This article will touch on the use of anti-CD20 antibodies, specifically obinutuzumab (Gazyva), the first type 2 monoclonal antibody.
The palliative treatment goal of a chronic lymphocytic leukemia (CLL) survivor is to reduce the suffering of cancer and to increase survival. One of these treatment options is obinutuzumab. For the patients who need treatment, anti-CD20 antibodies will often be part of the treatment armamentarium.
Most people know about antibodies because they are produced by our body’s immune system to help fight infections. These bacteria or viruses that cause infections are typically proteins and are also known as antigens. When an antigen or foreign protein enters the body, it stimulates the immune system to produce antibodies. Scientists discovered that if antibodies could be created to recognize specific proteins on cancer cells, the immune system could be used to destroy the cancer. One of the proteins on the CLL cell is called CD20.
Think of anti-CD20 antibodies as guided missiles. There is a type of cell in your blood called a B lymphocyte. This B lymphocyte is where the CLL cancer cell comes from. The missile is designed to destroy the B lymphocyte and as a result, kill the CLL cancer cell.
B lymphocytes fly a flag, or a cell surface marker, called CD20. CD20 is a phosphoprotein that is expressed on the surface of all B lymphocytes, starting at the immature pro-B phase. To simplify, think of CD20 as a flag that tells the drug that it is a B lymphocyte. Therefore, the drug will know what to destroy. There are three FDA approved anti-CD20 antibodies that take advantage of the above finding.
Rituximab is the oldest of the three approved antibodies. It was developed using cloning and recombinant DNA technology from human and murine (mice or rat) genes. It was originally FDA approved in 1997 for treatment of non-Hodgkin Lymphoma that was resistant to chemotherapy. This drug revolutionized the way we treat many lymphomas and leukemias. It is even used in rheumatologic and ocular diseases as it depletes all B cells, cancerous or not.
Ofatumumab and Obinutuzumab are more modern anti-CD20 antibodies that were approved in 2013 and 2014, respectively. These are approved in combination with chlorambucil for patients with previously untreated CLL.
Ofatumumab is the first fully humanized monoclonal antibody that targets the CD20 molecule and is approved for use in combination with chlorambucil, for the treatment of previously untreated patients with CLL.
Obinutuzumab is a glycoengineered antibody that demonstrated significantly higher efficacy over rituximab and other Type I monoclonal antibodies in B-cell malignancies such as CLL. The effect of the glycoengineering improves the binding of monoclonal antibodies with immune cells.
Obinutuzumab is a glycoengineered, humanized type II anti-CD20 antibody. As opposed to type I anti-CD20 mAbs (eg, rituximab) it induces no complement-dependent cytotoxicity. However, obinutuzumab is a much stronger inducer of direct cell death and antibody-dependent cellular cytotoxicity.
van Oers MHJ. CD20 Antibodies: Type II to Tango? Blood.2012;119 (22): 5061-3.http://www.bloodjournal.org/content/bloodjournal/119/22/5061.full.pdf
In other words, unlike rituximab that is dependent on adequate levels of serum complement to kill the cancer cells, obinutuzumab can do its killing directly.
The phase III CLL11 clinical trial [NCT01010061] led to the approval of obinutuzumab. First, we need to understand the purpose of the trial. The investigators wanted to test whether the use of obinutuzumab was better than chemotherapy (in this case, chlorambucil) or chlorambucil in combination with rituximab. CLL survivors who enrolled in this trial received one of three treatments: chlorambucil alone, chlorambucil + rituximab, or chlorambucil + obinutuzumab.
The median age of the trial participants was 73 years old, and the patient populations were similar in each treatment arm. All shared similar medical problems and disease severity of CLL.
The addition of antibodies, either rituximab or obinutuzumab resulted in better response rates than chlorambucil alone. In fact, the investigators stopped enrolling patients to the chlorambucil-alone arm, as it was quickly understood that these patients did not do as well. Side effects were more frequent with obinutuzumab + chlorambucil, specifically infusion reactions and lower blood counts.
The last question is whether obinutuzumab is better than rituximab when combined with chlorambucil. The results of the trial demonstrated that obinutuzumab is superior to rituximab regarding progression free survival, overall response rate and minimal residual disease negativity. There is no observed difference in overall survival. The obinutuzumab group had more adverse events with regard to infusion reactions and neutropenia. The rituximab group had more adverse events with regard to infections.
The results of this trial led to FDA approval in 2013. The combination of chlorambucil + obinutuzumab is approved for patients with previously untreated CLL.
Progression free survival is the time between starting the clinical trial and the disease getting worse or the patient dying from any cause, including non-CLL reasons. We often measure progression free survival because it takes too long to measure overall survival in various clinical trials. Some believe it is a surrogate marker for overall survival.
Overall response rate means that the cancer gets “smaller” due to treatment.
Minimal residual disease negativity means that the patient’s CLL has been diminished so much that it cannot be detected. It is thought that patients who have minimal residual disease negativity will ultimately have the longest time in remission. It is a powerful measurement to describe how well a drug is working.
Infusion reactions typically happen within 30 minutes to two hours after the initiation of drug infusion, although they can be delayed for up to 24 hours. Most occur after the first or second dose of the medication, but up to 30% can happen with later treatments.
Obinutuzumab is associated with strong infusion reactions. That is why the first dose is usually split into a small test dose the first day, followed the next day by the remainder of the full dose. Even so, the test dose often results in an infusion reaction.
Signs and symptoms of infusion reactions can include fever, chills, rigors, hives, hypotension and hypertension with headache, wheeze, breathlessness, hypoxia (low blood oxygen), and pulmonary infiltrates.
Patients are observed for infusion reactions during early administration of monoclonal antibodies and are often proactively treated with antihistamines and/or steroids and acetaminophen. When they do occur, though frightening, they can almost always be managed by stopping the infusion, giving IV steroids and antihistamines, and then restarting the IV at a slower pace.
Dr. Sharma is a hematologist/oncologist at St. Jude Medical Center in Fullerton, California. He is a member of the Medical Advisory Board for the CLL Society.
Originally published in The CLL Tribune Q4 2015.
