Obinutuzumab for chronic lymphocytic leukemia

Abstract

Chronic lymphocytic leukemia (CLL) is a frequent hematological malignancy that is incurable using standard approaches. Two anti-CD20 monoclonal antibodies (mAb), rituximab and ofatumumab, have been approved for CLL treatment. A new glycoengineered type II humanized anti-CD20 mAb, obinutuzumab (GA101), has been developed and demonstrates increased activity against B-cell malignancies by inducing direct cell death and better antibody-dependent cellular cytotoxicity. In a recent randomized Phase III study in patients with newly diagnosed CLL and coexisting conditions, obinutuzumab plus chlorambucil demonstrated significant improvement in progression-free survival and several other outcome parameters, in contrast to rituximab plus chlorambucil. Grade 3–4 infusion-related reactions and neutropenia occurred more frequently in patients who received obinutuzumab compared with those who received rituximab; however, the rate of serious infections was similar. Obinutuzumab represents a promising new option for patients with CLL and must be investigated with other chemotherapy regimens or with new targeted agents.

Keywords::

• antibody-dependent cellular cytotoxicity
• anti-CD20 monoclonal antibody
• chlorambucil
• chronic lymphocytic leukemia
• direct cell death
• infusion-related reaction
• obinutuzumab
• rituximab

Financial & competing interests disclosure

The authors are solely responsible of the manuscript contents and received no help or support for this manuscript. C Rioufol had received research funding from Roche. G Salles has received honoraria for board meetings and seminars from Roche, Mundipharma, Gilead, Janssen and Celgene; Research support from Roche and Alizee Pharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed

No writing assistance was utilized in the production of this manuscript.

Key issues

• As in other B-cell malignancies, anti-CD20 monoclonal antibodies constitute a pivotal component in the treatment of patients with chronic lymphocytic leukemia (CLL). Rituximab and ofatumumab are type I anti-CD20 mAb that are already approved for the treatment of CLL.

• Obinutuzumab is a new and distinct anti-CD20 antibody, which recognizes a different epitope of the CD20 molecule and engages different modes of action in vitro and in vivo to deplete B cells. Specifically, this type II glycoengineered and humanized mAb exerts a high level of direct cell kill and enhanced antibody-dependent cell-mediated cytotoxicity.

• In a Phase III randomized study for the first-line treatment of CLL patients with advanced age and co-morbidities, the combination of obinutuzumab plus chlorambucil demonstrated a significant clinical benefit over chlorambucil alone (significant overall survival benefit) and a superior efficacy (CR rate and PFS) over the combination of rituximab and chlorambucil. The obinutuzumab combination showed a favorable safety profile, with a higher incidence of infusion-related reactions at the time of the first infusion that must be prevented and monitored.

• Obinutuzumab has been approved as the first-line treatment of patients with CLL in combination with chlorambucil and is likely to play a key role in the evolving management of this disease in the future.