Although stem cells throughout the body acquire genetic mutations over time, usually these alterations do not affect how the stem cells function or cause disease. However, recent research in clonal hematopoiesis and aging has found an association between clonal expansion of hematopoietic cells with somatic mutations and the potential for the future development of a hematologic malignancy or cardiovascular death, a phenomenon termed clonal hematopoiesis of indeterminate potential (also known as CHIP) by David P. Steensma, MD, and his colleagues. According to Dr. Steensma, Co-Director of the Center for Prevention of Progression; Edward P. Evans Chair in Myelodysplastic Syndromes Research at Dana-Farber Cancer Institute; and Associate Professor of Medicine at Harvard Medical School, the specific somatic mutations leading to clonal expansion that are most commonly acquired include DNMT3A, ASXL1, and TET2.
David P. Steensma, MD
“These mutations were first discovered in patients with acute myeloid leukemia [AML] or myelodysplastic syndromes [MDS], and we assumed they were disease-specific. But it turned out that there are a lot of healthy people with these mutations, too,” explained Dr. Steensma. “That finding by itself was interesting, but then we learned that these mutations in blood cells are also associated with heart attack and stroke by promoting inflammation in the walls of the blood vessels, which was really a surprise.”
Research indicates that somatic exonic mutations in hematopoietic stem cells begin to accumulate in childhood, even in utero. Mutations in leukemia-associated genes are rarely detected in people younger than age 40, but they increase in frequency with age. Clonal hematopoiesis, in which at least 2% of the blood DNA is mutant, can be found in about 10% of people without known hematologic malignancies older than age 65; in nearly 12% of those in their 80s; and in more than 18% of people aged 90 and older.1 Although individuals with clonal hematopoiesis of indeterminate potential do not have symptoms of disease or abnormal blood cell counts, their risk of developing leukemia is more than 10 times greater than average, according to Dr. Steensma. Acquiring one of these mutations is also associated with increased all-cause mortality, mainly due to cardiovascular causes, which happens at twice the rate in people with this condition compared to those without mutations.1
In addition to aging, people with clonal hematopoiesis of indeterminate potential also have an increased risk of developing MDS or AML after treatment with cytotoxic chemotherapy or radiotherapy for a solid tumor, lymphoma, or multiple myeloma, usually due to expansion of preexisting TP53-mutant clones during therapy. Clonal hematopoiesis may also occur after hematopoietic cell transplant or induction chemotherapy for acute leukemia as well as during the course of aplastic anemia.2
The ASCO Post talked with Dr. Steensma about how clonal hematopoiesis of indeterminate potential influences the development of leukemia and cardiovascular disease, how to alter its course, and the clinical implications for patients.
Role of Clonal Hematopoiesis
Currently, clonal hematopoiesis of indeterminate potential is often discovered accidentally, usually via a genetic test or blood/bone marrow sample. Should testing for this condition become part of a person’s routine physical exam?
If we someday find that we are able to reduce the risk of cardiovascular disease, including heart attack and stroke, with an intervention, say an anti-inflammatory drug, then, yes, screening for clonal hematopoiesis of indeterminate potential would become feasible. It has already been shown that canakinumab, an antibody against interleukin-1β, may reduce the risk of second events in people who have this condition and previously had a heart attack. Given how common clonal hematopoiesis is, having a screening test that becomes part of a periodic physical exam, similar to a cholesterol screening, as a routine preventive measure could be useful if there were an intervention proven to reduce mortality. This condition is so prevalent in older people and is a strong risk for cardiovascular events on the same order of magnitude as high cholesterol or smoking. By the time a person reaches age 70, he or she has at least a 10% risk of clonal hematopoiesis, and the higher risk of developing cardiovascular disease combined with the population burden is quite meaningful.
Encouraging patients to quit smoking; eat a healthy diet; increase physical activity; and manage conditions such as hypertension, hyperlipidemia, or diabetes might help to mitigate the risk of heart attack and stroke in these patients. These measures are important for everyone, but likely to be especially important for folks with clonal hematopoiesis.
