CHICAGO – Adding an anti-CD20 antibody to chlorambucil significantly improved the progression-free survival of older patients with chronic lymphocytic leukemia and comorbidities, but it’s still unknown whether the novel agent obinutuzumab has added benefit over tried-and-true rituximab, researchers reported at the annual meeting of the American Society of Clinical Oncology.

In the phase III CLL11 study, median progression-free survival (PFS) was 23 months for patients treated with a combination of obinutuzumab (GA101) and chlorambucil (Leukeran), 15.7 months for those treated with rituximab (MabThera) and chlorambucil, and 10.9 months for chlorambucil alone. The respective PFS rates at 1 year were 84%, 63%, and 27%, reported principal investigator Dr. Valentin Goede, an oncologist at the University of Cologne, Germany.

"At this stage, my conclusion is that if an older, unfit CLL patient is put on chlorambucil treatment, then he or she in addition should receive an anti-CD20 monoclonal antibody," Dr. Goede said.

Anti-CD20 agents increased the risk of infusion reactions and neutropenias, but these side effects are manageable and should not outweigh the PFS benefits, he added.

Obinutuzumab is a type II anti-CD20 antibody with a mechanism of action that differs from that of rituximab. In preclinical models, obinutuzumab showed comparatively more direct killing action of B cells and an enhanced affinity for immunoglobulin receptors, with lower complement-dependent cytotoxicity.

The CLL11 study is a 2-stage trial asking whether chlorambucil and an anti-CD20 antibody can be superior to chlorambucil monotherapy in CLL patients with coexisting medical conditions (stage 1), and whether obinutuzumab plus chlorambucil could surpass rituximab plus chlorambucil (stage 2).

Dr. Goede reported final data from stage 1 of the trial, in which the investigators enrolled 581 adults aged 18 years and older with untreated CLL and comorbidities, defined as either a total Cumulative Illness Rating Scale score higher than 6 and/or a creatinine clearance rate lower than 70 mL/minute. An additional 190 patients are planned for stage 2 of the trial, which will be a head-to-head anti-CD20 comparison, Dr. Goede said.

The patients were randomized on a 1:2:2 ratio to either six cycles of chlorambucil 0.5 mg/kg on day 1 and day 15 of every 28-day cycle (110 patients), or to the same regimen plus either obinutuzumab 1,000 mg on days 1, 8 and 15 of the first cycle, and on day 1 of cycles two through 6 (238 patients), or to rituximab 375 mg/m² on day 1 of cycle one, and 500 mg/m² on day 1 of every subsequent cycle, for a total of six 28-day cycles (233 patients). Patients in the chlorambucil-only arm who experienced disease progression on treatment were allowed to cross over to the obinutuzumab combination.

The median patient age was about 73 years in each study arm and about three-fourths of patients were aged 65 years or older.

Overall response rates were 30.2% for patients assigned to chlorambucil alone, compared with 75.5% for patients assigned to obinutuzumab/chlorambucil, and 65.9% in the rituximab/chlorambucil arm. There were no complete responses (CR) in the monotherapy arm, 22.2% CR with obinutuzumab/chlorambucil, and 8.3% with rituximab/chlorambucil. Partial responses occurred in 30.2%, 53.3%, and 57.6%, respectively.

No patients on chlorambucil were found to be negative for minimal residual disease (MRD) in peripheral blood or bone marrow as assessed by a central laboratory at study end. In contrast, 31% of patients on obinutuzumab/chlorambucil and 2% of those on rituximab/chlorambucil were MRD-negative in peripheral blood; 17% and 2.8%, respectively, were MRD-negative in bone marrow.

The stratified hazard ratios for PFS with the anti-CD20 agent combinations, compared with chlorambucil monotherapy were 0.14 (P less than .0001) in the obinutuzumab/chlorambucil arm, and 0.32 (P less than .0001) in the rituximab/chlorambucil arm.

In a PFS subgroup analysis stratified by age, sex, comorbidity scores, mutational status, and other factors, both anti-CD20 agents showed a significant benefit over chlorambucil alone with the exceptions of patients with the 17p chromosomal deletion (both combination groups) and those with baseline chromosomal abnormalities (rituximab arm).

There were no significant differences in overall survival at a median follow-up of 14.2 months in the obinutuzumab group and 15.2 months in the rituximab group, but overall survival data are not yet mature, Dr. Goede noted.

Grade 3 or greater adverse events of any type occurred in 41% of patients on chlorambucil monotherapy, compared with 67% of patients on obinutuzumab, and 46% of those on rituximab.

Infusion-related reactions, neutropenia, and thrombocytopenia were more frequent with obinutuzumab than with the other two drugs, although adverse events leading to death were higher with chlorambucil monotherapy. The incidence of any new malignancy was 0.9% for patients on chlorambucil only, compared with 2.5% for obinutuzumab and 2.7% for rituximab.

The study was supported by Roche. Dr. Goede disclosed consulting to and receiving honoraria and research support from the company.

Obinutuzumab plus chlorambucil packs 1-2 punch against CLL in elderly