Targeted therapies have revolutionized the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). While chemotherapy broadly kills rapidly dividing cells, targeted therapies are drugs or other substances that target specific enzymes, proteins, or other molecules involved in the growth and spread of cancer cells. Blocking these molecules may kill cancer cells or may keep cancer cells from growing or spreading. Targeted therapies can also help the immune system kill cancer cells.
Venetoclax is a highly effective targeted therapy that inhibits the BCL2 protein involved in cell survival. Obinutuzumab is a CD20 monoclonal antibody that tags CLL cells for destruction by the immune system. The combination of venetoclax and obinutuzumab is already approved for the treatment of CLL and SLL. Still, researchers are interested in whether adding another drug might make the combination even more effective.
At the American Society of Hematology (ASH) 2021, Dr. Nicole Lamanna, Associate Clinical Professor of Medicine at Columbia University Medical Center, interviewed Dr. Nitin Jain, Associate Professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. They discussed early results from an ongoing study of a triple combination therapy with venetoclax, obinutuzumab, and atezolizumab, a PD-L1 checkpoint inhibitor.
- Venetoclax, in combination with obinutuzumab, is an FDA-approved treatment for CLL / SLL.
- Researchers wanted to see if adding a checkpoint inhibitor might provide additional benefit by increasing the number of patients who can reach undetectable measurable residual disease (uMRD).
- Checkpoint proteins are found on the surface of some types of immune system cells, such as T cells and some cancer cells.
- Checkpoint proteins keep immune responses from being too strong, but they can also prevent T cells from killing cancer cells.
- Checkpoint inhibitors are a class of drugs that block checkpoint proteins allowing T cells to kill cancer cells.
- Atezolizumab is a checkpoint inhibitor that blocks PD-L1, a checkpoint protein found on cancer cells. It is already approved to treat certain types of bladder and lung cancers.
- This phase 2 clinical trial is testing the combination of:
- Venetoclax – a BCL2 inhibitor
- Obinutuzumab – a CD20 monoclonal antibody
- Atezolizumab – a PD-L1 checkpoint inhibitor
- This is an ongoing phase 2 clinical trial of this triple combination therapy in patients who have not received treatment before.
- Thus far, 26 patients have enrolled in the study, and participants are treated with all three drugs for about one year.
- So far, researchers are seeing earlier and faster bone marrow remission in patients receiving the triple combination therapy compared with what is usually seen in patients receiving venetoclax plus obinutuzumab.
- Within three months of receiving all three drugs together, approximately 90% of patients were negative for MRD in the bone marrow.
- One caveat with atezolizumab is that immune-activating drugs can cause immune-related side effects. For example, one patient had to stop treatment due to inflammation of the colon (colitis). Another patient developed inflammation of the kidney (nephritis).
- After completing one year of therapy, patients are monitored to see how long these remissions last.
It remains to be seen whether adding atezolizumab will provide better efficacy than standard-of-care venetoclax plus obinutuzumab and whether any benefits outweigh possible risks with additional side effects. However, the early results from this trial are promising. Hopefully, in one to two years, we will have a better sense of whether this triple combination therapy provides deep, long-lasting remissions for patients. Results with PD-L1 checkpoint inhibitors in CLL until now have not been strong. Immune checkpoint inhibitors and other immune therapies are reviewed by CLL Society here: Immunotherapy.
Please enjoy this interview with Dr. Jain from the ASH meeting, held both live and virtually in December 2021 in Atlanta, GA.
You can read the actual abstract here: Venetoclax, Obinutuzumab and Atezolizumab (PD-L1 Checkpoint Inhibitor) for First-Line Treatment for Patients with Chronic Lymphocytic Leukemia (CLL)
Take care of yourself first.
Ann Liu, PhD