Unfortunately, we have no idea how to prevent MDS or leukemia in people with clonal hematopoiesis–associated mutations. Thankfully, for those with normal blood cell counts, the risk of developing MDS or AML is relatively low, 0.5% to 1% per year. The people who are at greatest risk of developing MDS or AML are those with both a clonal hematopoiesis–associated mutation and a low blood cell count. We call that situation “clonal cytopenia of undetermined significance.” For those patients, we recommend periodic monitoring of blood cell counts, since most patients with clonal cytopenia of undetermined significance will develop MDS or AML within 5 years.
Researchers are looking at different ways to alter MDS or AML risk in patients with clonal hematopoiesis of indeterminate potential.
For example, there are U.S. Food and Drug Administration–approved targeted inhibitors for the treatment of AML with an IDH1 or IDH2 mutation: ivosidenib and enasidenib, respectively. It has been proposed to study those drugs in patients with the rare IDH1/2-mutant clonal hematopoiesis of indeterminate potential/clonal cytopenia of undetermined significance subtype to test whether they can change the natural history and delay or prevent MDS or AML.
Mutations in the TET2 gene are increasingly common in healthy individuals as they age, and research led by Luisa Cimmino, PhD, Assistant Professor at the University of Miami Miller School of Medicine, recently found that high-dose vitamin C treatment may restore disrupted TET2 function.3 Studies are underway to investigate high-dose vitamin C in patients with TET2-associated clonal hematopoiesis or clonal cytopenia to see whether they benefit from that treatment.
Researchers are also discussing using very low doses of drugs that are active in MDS, including the DNA methyltransferase inhibitors decitabine and azacitidine, to potentially reduce the size of the clonal hematopoiesis clone. However, these ideas are all in their infancy, and we don’t know whether any of them will work. As I mentioned previously, we have no idea how to prevent this condition from progressing to MDS or AML. It is a top priority for us to determine how to prevent these common precursor conditions from progressing to a cardiovascular event or leukemia.
Clonal Hematopoiesis Link to Heart Attack and Stroke
How does clonal hematopoiesis of indeterminate potential increase the risk of developing cardiovascular disease?
We have good evidence from murine models and from actually looking at the atherosclerotic fatty plaques in human blood vessels that clonal hematopoiesis–associated mutations, especially TET2 and DNMT3A, promote vascular disease—particularly in combination with other traditional risk factors. We have long known that atherosclerosis is an inflammatory disease, but what was driving that inflammation was unknown until 5 years ago, when we learned that clonally derived mutant monocytes and macrophages are key drivers of endothelial inflammation.
Clonal hematopoiesis of indeterminate potential is being studied to see if it is a risk for the development of certain types of arthritis and other autoimmune diseases. There are a number of studies underway looking at other diseases possibly influenced by this condition, including dementia. So far, the most convincing evidence is with cardiovascular disease and leukemia.
Tracking Germline Changes That May Lead to Clonal Hematopoiesis
Aging is a critical risk factor in developing clonal hematopoiesis of indeterminate potential. What other factors besides the acquired genetic mutations in the DNA of hematopoietic stem cells contribute to clonal progression in the bone marrow leading to this condition?
Being male and smoking cigarettes are associated with a slight increased risk of clonal hematopoiesis, and there appears to be a connection with a germline variant in the telomere-associated gene TERT. Just like we are born with various genes that make it more likely for people to develop colorectal cancer or other solid tumors, there seem to be certain germline changes, such as in genes encoding DNA-repair enzymes, that increase the risk of developing clonal hematopoiesis with aging. Unfortunately, we do not understand exactly how these factors predispose some people to acquire clonal hematopoiesis of indeterminate potential.
Counseling Patients With Clonal Hematopoiesis
With so many unknown factors about clonal hematopoiesis and its potential to cause disease, how do you counsel patients with these mutations?
Although clonal hematopoiesis of indeterminate potential increases the risk for heart disease and leukemia, there are many people with this condition who will never have a heart attack or stroke or develop a blood cancer, so often I need to talk patients off the ledge, so to speak. They may have been told they have a mutation (picked up in a blood test or DNA test as part of treatment for another disease) and it could cause leukemia, but more likely it will cause a heart attack or stroke, and there isn’t anything to be done about it. Many people are devastated when they hear information like that.
