The success of rituximab as an antibody drug targeting B-cells has led to the development of obinutuzumab – a similar, third-generation drug
Chronic lymphocytic leukemia (CLL) is a B-cell disease that is currently incurable. Combining targeted drugs has improved overall survival. However, not all patients benefit, because B-cells can harness any of several mechanisms to gain unrestricted proliferative capacity (see here).
Rituximab is an antibody drug that destroys B-cells through binding to surface CD20 molecules specifically found on B-cells. The success of this drug as combination therapy with other drugs has led to the development of other anti-CD20 drugs. Clinical trials have demonstrated that it is not just the improved biological properties of newer anti-CD20 drugs, but also the dose level that is imperative for improving survival for patients.
Obinutuzumab is a third generation anti-CD20 antibody that acts by antibody-dependent cell-mediated toxicity (ADCC, see here) and by direct killing of B-cells. Several clinical trials exploring regimens with different doses and different drug combinations with obinutuzumab have established promising outcomes. In the current study, investigators further pursued the single-agent activity of obinutuzumab and explored whether there is a dose response to this treatment that could guide future investigation of this agent.
Eighty patients with CD20-positive CLL and no previous treatment were enrolled in a clinical trial that encompassed 9 treatments cycles for two treatment arms - 1000 mg and 2000 mg. Two patients did not receive any treatment while 78 completed ≥ 90% of the planned study treatment.
This trial generated curious data. While the 18 month progression-free survival (PFS) was 59% on the 1000 mg arm and 83% on the 2000 mg arm, the difference became insignificant at later time points because the survival curves of the two arms merged. Previously, dose escalation of rituximab as combination therapy did not yield any advantages, but obinutuzumab has been engineered to mediate cell death through ADCC and direct killing – the latter of which may be influenced by dose modifications.
Investigators on this study see a need for further follow-up on this study to decipher results, and also suggest investigating higher doses of obinutuzumab in combination therapy which could potentially lead to improved survival. At HemaCare, we provide normal B-cells and cells from CLL patients for research, and look forward to all studies leading to improved odds for CLL patients.
- Byrd JC, Flynn J, Kipps TJ, Boxer M, Kolibaba KS, Carlile DJ, Fingerle-Rowson G, Tyson N, Hirata J, Sharman JP. Randomized phase II study of obinutuzumab monotherapy in symptomatic, previously untreated chronic lymphocytic leukemia (CLL). Blood. 2015 Oct 15. [Epub ahead of print]