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While it is increasingly apparent that , it has not been clear what to do about it.
Now, researchers at the cutting edge of both oncologic and cardiovascular research are not only defining the prognosis of CHIP with greater granularity but are also finding clues to mitigate the risks.
“It’s a very, very rapidly moving area,” said Christie M. Ballantyne, MD, Director, Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, Houston, adding that, in many respects, “it’s a totally new area.”
CHIP Defined
CHIP was first recognized in the 1990s, when Martin F. Fey, MD, and colleagues from University and Inselspital, Bern, Switzerland, found X-linked inactivation in older women and suggested it was the result of acquired clonality later referred to as being of “indeterminate potential,” although that added syntax is currently a matter of debate.
Further work showed that, while somatic gene mutations occur spontaneously and are an unavoidable consequence of aging, their impact can vary widely.
The majority are “functionally silent,” while others may affect genes crucial to tissue self-renewal and differentiation, Lukasz Gondek, MD, PhD, assistant professor, Johns Hopkins Cellular and Molecular Medicine Program, Baltimore, and colleagues, noted in a recent review.
This results in the outgrowth of affected cells, known as clonal expansion, further dubbed clonal hematopoiesis when it occurs in hematopoietic tissue.
“Even though there’s clonal expansion, there’s no one CHIP,” Dr. Gondek said. “There are different flavors, and it depends on the genes that are mutated in the hematopoietic cells.”
He continued: “The older we get, the more mutations we acquire, and the probability that this mutation will hit the gene that’s responsible for expansion of the clone is higher.”
“That’s why CHIP is very uncommon in people under the age of 40, but it becomes more common in the fifth, sixth, and seventh decade of life and beyond.”
Indeed, it occurs in 10% to 15% of people aged 65 years or older, and in at least 30% of individuals by 80 years of age. In contrast, just 1% of those aged less than 50 years have the condition.
The most commonly affected genes, in around 80% of patients with CHIP, are the epigenetic regulators DNMT3A, TET2, and ASXL1; the DNA damage repair genes PPM1D and TP53; the regulatory tyrosine kinase JAK2; and the messenger RNA spliceosome components SF3B1 and SRSF2.
These mutations can have “two potential consequences,” explained Lachelle D. Weeks, MD, PhD, a hematologist at the Dana-Farber Cancer Institute, Boston.
“One is that there’s a risk of blood cancer development,” as several of the mutations are known drivers of leukemia or myelodysplastic syndromes (MDS).
Although the majority of individuals who acquire clonal hematopoiesis with age will never develop MDS, it nevertheless confers an 11- to 13-fold increased risk or an absolute risk of approximately 0.5%-1.0% per year.
Dr. Weeks continued that “the other side of it, though, is that those cells that have these mutations can also accelerate the risk of developing nonmalignant diseases like cardiovascular disease.”
This, Dr. Gondek explained, is because the mutations will be retained when the stem cells become monocytes or macrophages and, by either silencing or activating individual genes, they can make the cells more pro-inflammatory.
The result is that CHIP is associated with a marked increased risk for arteriosclerotic events such as stroke, myocardial infarction, decompensated heart failure, and cardiogenic shock, and worse outcomes after these events.
Researchers have shown that CHIP-related somatic mutations are associated with a twofold increased risk for coronary heart disease, a more than 2.5-fold increased risk for ischemic stroke, and a fourfold greater risk for myocardial infarction. A study from earlier this year found that CHIP also increases the risk for heart failure with preserved ejection fraction more than twofold.
There is even evidence to suggest that CHIP is associated with more severe acute kidney injury (AKI) and greater post-AKI kidney fibrosis.
The consequence is that individuals with CHIP face a 40% increased risk for all-cause mortality over 8 years.
No CHIP Test Yet
All of which has led for some to call for CHIP testing.
However, there are currently no screening programs for CHIP and no plans to introduce any. “So most CHIP is actually being diagnosed incidentally, when patients get genetic testing for some other indication,” said Dr. Weeks.
“The patients that we see in our CHIP clinic at Dana-Farber have genetic testing because they have low blood counts,” she continued, “and somebody’s trying to figure out: Do you have MDS?”
Other patients have genetic testing due to a family history of other cancers, “and so they’re getting hereditary cancer panels to determine if they have Lynch syndrome, or other hereditary syndromes,” which are picking up gene mutations associated with CHIP.
In other cases, study protocols are identifying CHIP “in various research contexts, and then as a follow-up, some of those patients end up with our clinic,” added Dr. Weeks.
Due to the associated risks for CHIP, “obviously everyone wants to know whether they are at risk for hematologic malignancy, or not,” said Dr. Gondek. To those ends, Dr. Weeks and colleagues developed the clonal hematopoiesis risk score (CHRS).
