Peter G. Miller, MD, PhD, discusses the characteristics and risks associated with clonal hematopoiesis and risk-stratification efforts for patients with cancer who are at risk of developing therapy-related secondary malignancies from clonal hematopoiesis.
Acquired clonal hematopoiesis of indeterminate potential in healthy individuals without hematologic diseases appears to confer an increased risk of developing myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and ischemic cardiovascular events, said Peter G. Miller, MD, PhD, who added that patients with cancer who received cytotoxic chemotherapy or radiation therapy are at an increased risk of developing clonal hematopoiesis and, subsequently, therapy-related secondary malignancies.
“If we can understand why these mutations arise and how they drive abnormal cell growth, we can provide very important therapeutic insights into different areas to target in healthy [individuals] with clonal hematopoiesis and patients with leukemia,” Miller said.
In an interview with OncLive®, Miller, a physician at Dana-Farber Cancer Institute and an instructor of medicine at Harvard Medical School, discussed the characteristics and risks associated with clonal hematopoiesis, risk-stratification efforts for patients with cancer who are at risk of developing therapy-related secondary malignancies from clonal hematopoiesis, and ongoing research efforts directed toward understanding why these acquired mutations arise.
Miller: As we age, all the cells in our body acquire mutations, most of which have no effect on cell growth. [However,] a few [mutations] can affect cell growth and, in extreme cases, lead to cancer. The best example of this is probably in the colon, where someone can develop a colon polyp with some mutations. With the acquisition of additional genetic events, one can develop dysplasia and, ultimately, cancer.
It turns out that this is the case in the hematopoietic system as well. In cases where multiple or certain genetic events occur, somebody can develop myeloid neoplasia, including MDS or AML. We now know, based off work that has been [published] in the past 5 to 10 years, that a large percentage of the population that is otherwise healthy without blood abnormalities carries one of these mutations in their blood cells in a clonal population. Therefore, [these individuals] have clonal hematopoiesis, which is defined as the presence of a mutation in a blood cell in an individual who is otherwise healthy.
Like the colon cancer scenario, the presence of these mutations increases the risk of developing MDS or AML. In that sense, we think of [these individuals as having] pre-leukemic conditions.
What is surprising is that we have subsequently learned that outside of the risk of developing leukemia, people who carry these mutations in their blood also have an increased risk of developing and dying from ischemic cardiovascular diseases, including myocardial infarctions and stroke. This is independent of other known risk factors, such as cholesterol levels.
It is amazing to try to understand how our blood system, which divides billions of times per day, can maintain its integrity so well. We know and think a lot about leukemia, but it is a rare disease. Our cells are good at protecting us against cancer, but this doesn’t always occur. I’m really interested in understanding the events that lead to these mutations in blood cells that [lead to] a phase of clonal hematopoiesis and, ultimately, to developing leukemia.
A few [pieces of information] have come to light. [We are] getting a deeper understanding of how common [clonal hematopoiesis] is among different populations of healthy individuals as they age. [Clonal hematopoiesis] is probably present in upward of 10% to 15% of the population, perhaps even higher if we can use more sensitive sequencing technologies.
In cancer populations, many of which have been exposed to cytotoxic therapies, such as chemotherapy or radiation therapy, the rate of clonal hematopoiesis is probably 5- to 10-fold higher [compared with healthy populations]. That seems to be the case because chemotherapy or radiation therapy selects for the cells that carry these abnormal mutations and drive development of the abnormal clonal populations.
We are also developing a deeper understanding of being able to risk-stratify patients or the combinations of mutations that may confer a risk for leukemia. We are also getting a better understanding of [whether] these clones change over the lifetime of an individual. There may be some people who have clonal hematopoiesis that never changes vs others whose very little bit of clonal hematopoiesis grows to a much larger [problem] and confers the increased risk of leukemia and cardiovascular disease.
In patients with cancer, we are now thinking in terms of the survivorship population, [which comprises patients] who are going to live for a very long period of time but are now at an increased risk of having clonal hematopoiesis. How does that relate to subsequent risk of developing leukemia? We think about this mostly in the context of therapy-related leukemias [in] individuals who develop cancers after they received cytotoxic therapy for a primary malignancy. This is a very feared complication, so being able to risk-stratify that population [is important].
