Treatment with obinutuzumab plus chlorambucil led to greater improvements in progression-free survival (PFS) and overall survival (OS) than the combination of rituximab and chlorambucil, or chlorambucil alone, in older patients with previously untreated chronic lymphocytic leukemia (CLL). The final analysis of the CLL11 study was presented by Valentin Goede, MD, from St. Marien Hospital in Cologne, Germany, at the 23rd Congress of the European Hematology Association.
“The final analysis of the trial after its closure in 2017 robustly demonstrates superiority of the obinutuzumab arm with regard to PFS, time to next treatment (TTNT), and OS,” Dr. Goede said, adding that “the finding to highlight [in this trial] is the OS benefit of obinutuzumab over rituximab.”
In this phase III study, researchers randomized 781 patients (median age = 73 years; age range = 39-90 years) with previously untreated CD20-positive CLL to frontline treatment with one of three therapeutic strategies: chlorambucil (n=118), rituximab plus chlorambucil (n=330, or obinutuzumab plus chlorambucil (n=333).
Each group received treatment in six 28- day cycles, delivered at the following doses:
- chlorambucil 0.5 mg/kg on day 1 and day 15 of cycles 1-6
- rituximab 375 mg/m2 on day 1 of cycle 1 and 500 mg/m2 on day 1 of cycles 2-6
- obinutuzumab 1,000 mg, with 100 mg on day 1; 900 mg on days 2, 8, and 15 of cycle 1; and day 1 of cycles 2-6
At a median follow-up of 59.4 months (range not reported), the median investigator-assessed PFS (primary endpoint) for the obinutuzumab-treated patients was significantly longer than for the rituximab-treated patients: 28.9 months versus 15.7 months (hazard ratio [HR] = 0.49; 95% CI 0.41-0.58; p<0.0001). Patients receiving obinutuzumab with chlorambucil also experienced greater improvements in OS (not reached vs. 73.1 months; HR=0.76; 95% CI 0.60-0.97; p=0.0245) and extended TTNT (56.4 months vs. 34.9 months; HR=0.58; 95% CI 0.46-0.73; p<0.0001).
Compared with chlorambucil alone, the combination of obinutuzumab with chlorambucil resulted in significant improvements in all endpoints, at a median follow-up of 62.5 months (range not reported):
- PFS: 11.1 months vs. 31.1 months (HR=0.21; 95% CI 0.16-0.28; p<0.0001)
- OS: 66.7 months vs. not reached (HR=0.68; 95% CI 0.49-0.94; p=0.0196)
- TTNT: 15.1 months vs. 55.7 months (HR=0.25; 95% CI 0.19- 0.35; p<0.0001)
In the obinutuzumab plus chlorambucil arm, the two- and five-year survival rates were 91 percent and 66 percent, respectively, versus 84 percent and 57 percent among those receiving rituximab plus chlorambucil. Fewer deaths were observed in the obinutuzumab versus rituximab treatment arms (37% vs. 45%, respectively), and disease progression was deemed the most common cause of mortality in this patient population.
According to Dr. Goede, the varying doses of antibodies and chlorambucil used in this trial represent the primary limitation of the analysis.
He also noted that these findings support treatment guidelines that suggest that the combination of obinutuzumab and chlorambucil represents a valid frontline therapeutic strategy for older patients with CLL or those who are deemed unfit for intensive chemotherapy. The observed OS benefit associated with using a type 2 glycoengineered versus a type 1 anti-CD20 antibody also indicates that the CD20-targeting quality should be considered an important factor in modifying CLL prognosis. “In CLL, optimized CD20 targeting by use of obinutuzumab within new treatment combinations therefore makes perfect sense,” he concluded.
Dr. Goede reports financial relationships with Janssen, Gilead, AbbVie, and Roche, which also sponsored this study.
Goede V, Fischer K, Dyer MJS, et al. Overall survival benefit of obinutuzumab over rituximab when combined with chlorambucil in patients with chronic lymphocytic leukemia and comorbidities: final survival analysis of the CLL11 study. Abstract #S151. Presented at the EHA 23rd Congress, June 15, 2018; Stockholm, Sweden.