Published by NEJM Evidence in 2023, the score takes a range of predictive variables, such as age, number of mutations and their degree of associated risk, the variant allele fraction, and a series of blood indices to define patients as low-, intermediate-, or high-risk.
“A little over half” of high-risk individuals “will develop a blood cancer” such as MDS or acute myeloid leukemia (AML)” over the next 10 years, Weeks explained, while “for your intermediate risk folks, in that same time period, 7%-8% of them will develop a blood cancer.”
In low-risk individuals, the 10-year risk for MDS or AML is just 1%.
Dr. Weeks noted the “caveat that there are environmental factors or patient-specific issues that might increase your risk that are not considered in the calculator,” such the presence of hereditary cancer syndromes, “or if you’re getting chemotherapy for other cancers.”
From a cardiology point of view, Dr. Ballantyne said that, above all, “cardiologists need to be aware that some of these people are at increased risk for cardiovascular events.” This prompted a team including Dr. Weeks and Dr. Ballantyne to study whether the CHRS can also predict cardiovascular risk.
They found that people designated low-risk on the score faced an 8% increased risk for all-cause mortality vs individuals without CHIP during a median follow-up of 7 years. This rose to a 12% increase in intermediate-risk individuals.
And those deemed high-risk had a 2.5-fold increased risk for early mortality and a threefold higher risk for cardiovascular death.
Dr. Weeks noted: “We have not done a dedicated study to define a cardiovascular disease-specific calculator for CHIP,” but in the meantime, the CHRS is a “very reasonable way to estimate what someone’s risk of progression or adverse events is for cardiovascular disease.”
For clinicians, however, the key question becomes: What can be done to mitigate the risks, particularly in high-risk individuals?
For malignant conditions, the approach is to monitor patients, although “we and other centers are in the process of developing various interventional clinical trials to test various agents on their ability to improve blood counts, as well as to mitigate the risk of progression to overt blood cancer,” said Dr. Weeks.
Treat CHIP Like Lipoprotein(a)?
As for cardiovascular risk, Dr. Ballantyne believes that, because CHIP is an unmodifiable risk factor, an example to follow could be lipoprotein(a) (LP[a]).
“We don’t have a therapy specifically to target LP(a) yet, but we do know that the things that benefit in general,” he said, such as “taking a statin, lowering blood pressure into the optimal zone, diet ,and exercise.”
“What we do in our clinic, and what others have been doing,” Dr. Weeks added, “is for every patient who comes in and is diagnosed with CHIP, we are referring them to preventative cardiology for very aggressive preventative management.”
Finally, both Dr. Ballantyne and Dr. Weeks agree that there are many potential innovations on the horizon.
“It’s pretty exciting in terms of beginning to understand some of the links between aging, cardiovascular disease, and cancer that we had not been thinking about,” Dr. Ballantyne said.
On the malignant side, Dr. Weeks is already working on a prospective study to determine how the risks associated with CHIP evolve when patients undergo chemotherapy and radiation for other cancers.
“That will be really exciting and will help us to develop a specific calculator in that context,” she said, adding that a cardiovascular-specific calculator “is also coming down the line.”
Dr. Weeks declared relationships with Abbvie, Vertex, and Sobi. Dr. Ballantyne declared a relationship with Ten Sixteen Bio, and funding from the National Heart, Lung, and Blood Institute. No other relevant financial relationships were declared.
A version of this article appeared on Medscape.com.
While it is increasingly apparent that , it has not been clear what to do about it.
Now, researchers at the cutting edge of both oncologic and cardiovascular research are not only defining the prognosis of CHIP with greater granularity but are also finding clues to mitigate the risks.
“It’s a very, very rapidly moving area,” said Christie M. Ballantyne, MD, Director, Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, Houston, adding that, in many respects, “it’s a totally new area.”
CHIP Defined
CHIP was first recognized in the 1990s, when Martin F. Fey, MD, and colleagues from University and Inselspital, Bern, Switzerland, found X-linked inactivation in older women and suggested it was the result of acquired clonality later referred to as being of “indeterminate potential,” although that added syntax is currently a matter of debate.
Further work showed that, while somatic gene mutations occur spontaneously and are an unavoidable consequence of aging, their impact can vary widely.
The majority are “functionally silent,” while others may affect genes crucial to tissue self-renewal and differentiation, Lukasz Gondek, MD, PhD, assistant professor, Johns Hopkins Cellular and Molecular Medicine Program, Baltimore, and colleagues, noted in a recent review.
This results in the outgrowth of affected cells, known as clonal expansion, further dubbed clonal hematopoiesis when it occurs in hematopoietic tissue.
“Even though there’s clonal expansion, there’s no one CHIP,” Dr. Gondek said. “There are different flavors, and it depends on the genes that are mutated in the hematopoietic cells.”
