There has been a lot of interest in testing combination therapies for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). The idea is that combining multiple drugs with synergistic mechanisms of action will get patients to remission or undetectable measurable residual disease faster and allow for limited-duration therapies.
In this interview, Dr. Brian Koffman spoke with Dr. Mark Roschewski, Clinical Director of the Lymphoid Malignancies Branch at the National Cancer Institute. They discussed a now-closed clinical trial testing the combination of venetoclax with obinutuzumab and magrolimab for relapsed / refractory B-cell lymphomas.
While the trial has produced excellent results in some CLL patients, it is now closed to new patients, and it is doubtful that magrolimab will be developed to treat any type of blood cancer, including CLL. This decision was primarily driven by the poor results of adding magrolimab to other drugs in trials for more aggressive blood cancers. Still, stopping the CLL / SLL trial was swept into the larger plan.
According to the manufacturer, Gilead, trials for acute myeloid leukemia and myelodysplastic syndromes “demonstrated futility, and an increased risk of death was observed.” Gilead has now halted supplies of magrolimab for all trials involving hematological malignancies.
We still strongly recommend that you read this article and watch the video interview, as there is valuable information about how we can manipulate the immune system, why these strategies have been less successful in CLL in many different approaches (CAR-T, bispecific antibodies, other checkpoint inhibitors) compared to when used in other cancers, and why clinical trials that are closed prematurely might still be of real value to the patients in them and to the larger community.
Why use combination therapies?
Combination therapies that target multiple different pathways have the potential to provide durable remissions without having to give therapy indefinitely. The goal is to drive the disease down to the lowest possible levels, such as undetectable measurable residual disease (uMRD), and then safely stop treatment.
What is the new combination you are testing?
The combination therapy we are testing is venetoclax with obinutuzumab and magrolimab. Venetoclax and obinutuzumab are already being used to treat CLL / SLL, and magrolimab is a new drug being tested in clinical trials.
Magrolimab is an immune checkpoint inhibitor, a type of immunotherapy that stops the immune system from turning off before cancer cells are destroyed. Immune checkpoint inhibitors have been very effective in several solid tumors when blocking the adaptive immune system. The adaptive immune system is composed mainly of B and T cells, and it works by learning and remembering pathogens, including cancer cells. However, immune checkpoint inhibitors targeting the adaptive immune system have been ineffective in B-cell lymphomas.
Magrolimab is an immune checkpoint inhibitor that targets the innate immune system. The innate immune system can destroy cancer cells without having seen them before through phagocytosis, where the immune cell eats the cancer cell. Magrolimab blocks CD47, a checkpoint in the innate immune system that is overexpressed on cancer cells. CD47 is a signal that tells immune cells, “Don’t eat me.” Blocking CD47 removes the “don’t eat me” signal and allows immune cells like macrophages to eat the cancer cells.
Now, you have to be careful because you want to make sure that the immune cells are only eating the cancer cells and not anything else. Obinutuzumab helps achieve this because it binds to CD20 on B cells and places an “eat me” signal, which tells immune cells to eat the cancerous B cells. Venetoclax was also added because it is a very effective treatment that can be used in combination therapies to get patients to uMRD.
Immunotherapies have been disappointing for CLL patients in the past. Is that a concern with this therapy?
The immune system of patients with CLL does not function normally because CLL is a cancer of B cells, and it is also associated with an exhausted T cell profile. Overall, the adaptive immune system is not functioning well, which may be a reason why previous checkpoint inhibitors have yielded disappointing results. They mainly targeted the T cells of the adaptive immune system. Thus far, there is no evidence that the innate immune system cells become exhausted, so this combination therapy should be effective.
What side effects are you seeing with this combination?
Magrolimab has an immune-stimulating effect, and CD47 is expressed on other cells in the body, not just B cells. Older red blood cells seem to be particularly affected, so patients may experience low red blood cell counts during the start of treatment, but this appears to recover as treatment progresses and younger red blood cells form.
Venetoclax and obinutuzumab may contribute to immune suppression since they are both known to cause low neutrophil counts. Venetoclax is known to cause diarrhea. This is one of the main reasons researchers are interested in being able to give therapies for shorter periods. Specific side effects can be tolerated for a limited amount of time but not indefinitely.
Can you share any efficacy results yet?
Thus far, a small number of patients with CLL and other lymphomas have achieved uMRD, including patients who have yet to achieve uMRD on prior therapies. However, it is still early days, and we need more patients.
What should patients who are interested in participating know about the trial?
The study is no longer open to new patients with relapsed / refractory B-cell lymphomas. Patients with CLL should have had at least two prior therapies, including a BTK inhibitor. You can contact Dr. Roschewski directly at mark.roschewski@nih.gov if you have questions.
Links and Resources:
Watch the interview here:
Take care of yourself first.
Ann Liu, PhD
