ISAL 2023 | Clonal hematopoiesis in AML & insights into a novel CHIP risk stratification score being explored

So this has been a phenomenal meeting because it really brings together the scientists and the clinicians. But my talk was about clonal hematopoiesis and this is a pre-malignant state where there are somatic mutations in blood cells that lead to an expanded clone of cells in the peripheral blood. And we’ve been able to study this at massive scale because there are many hundreds of thousands of individuals with exome sequencing of their blood cells and detailed clinical phenotyping. And so we can really understand this at an enormous scale. And having clonal hematopoiesis, having a mutation in the blood, turns out to be very common. About 10% of everybody by the age of 70 has a large clone in their peripheral blood with a mutation in DNMT3A, TET2, ASXL1 or other genes. And having one of those mutations increases the risk of developing leukemia and other myeloid malignancies. It also increases overall mortality dying of all causes, including not from leukemia. And we found that individuals with these mutations in their blood alter the function of the mutated blood cells in a way that leads them to have more inflammation. And that has led to the discovery that CHIP, which is these individuals with these mutations, have an increased risk of cardiovascular disease as well as other inflammatory diseases, including emphysema and gout and osteoporosis. And one story I told today is that there’s really quite a large increase in liver disease. NASH, which is nonalcoholic steatohepatitis as well as fibrosis and cirrhosis. And so there are many negative consequences for health having these mutations. One quite striking finding is that while many inflammatory diseases have an increased risk in individuals with CHIP, Alzheimer’s disease and other neurodegenerative diseases have a decreased risk in individuals with CHIP and that biology is still being worked out. And the other thing I talked about today is that we’ve put together a risk score, a clonal hematopoiesis risk score where you can put together the mutations, the specific genes that are mutated, whether there are one or more genes that are mutated, whether there are altered blood cell parameters, cytopenias, altered red cell distribution width or MCV and integrate all of that together into a clonal hematopoiesis risk score. Individuals with high risk have an over 50% risk of developing a myeloid malignancy in the next ten years. People with low risk, which is about 90% of people with CHIP, have an extremely low risk of leukemia or other myeloid malignancy and really probably don’t need close follow up.