Current and emerging monoclonal antibody treatments for chronic lymphocytic leukemia: state of the art

Abstract

Anti-CD20 monoclonal antibodies (mAbs), rituximab, ofatumumab and obinutuzumab, have a significant impact in the treatment of chronic lymphocytic leukemia (CLL), particularly in combination with chemotherapy. Over the last few years, several new mAbs have been developed and investigated in CLL. The most promising newer mAbs are directed against CD20, CD19, CD37 and CD40. Combinations of antibodies with targeted drugs like ibrutinib, idelalisib or lenalidomide will probably replace chemotherapy-based combinations in the near future. This review gives a critical overview of established mAbs as well as new antibodies potentially useful in CLL.

Keywords::

• CD19
• CD20
• CD23
• CD37
• CD40
• CD52
• CLL
• dacetuzumab
• GA-101
• lucatumumab
• lumiliximab
• MOR208
• ocrelizumab
• ofatumumab
• otlertuzumab
• TRU-016
• veltuzumab

Financial & competing interests disclosure

This work was supported in part by Medical University of Lodz grant No 503/1-093-01/503-0. The author received research grants and travel grants from F. Hoffmann-La Roche, and research grants from GlaxoSmithKline, Trubion Pharmaceuticals Inc, Janssen and Gilead. The author has 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

• The anti-CD20 monoclonal antibodies rituximab, ofatumumab and alemtuzumab play an important role in the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL) and relapsed/refractory patients.

• Rituximab when used as a single agent demonstrated lower activity than in combination with cytotoxic or targeted drugs.

• Ofatumumab monotherapy shows promising efficacy in heavily pretreated patients with fludarabine- and alemtuzumab-refractory CLL.

• Chlorambucil in combination with rituximab or ofatumumab is currently accepted as the first-line treatment of progressive CLL in unfit, usually elderly, patients.

• Obinutuzumab combined with chlorambucil was approved by the US FDA for older patients with previously untreated CLL who are not as fit.

• New anti-CD20 monoclonal antibodies, veltuzumab (IMMU-106) and ocaratuzumab, are under evaluation for safety and efficacy in patients with CLL.

• Alemtuzumab, directed against the CD52 antigen, is highly active in previously treated and untreated CLL patients, including those with del(17p13) and/or TP53 abnormality or who are refractory to fludarabine.

• The results of preclinical and early clinical studies suggest that the anti-CD37 antibodies otlertuzumab (TRU-016) and BI 836826 (MAb 37.1) are active and show promising activity in CLL.

• MOR208 (XmAb5574), a novel humanized IgG1 anti-CD19 mAb, showed a tolerable toxicity profile and preliminary evidence of antitumor activity in high-risk patients with relapsed/refractory CLL.

• Lumiliximab, an anti-CD23mAb, has antitumor activity against CLL cells in preclinical studies, but its development in CLL was discontinued due to low clinical activity in Phase III study.

• Dacetuzumab and lucatumumab are anti-CD40 antibodies undergoing tests for treating CLL.