“What is important for oncologists to know is that chemotherapy clearly accelerates the progression of clonal hematopoiesis of indeterminate potential to MDS or AML."— David P. Steensma, MD
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I explain to patients, that, yes, although their risk may be increased for these diseases, it is not an absolute risk or a certainty. We discuss how to manage clonal hematopoiesis, for example, with the lifestyle changes that may mitigate risk I discussed previously. For certain patients, such as those with large clones, multiple mutations, or cytopenias, I also recommend undergoing a blood cell count every 3 to 6 months. We often have cardiology colleagues interested in clonal hematopoiesis see these patients as well to discuss whether a stress test or some other heart screening might be useful.
Therapy-Related Leukemia
Is there evidence that clonal hematopoiesis of indeterminate potential can lead to blood cancers other than leukemia?
There have been a couple of case reports showing there was a clonal hematopoiesis clone that eventually became non-Hodgkin lymphoma, but that is much less common than evolving into MDS or AML. What is important for oncologists to know, especially those treating patients with solid tumors such as breast cancer, is that chemotherapy clearly accelerates the progression of this condition to MDS or AML.
Let’s imagine that a patient with breast cancer is found to have a high-risk clonal hematopoiesis mutation, such as TP53 or PPM1D, and a calculator predicts that the benefit she may derive from adjuvant cytotoxic chemotherapy is meaningful but small, say a 3% or 4% increase in survival. However, in her specific case, the chance of therapy-related MDS or AML, which is associated with a high mortality rate, is much greater, as high as 25%. The clinician may want to take that information into consideration before recommending chemotherapy.
So, chemotherapy does not cause clonal hematopoiesis of indeterminate potential, but it can accelerate the speed of developing MDS or AML in patients with the mutation?
Correct. We once thought that chemotherapy or radiotherapy caused the mutations that led to therapy-related MDS or AML by injuring DNA. However, now evidence strongly suggests that in most cases, there is already a tiny preexisting group of mutant cells that chemotherapy or radiotherapy allows to expand when it suppresses healthy cells, promoting their growth rather than causing the mutant cells to exist.
Clonal hematopoiesis at the time of autologous transplant for non-Hodgkin lymphoma and multiple myeloma is also associated with increased therapy-related MDS and AML and inferior overall survival. In addition, poorer outcomes have been seen with clonal hematopoiesis in older allogeneic stem cell transplant donors, leading some physicians to favor younger donors in these circumstances, although that is a complicated discussion.
Consequences of Aging
Why is aging such a large component in the development of clonal hematopoiesis of indeterminate potential?
Aging seems to be the principal risk factor for developing clonal hematopoiesis of indeterminate potential, but this condition is not an inevitable consequence of aging. Just as our skin accumulates wrinkles and scars and other injuries as we get older, so does the DNA in our cells. This has been shown now for most tissues in the body, including those in the esophagus, brain, and colon. In hematopoietic stem cells, occasionally a mutation will occur in a gene such as TET2 or DNMT3A that can cause cells to expand and these clones to grow. The key difference with other tissues is that cells from the esophagus and colon do not circulate around the body in large numbers and interact with other tissues in harmful ways, as blood does.
Although there are people who are predisposed to acquiring clonal hematopoiesis from smoking or inborn disorders, thereby accelerating that process, this condition is something that can happen to anyone. It is just part of human aging.
DISCLOSURE: Dr. Steensma reported no conflicts of interest.
REFERENCES
1. Bejar R, Sekeres MA: Attack of the clones: CHIP in the clinic. The Hematologist 16(1), Jan-Feb 2019.
2. Steensma DP: Clinical consequences of clonal hematopoiesis of indeterminate potential. Blood Adv 2:3404-3410, 2018.
3. Chong T, Ahearn EL, Cimmino L: Reprogramming the epigenome with vitamin C. Front Cell Dev Biol 7:128, 2019.
