Medically reviewed by Dr. Brian Koffman
The Bottom Line:
When treated with BCL2 inhibitors, about 20-50% of patients with different types of cancer develop clonal hematopoiesis with mutations in the protein BAX. While BAX mutations confer a survival advantage to cells in the presence of BCL2 inhibitors, there is currently no evidence that this leads to more secondary cancers.
Who Performed the Research and Where Was it Presented:
Dr. Piers Blombery from Peter MacCallum Cancer Centre and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting 2023.
Background:
All blood cells, including red and white blood cells, are made through a process called hematopoiesis. Blood comprises two main compartments: the lymphoid compartment and the myeloid compartment. The myeloid compartment (neutrophils, monocytes, eosinophils) is like the infantry; they are the immune cells on the ground directly fighting pathogens. The lymphoid compartment (B cells and T cells) is more like an intelligence agency, where they are orchestrating the immune response from afar. Both are needed for a functional immune system, but you can also get cancers arising from each compartment. Chronic lymphocytic leukemia (CLL) originates from the lymphoid compartment, while acute myeloid leukemia (AML) arises from the myeloid compartment.
As people age, they accumulate mutations in their DNA. Most of the time, these mutations don’t have any functional consequence, but every once in a while, a mutation can confer a survival advantage to a cell. These cells replicate and produce more cells with the same genetic mutation. In the bone marrow, this process is called clonal hematopoiesis, an overgrowth of blood cells with the same genetic mutation. Clonal hematopoiesis is a premalignant state that is a risk factor for developing cancer, but the overall risk of actually progressing to cancer is low.
The BCL2 pathway is essential for hematopoiesis and is needed to form myeloid and lymphoid cells. However, BCL2 inhibitors are one of the leading therapies for treating CLL. When patients are treated with the BCL2 inhibitor venetoclax, the blood systems develop mutations in a protein called BAX to get around this. These BAX-mutated cells undergo clonal hematopoiesis because BAX mutation confers a survival advantage. Researchers wanted to learn more about how common BAX mutations are after exposure to BCL2 inhibitors.
Methods and Participants:
Researchers assessed the prevalence of BAX variants in both blood cancers (AML and CLL) and breast cancer.
Results:
- BAX mutations were detected in 35-55% of AML patients in complete remission after venetoclax treatment. For comparison, only 7% of AML patients had BAX mutations after chemotherapy.
- BAX mutations were detected in 31% of patients with metastatic breast cancer who had been treated with venetoclax in combination with tamoxifen. In comparison, no BAX mutations were detected in similarly-aged breast cancer patients who had not been exposed to venetoclax.
- BAX mutations were detected in 22% of CLL patients treated with second-generation BCL2 inhibitor BGB-11417
Conclusions:
About 20-50% of patients with different types of cancer develop BAX-mutated clonal hematopoiesis when treated with BCL2 inhibitors. While BAX mutations confer a survival advantage in the presence of BCL2 inhibitors, there is currently no evidence that this leads to more secondary cancers. As patients with CLL live longer and longer, this type of research is essential for understanding some of the long-term risks associated with specific treatments.
Links and Resources:
Watch the interview on the abstract here:
You can read the actual ASH abstract here: BAX Mutated Clonal Hematopoiesis Arises Following Treatment with the BCL2 Inhibitor Class of Therapeutics across a Range of Hematological and Non-Hematological Neoplasms
Take care of yourself first.
Ann Liu, PhD
