Obinutuzumab plus bendamustine: a new treatment option for patients with untreated CLL

Results of the ongoing, phase III GREEN study demonstrate that treatment with a combination of obinutuzumab and bendamustine in previously untreated chronic lymphocytic leukemia (CLL) patients is generally well tolerated, with manageable and expected toxicities. Interestingly, the combination of obinutuzumab and bendamustine was shown to be associated with a promising rate of complete responses in these patients and was able to induce a high rate of minimal residual disease (MRD) negative remissions. As such, obinutuzumab in combination with bendamustine may represent a new first-line treatment option for both fit and non-fit patients with CLL.

Obinutuzumab is a glyco-engineered, type II anti-CD20 monoclonal antibody. When combined with chlorambucil, it was shown to have superior efficacy to chlorambucil monotherapy and to a combination of chlorambucil with rituximab in patients with CLL. Moreover, in this study (CLL11), obinutuzumab plus chlorambucil had an acceptable safety profile.

The GREEN study is an ongoing, non-randomized, multi-cohort phase IIIb study investigating the safety and efficacy of obinutuzumab alone or in combination with chemotherapy in patients with previously untreated or relapsed/refractory CLL. At ASH 2015, safety and efficacy data were presented from a subgroup of previously untreated patients in cohort 1 of the GREEN study who received a combination of obinutuzumab and bendamustine.

The planned overall sample size of the GREEN study is 950 patients. Eligible patients for GREEN had to be 18 years or older and have a documented CLL, with an ECOG performance status of 0–2 and adequate hematologic function. In the study, unfit patients were defined as patients with a creatinine clearance of

The observed safety profile of the obinutuzumab-bendamustine combination was in line with the expectations. In total, 50% of patients developed grade 3–5 neutropenia and 12.7% developed a grade 3–5 infection. Other common grade 3–5 adverse events included thrombocytopenia (12.7%) and tumor lysis syndrome (10.1%). The most common serious adverse events were neutropenia (10.8%), pyrexia (7.6%), febrile neutropenia (7.0%), and tumor lysis syndrome (5.1%). In total, 9 deaths were reported, of which 6 were unfit patients: one due to progression, and eight deaths were related to an adverse event. Of these deaths due to an adverse event, four were considered to be treatment-related: 1 infection, 1 sudden death, 1 acute hepatic failure, and 1 febrile neutropenia combined with tumor lysis syndrome. Overall, 26 patients (16.5%) prematurely discontinued their treatment due to one or more adverse events.

With respect to efficacy, a promising overall response rate of 78.5% was reported. In 51 patients (32,3%) a complete response (CR), or a CR with incomplete bone marrow recovery (CRi) was reported. A partial response (PR) was seen in 73 patients (46,2%) and in 17 patients (10.8%) disease stabilization was observed. Of note, these response rates were similar for both fit and unfit patients with a CR/CRi rate of 34.7% in unfit and 29,7% in fit CLL patients. An analysis of the MRD-negativity in the total intent-to-treat population revealed a rate of MRD-negativity in the blood in 58,9%, and in 28,5% of the patients bone marrow MRD-negativity was reported. Only taking into account the patients that were evaluable for the MRD analysis (excluding patients with missing data), MRD negativity in the blood was seen in 93 of 102 evaluated patients (91,2%). Of the 64 patients evaluable for MRD-negativity in the bone marrow, 45 (70,3%) were shown to be MRD-negative. Of note, similar rates of CR/CRi and MRD-negativity were seen in all investigated subgroups, except for patients with a deletion of 17p where lower rates were reported (50% MRD negativity, 18,2% CR/CRi).

In summary, obinutuzumab plus bendamustine achieves promising CR and MRD-negativity rates in both fit and non-fit patients with CLL. Moreover, the treatment was well tolerated, with no unexpected safety signals.

Reference

Stilgenbauer S, Ilhan O, Woszczyk D, et al. Safety and Efficacy of Obinutuzumab Plus Bendamustine in Previously Untreated Patients with Chronic Lymphocytic Leukemia: Subgroup Analysis of the Green Study. Presented at ASH 2015; Abstract #493.