He continued: “The older we get, the more mutations we acquire, and the probability that this mutation will hit the gene that’s responsible for expansion of the clone is higher.”
“That’s why CHIP is very uncommon in people under the age of 40, but it becomes more common in the fifth, sixth, and seventh decade of life and beyond.”
Indeed, it occurs in 10% to 15% of people aged 65 years or older, and in at least 30% of individuals by 80 years of age. In contrast, just 1% of those aged less than 50 years have the condition.
The most commonly affected genes, in around 80% of patients with CHIP, are the epigenetic regulators DNMT3A, TET2, and ASXL1; the DNA damage repair genes PPM1D and TP53; the regulatory tyrosine kinase JAK2; and the messenger RNA spliceosome components SF3B1 and SRSF2.
These mutations can have “two potential consequences,” explained Lachelle D. Weeks, MD, PhD, a hematologist at the Dana-Farber Cancer Institute, Boston.
“One is that there’s a risk of blood cancer development,” as several of the mutations are known drivers of leukemia or myelodysplastic syndromes (MDS).
Although the majority of individuals who acquire clonal hematopoiesis with age will never develop MDS, it nevertheless confers an 11- to 13-fold increased risk or an absolute risk of approximately 0.5%-1.0% per year.
Dr. Weeks continued that “the other side of it, though, is that those cells that have these mutations can also accelerate the risk of developing nonmalignant diseases like cardiovascular disease.”
This, Dr. Gondek explained, is because the mutations will be retained when the stem cells become monocytes or macrophages and, by either silencing or activating individual genes, they can make the cells more pro-inflammatory.
The result is that CHIP is associated with a marked increased risk for arteriosclerotic events such as stroke, myocardial infarction, decompensated heart failure, and cardiogenic shock, and worse outcomes after these events.
Researchers have shown that CHIP-related somatic mutations are associated with a twofold increased risk for coronary heart disease, a more than 2.5-fold increased risk for ischemic stroke, and a fourfold greater risk for myocardial infarction. A study from earlier this year found that CHIP also increases the risk for heart failure with preserved ejection fraction more than twofold.
There is even evidence to suggest that CHIP is associated with more severe acute kidney injury (AKI) and greater post-AKI kidney fibrosis.
The consequence is that individuals with CHIP face a 40% increased risk for all-cause mortality over 8 years.
No CHIP Test Yet
All of which has led for some to call for CHIP testing.
However, there are currently no screening programs for CHIP and no plans to introduce any. “So most CHIP is actually being diagnosed incidentally, when patients get genetic testing for some other indication,” said Dr. Weeks.
“The patients that we see in our CHIP clinic at Dana-Farber have genetic testing because they have low blood counts,” she continued, “and somebody’s trying to figure out: Do you have MDS?”
Other patients have genetic testing due to a family history of other cancers, “and so they’re getting hereditary cancer panels to determine if they have Lynch syndrome, or other hereditary syndromes,” which are picking up gene mutations associated with CHIP.
In other cases, study protocols are identifying CHIP “in various research contexts, and then as a follow-up, some of those patients end up with our clinic,” added Dr. Weeks.
Due to the associated risks for CHIP, “obviously everyone wants to know whether they are at risk for hematologic malignancy, or not,” said Dr. Gondek. To those ends, Dr. Weeks and colleagues developed the clonal hematopoiesis risk score (CHRS).
Published by NEJM Evidence in 2023, the score takes a range of predictive variables, such as age, number of mutations and their degree of associated risk, the variant allele fraction, and a series of blood indices to define patients as low-, intermediate-, or high-risk.
“A little over half” of high-risk individuals “will develop a blood cancer” such as MDS or acute myeloid leukemia (AML)” over the next 10 years, Weeks explained, while “for your intermediate risk folks, in that same time period, 7%-8% of them will develop a blood cancer.”
In low-risk individuals, the 10-year risk for MDS or AML is just 1%.
Dr. Weeks noted the “caveat that there are environmental factors or patient-specific issues that might increase your risk that are not considered in the calculator,” such the presence of hereditary cancer syndromes, “or if you’re getting chemotherapy for other cancers.”
From a cardiology point of view, Dr. Ballantyne said that, above all, “cardiologists need to be aware that some of these people are at increased risk for cardiovascular events.” This prompted a team including Dr. Weeks and Dr. Ballantyne to study whether the CHRS can also predict cardiovascular risk.
They found that people designated low-risk on the score faced an 8% increased risk for all-cause mortality vs individuals without CHIP during a median follow-up of 7 years. This rose to a 12% increase in intermediate-risk individuals.
And those deemed high-risk had a 2.5-fold increased risk for early mortality and a threefold higher risk for cardiovascular death.
