Obinutuzumab plus Bendamustine in Previously Untreated Patients with CLL: Subgroup Analysis of the Phase 3 GREEN Study
Obinutuzumab is a glycoengineered anti-CD20 monoclonal antibody that showed superior survival outcomes in combination chlorambucil compared with chlorambucil alone and with an acceptable safety profile in patients with chronic lymphocytic leukemia (CLL) in the CLL11 study.1 GREEN is an ongoing, nonrandomized, multicohort phase 3b study that is investigating the safety and efficacy of obinutuzumab with or without chemotherapy in patients with previously untreated or relapsed/refractory CLL, with cohorts 1-3 assessing strategies to reduce the rate of infusion-related reactions during the first infusion of obinutuzumab. Stilgenbauer and colleagues reported the safety and efficacy data of a subgroup of previously untreated patients in cohort 1 who received obinutuzumab/bendamustine (obinutuzumab administered day 1/day 2 of cycle 1 [split dose: 25 mg day 1/975 mg day 2], and 1000 mg on day 8 and day 15 of cycle 1 and day 1 of cycles 2-6). Safety end points included incidence, type, and severity of adverse events; efficacy end points included investigator-assessed overall response rate (ORR) and minimal residual disease (MRD; defined as <1 x 10-4 malignant B-cells in peripheral blood or bone marrow) measured 3 months posttreatment.2
Cohort 1 was comprised of 158 patients, with a median age of 67.6 years; 74 patients were deemed fit and 84 nonfit; 15.8% of patients had a Cumulative Illness Rating Scale score of >6, 44.9% with clearance creatinine of <70 mL/min; and 58.2% harbored unmutated IgHV. The most predominant grade ?3 adverse event (AE) was neutropenia, occurring in 50% of patients; other grade ?3 AEs included infection (12.7%), thrombocytopenia (12.7%), and tumor lysis syndrome (TLS; 10.1%). The most common serious AEs were neutropenia (10.8%), pyrexia (7.6%), febrile neutropenia (7.0%), and TLS (5.1%). Overall, 9 deaths were reported; of these, 4 were due to treatment-related AEs of infection, sudden death, acute hepatic failure, and febrile neutropenia combined with TLS. Infusion-related reactions were reported in 55.7% of patients; 15.2% of these were of grade 3/4 severity. Overall, 26 (16.5%) patients discontinued study treatment due to ?1 AEs. In the intent-to-treat analysis, the ORR was 78.5%, including a complete response (CR)/incomplete complete response (CRi) of 32.3%, and partial response (PR) of 46.2%. Response rates were found to be similar in both nonfit (CR/CRi: 34.5%; PR: 41.7%) and fit (CR/CRi: 29.7%; PR: 51.4%) patients. MRD negativity was achieved in 58.9% blood and 27.8% bone marrow samples. With a median observation time of 11.2 months, PFS data were immature and the median was not reached. Based on the preliminary results, the authors concluded that the obinutuzumab/bendamustine treatment in previously untreated CLL patients was associated with a not unexpected and manageable toxicity profile, and showed promising activity in both fit and nonfit patients with CLL.
- Goede V, et al. N Engl J Med. 2014;370:1101-1110.
- Stilgenbauer S, et al. ASH 2015. Abstract 493.