Obinutuzumab/Chlorambucil in the First-Line Treatment of Older CLL Patients

Results of a large randomised phase III trial of first-line chemo-immunotherapy in patients with comorbidities

Obinutuzumab/chlorambucil is superior to rituximab/chlorambucil in the first-line treatment of older patients with chronic lymphocytic leukaemia (CLL) suffering from comorbidities. Obinutuzumab/chlorambucil combination led to a prolongation in progression-free survival (PFS) which was the study primary endpoint. Secondary efficacy endpoints of higher response rate and minimal residual disease (MRD) negativity rate were also achieved. Prolonged overall survival (OS) was seen when compared obinutuzumab/chlorambucil vs. chlorambucil alone. The final results of the phase III CLL11 trial were presented during a Plenary Session at the 55th American Society of Hematology (ASH) Annual Meeting (7-10 December 2013, New Orleans, USA).  

The CLL11 study conducted by German CLL Study Group is a large randomised phase III trial investigating first-line chemo-immunotherapy in CLL patients with comorbidities who are typical patients treated in daily practice. The team of researchers from Germany, Russia, Spain, France, Australia, Canada and The Netherlands led by Dr Valentin Goede of the Department I of Internal Medicine, University Hospital Cologne, Germany presented the final stage 2 analysis with efficacy and safety results of the head-to-head comparison between obinutuzumab plus chlorambucil and rituximab plus chlorambucil. At the pre-planned interim analysis, the primary endpoint was met early and the results were released by the independent data monitoring board. In addition, the researchers presented an update on the stage 1 analysis (obinutuzumab/chlorambucil vs. chloramabucil and rituximab/chlorambucil vs. chlorambucil comparisons) with longer observation time; the final stage 1 analysis recently showed that cholrambucil combination with either obinutuzumab or rituximab has superior efficacy to chemotherapy with chlorambucil alone.

The CLL11 study design and results

Treatment-naïve CLL patients with a Cumulative Illness Rating Scale (CIRS) total score >6 and/or an estimated creatinine clearance (CrCl) <70 mL/min were eligible for the study. The study enrolled 781 patients and randomly assigned them in a 2:1:2 ratio: obinutuzumab/chlorambucil for six cycles, chlorambucil for six cycles, or rituximab/chlorambucil for six cycles.

Obinituzumab is a novel, glycoengineered, type II CD20 antibody that is designed to enhance direct cell death and antibody-dependent cellular cytotoxicity. It is being investigated in CLL, Non-Hodgkin’s lymphoma and other haematologic indications.

Final results of the stage 2 analysis with a median observation time of 19 months showed that the obinituzmuab/chlorambucil and rituximab/chlarmabucil arms were well balanced for baseline characteristics. Median age at baseline was 73 year, CIRS score 8, and CrCl 63 mL/min, respectively.

The PFS benefit of obinituzmuab/chlorambucil over rituximab/chlarmabucil was supported by all pre-planned subgroup analyses, including the cytogenetic subgroups 17p-, 11q-, 12+, 13q-. For the primary endpoint, obinutuzumab/chlorambucil led to a 61% improvement in the likelihood of achieving PFS. Median PFS was 26.7 months vs. 15.2 months, respectively (p < 0.0001).

Overall response rate was higher with obinutuzumab/chlorambucil vs. rituximab/chlorambucil: 78% vs. 65%. Obinutuzumab/chlorambucil was also superior in eradicating detectable disease in the bone marrow and in blood; the rate of minimal residual disease–negative status in bone marrow was 19.5% for obinutuzumab/chlorambucil vs 2.6% for rituximab/chlorambucil (p < 0.0001), and minimal residual disease–negative status in blood was observed in 37.3% vs. 3.3% of patients, respectively (p < 0.0001).

Grade 3-4 infusion-related reactions with obinituzmuab/chlorambucil occurred at first infusion only.

Updated results of the stage 1 analysis with median observation time of 23 months show that obinituzmuab/chlorambucil or rituximab/chlarmabucil compared with chlorambucil alone was associated with statistically significant and clinically meaningful improvement in PFS (p<0.0001). The updated median PFS in obinituzmuab/chlorambucil, rituximab/chlormabucil and chlorambucil arms were 26.7, 16.3 and 11.1 months, respectively. Updated OS analysis demonstrated a benefit of obinituzmuab/chlorambucil over chlorambucil (HR 0.41, CI 0.23-0.74, p=0.002). OS analysis for rituximab/chlormabucil over chlorambucil showed HR 0.66, CI 0.39-1.11, p=0.113. At the data cut-off, 9%, 15%, and 20% of the patients in the obinituzmuab/chlorambucil, rituximab/chlormabucil, and chlorambucil arms, respectively, had died. However, OS medians were not reached.

Potentially practice-changing findings

The authors concluded that obinituzumab in combination with chlorambucil demonstrated statistically significant and clinically meaningful prolongation of PFS, and higher complete response rate and MRD negativity rate compared with rituximab/chlorambucil in previously untreated CLL patients with comorbidities.

Obinutuzmab/chlorambucil was associated with more grade 3-4 adverse events, mainly infusion-related reactions that occured during the first infusion (20% in patients treated with obinutuzumab/chlorambucil vs. 4% with rituximab/chlorambucil) and neutropenia.

Obinituzumab/chlorambucil vs. chlorambucil alone demonstrated a prolongation of OS. However, OS data are not yet mature, but at present obinutuzumab/chlorambucil appears to be significantly better than rituximab/chlorambucil and according to study investigators these results may suggest that obinutuzumab can replace rituximab when combined with chlorambucil as first-line treatment for older CLL patients with comorbidities. This may mean a potential decrease in the amount of chemotherapy required for an effective combination regimen, translating to less toxicity for patients. They stated the findings are significant and potentially practice-changing.

Disclosures: Valentin Goede: Mundipharma: Honoraria; F. Hoffmann-La Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Kirsten Fischer: Mundipharma: Travel grants, Travel grants Other; F. Hoffmann-La Roche: Travel grants Other. Anja Engelke: F. Hoffmann-La Roche: Travel grants Other. Barbara Eichhorst: Mundipharma: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Consultancy; F. Hoffman-La Roche: Honoraria, Research Funding. Clemens M Wendtner: F. Hoffmann-La Roche: Consultancy, Research Funding. Marie-Sarah Dilhuydy: F. Hoffmann-La Roche: Consultancy. Stephen Opat: F. Hoffmann-La Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Alexion Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees; Novartis Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Carolyn J Owen: F. Hoffmann-La Roche: Honoraria. Karl-Anton Kreuzer: F. Hoffmann-La Roche: Consultancy, Honoraria. Anton W Langerak: F. Hoffmann-La Roche: Research Funding. Matthias Ritgen: F. Hoffmann-La Roche: Research Funding. Stephan Stilgenbauer: F. Hoffmann-La Roche: Consultancy, Honoraria, Research Funding. Elina Asikanius: F. Hoffmann-La Roche: Employment. Kathryn Humphrey: F. Hoffmann-La Roche: Employment. Michael K Wenger: F. Hoffmann-La Roche: Employment, Ownership interests (including stock options) in a start-up company, the stock of which is not publicly traded Other. Michael Hallek: F. Hoffmann-La Roche: Consultancy, Honoraria, Research Funding.