Also, we are thinking about the long-term consequences [of clonal hematopoiesis], such as cardiovascular disease. After our patient population has been treated for cancer, understanding to what extent clonal hematopoiesis affects their risk of [developing cardiovascular disease] and being able to mitigate that risk [will be important].
We now know that, like the colon cancer example, individuals can start with clonal hematopoiesis and progress through multiple stages before developing frank leukemia or MDS. Many of those intermediate stages present with cytopenias, which are very common in our patient population. Understanding the risks [of cytopenias] and whether patients have clonal hematopoiesis can inform what may be driving low white or red blood cell counts and what the consequential sequelae may be.
To date, the identification of clonal hematopoiesis has been largely restricted to the academic community, largely because it is defined by the presence of abnormal DNA sequencing results. These tests have, to date, not been widely used within the community, although they are increasingly being used in that setting.
Now, in a patient who has a malignancy already, looking at their bone marrow or peripheral blood for the presence of a mutation is very important for diagnostic, prognostic, and predictive purposes for their cancer. However, it doesn’t tell us much about clonal hematopoiesis because they have already progressed past the pre-leukemic stage.
On the other hand, we are now testing a lot of patients’ peripheral blood for the presence of mutations in other settings. For example, we see a lot of patients who are tested for germline syndromes of having DNA repair gene mutations or patients who have histories of breast or ovarian cancer and are tested for germline [syndromes] where mutations can be identified in a subset of genes. [However, sometimes, these mutations are not identified] at a frequency that suggests that they are inherited mutations from [the patient’s] mother or father, but rather have arisen over the course of [the patient’s] life, and therefore, reflect clonal hematopoiesis.
I [emphasize to] people that if they identify patients for whom mutation testing in the peripheral blood or bone marrow has identified a mutation that doesn’t look truly inherited and may have arisen, it likely reflects clonal hematopoiesis and warrants further investigation by the clinician, hematologist, or center that specializes in these patients. [They can] provide further work up and provide risk-mitigation strategies.
My main focus in the lab right now is trying to understand why particular mutations arise and whether targeting those mutations could render both clonal hematopoietic cells and, ultimately, myelodysplastic or leukemic cells, sensitive to new types of therapies. I am particularly interested in studying the genes involved in DNA damage response. The most common ones we think about are p53, PPM1D, CHEK2, and ATM. The reason I care about those genes is because the cancer population that we see in our clinical [practice comprise] patients who have received cytotoxic therapies for their primary malignancy and are at risk for developing clonal hematopoiesis and therapy-related myeloid neoplasms.
My lab focuses on understanding the DNA damage response in hematopoietic cells in the context of cytotoxic stresses so that we can better prevent [those complications] from occurring. Then, if they do occur, [we are working to] develop new therapies to treat [clonal hematopoiesis and therapy-related myeloid neoplasms] in a more efficacious fashion.
Something that is becoming increasingly common, particularly among academic centers, are clinics that are geared specifically toward patients who have precursor malignancy lesions in their bone marrow. The most common ones that we think about are monoclonal gammopathy of undetermined significance, which is a precursor for multiple myeloma, and monoclonal B-cell lymphocytosis, which is a precursor for [chronic lymphocytic leukemia]. As I’ve mentioned, clonal hematopoiesis is potentially a precursor for MDS or AML.
At our institution and numerous other institutions, we’ve developed a clinic where if we find these patients with somatic mutations in their blood in which we are not entirely sure what we should do, we bring them into the clinic to try to explain to [the patient] what this means and what the potential clinical implications are. We also do additional testing to try to determine whether they truly have clonal hematopoiesis or a more advanced case, such as dysplasia. We also talk about risk-mitigation strategies, both related to the development of potential leukemia and whether they should be screened more frequently with peripheral blood counts to monitor for cytopenias. We’re also looking for risk-mitigation strategies for cardiovascular disease, including statin and lifestyle interventions. These clinics are already online, and they are going to become increasingly common through the academic setting. I believe that they will also filter down to the community setting to provide a lot of value moving forward.