 118 patients had been randomly assigned to the chlorambucil-alone group, the group was closed, with 238 obinutuzumab/chlorambucil patients and 233 rituximab/chlorambucil patients constituting the combination treatment groups that were compared with chlorambucil alone. An additional 192 patients were then randomly assigned to combination treatment.
Treatment was given in six 28-day cycles, with oral chlorambucil given at 0.5 mg/kg on days 1 and 15; obinutuzumab given at 1,000 mg IV on days 1, 8, and 15 of cycle 1 and day 1 of cycles 2 to 6; and rituximab given at 375 mg/m2 IV on day 1 of cycle 1 and 500 mg/m2 on day 1 of cycles 2 to 6. Patients had to have clinically meaningful coexisting conditions as indicated by a score > 6 on the Cumulative Illness Rating Scale (range, 0–56, higher scores indicate worse health) or calculated creatinine clearance of 30 to 69 mL/min. The primary endpoint was progression-free survival.
There were no significant differences in baseline characteristics in treatment groups according to the three pairwise comparisons of obinutuzumab/chlorambucil vs chlorambucil, rituximab/chlorambucil vs chlorambucil, or obinutuzumab/chlorambucil vs rituximab/chlorambucil. The obinutuzumab/chlorambucil and rituximab/chlorambucil groups were balanced for age (median, 74 and 73 years), Cumulative Illness Rating Scale score (median, 8 in both), affected organ system or disorder (eg, hypertension in 68% in both, cardiac in 51% and 50%, endocrine/metabolic in 55% and 49%), median calculated creatinine clearance (63 mL/min in both), Binet stage (B in 43% and 41%, C in 35% and 37%), unmutated IGHV (62% and 61%), and presence of del(17p) (7% in both).
Progression-Free Survival and Objective Response
The obinutuzumab/chlorambucil group (26.7 vs 11.1 months, hazard ratio [HR] = 0.18, P < .001) and the rituximab/chlorambucil group (16.3 vs 11.1 months, HR = 0.44, P < .001) had significantly prolonged median progression-free survival vs the chlorambucil-alone group. The obinutuzumab/chlorambucil group had significantly prolonged median progression-free survival vs the rituximab/chlorambucil group (26.7 vs 15.2 months, HR = 0.39, P < .001).
The benefit of obinutuzumab/chlorambucil was significant in all subgroup analyses for age, sex, Binet stage, baseline circulating lymphocyte count, Cumulative Illness Rating Scale score, calculated creatinine clearance, β2-microglobulin level, IGHV mutational status, and cytogenetics, except for del(17p) and "other" cytogenetics subgroups.
Objective response was observed in 78% of the obinutuzumab/chlorambucil group (complete response in 21%) vs 65% of the rituximab group (complete response in 7%, P < .001). Rates of negative minimal residual disease were significantly greater with obinutuzumab/chlorambucil in both bone marrow (19.5% vs 3%, P < .001) and blood (38% vs 3%, P < .001).
At the time of analysis, there was no significant difference in overall survival between the obinutuzumab/chlorambucil group and the rituximab/chlorambucil group (medians not reached; HR = 0.66, 95% confidence interval = 0.41–1.06, P = .08). Mortality rates were 8% vs 12%.
Obinutuzumab/chlorambucil was associated with significantly greater overall survival vs chlorambucil alone (mortality, 9% vs 20%; HR = 0.41, P = .002). The overall survival benefit of rituximab/chlorambucil vs chlorambucil alone was not significant (mortality, 15% vs 20%; HR = 0.66, P = .11).
Toxicity
Adverse events were more common with obinutuzumab/chlorambucil vs rituximab/chlorambucil. Grade 3 or higher adverse events occurred in 70% vs 55%, with the most common being neutropenia (33% vs 28%), infections (12% vs 14%, including pneumonia in 4% vs 5% and febrile neutropenia in 2% vs 1%), and infusion-related reactions (20% vs 4%). All grade 3 or 4 infusion reactions in the obinutuzumab/chlorambucil group occurred during the first infusion. Grade 3 or 4 thrombocytopenia (10% vs 3%) and leukopenia (4% vs 1%) were also more common with obinutuzumab/chlorambucil (anemia occurred in 4% of both groups). Grade 3 or 4 tumor lysis syndrome occurred in 2% vs 0%. Serious adverse events occurred in 39% vs 32%, with the most common being infection (13% vs 14%), neoplasms (6% in both), and infusion-related reaction (10% vs 2%); 4% vs 6% of patients died due to an adverse event.
The investigators concluded, “Combining an anti-CD20 antibody with chemotherapy improved outcomes in patients with CLL and coexisting conditions. In this patient population, obinutuzumab was superior to rituximab when each was combined with chlorambucil.”
Valentin Goede, MD, and Michael Hallek, MD, both of University Hospital Cologne, are the lead authors of The New England Journal of Medicine article.
The study was funded by F. Hoffmann-La Roche. For full disclosures of the study authors, visit www.nejm.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