Dr. Weeks noted: “We have not done a dedicated study to define a cardiovascular disease-specific calculator for CHIP,” but in the meantime, the CHRS is a “very reasonable way to estimate what someone’s risk of progression or adverse events is for cardiovascular disease.”
For clinicians, however, the key question becomes: What can be done to mitigate the risks, particularly in high-risk individuals?
For malignant conditions, the approach is to monitor patients, although “we and other centers are in the process of developing various interventional clinical trials to test various agents on their ability to improve blood counts, as well as to mitigate the risk of progression to overt blood cancer,” said Dr. Weeks.
Treat CHIP Like Lipoprotein(a)?
As for cardiovascular risk, Dr. Ballantyne believes that, because CHIP is an unmodifiable risk factor, an example to follow could be lipoprotein(a) (LP[a]).
“We don’t have a therapy specifically to target LP(a) yet, but we do know that the things that benefit in general,” he said, such as “taking a statin, lowering blood pressure into the optimal zone, diet ,and exercise.”
“What we do in our clinic, and what others have been doing,” Dr. Weeks added, “is for every patient who comes in and is diagnosed with CHIP, we are referring them to preventative cardiology for very aggressive preventative management.”
Finally, both Dr. Ballantyne and Dr. Weeks agree that there are many potential innovations on the horizon.
“It’s pretty exciting in terms of beginning to understand some of the links between aging, cardiovascular disease, and cancer that we had not been thinking about,” Dr. Ballantyne said.
On the malignant side, Dr. Weeks is already working on a prospective study to determine how the risks associated with CHIP evolve when patients undergo chemotherapy and radiation for other cancers.
“That will be really exciting and will help us to develop a specific calculator in that context,” she said, adding that a cardiovascular-specific calculator “is also coming down the line.”
Dr. Weeks declared relationships with Abbvie, Vertex, and Sobi. Dr. Ballantyne declared a relationship with Ten Sixteen Bio, and funding from the National Heart, Lung, and Blood Institute. No other relevant financial relationships were declared.
A version of this article appeared on Medscape.com.
While it is increasingly apparent that , it has not been clear what to do about it.
Now, researchers at the cutting edge of both oncologic and cardiovascular research are not only defining the prognosis of CHIP with greater granularity but are also finding clues to mitigate the risks.
“It’s a very, very rapidly moving area,” said Christie M. Ballantyne, MD, Director, Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, Houston, adding that, in many respects, “it’s a totally new area.”
CHIP Defined
CHIP was first recognized in the 1990s, when Martin F. Fey, MD, and colleagues from University and Inselspital, Bern, Switzerland, found X-linked inactivation in older women and suggested it was the result of acquired clonality later referred to as being of “indeterminate potential,” although that added syntax is currently a matter of debate.
Further work showed that, while somatic gene mutations occur spontaneously and are an unavoidable consequence of aging, their impact can vary widely.
The majority are “functionally silent,” while others may affect genes crucial to tissue self-renewal and differentiation, Lukasz Gondek, MD, PhD, assistant professor, Johns Hopkins Cellular and Molecular Medicine Program, Baltimore, and colleagues, noted in a recent review.
This results in the outgrowth of affected cells, known as clonal expansion, further dubbed clonal hematopoiesis when it occurs in hematopoietic tissue.
“Even though there’s clonal expansion, there’s no one CHIP,” Dr. Gondek said. “There are different flavors, and it depends on the genes that are mutated in the hematopoietic cells.”
He continued: “The older we get, the more mutations we acquire, and the probability that this mutation will hit the gene that’s responsible for expansion of the clone is higher.”
“That’s why CHIP is very uncommon in people under the age of 40, but it becomes more common in the fifth, sixth, and seventh decade of life and beyond.”
Indeed, it occurs in 10% to 15% of people aged 65 years or older, and in at least 30% of individuals by 80 years of age. In contrast, just 1% of those aged less than 50 years have the condition.
The most commonly affected genes, in around 80% of patients with CHIP, are the epigenetic regulators DNMT3A, TET2, and ASXL1; the DNA damage repair genes PPM1D and TP53; the regulatory tyrosine kinase JAK2; and the messenger RNA spliceosome components SF3B1 and SRSF2.
These mutations can have “two potential consequences,” explained Lachelle D. Weeks, MD, PhD, a hematologist at the Dana-Farber Cancer Institute, Boston.
“One is that there’s a risk of blood cancer development,” as several of the mutations are known drivers of leukemia or myelodysplastic syndromes (MDS).
Although the majority of individuals who acquire clonal hematopoiesis with age will never develop MDS, it nevertheless confers an 11- to 13-fold increased risk or an absolute risk of approximately 0.5%-1.0% per year.
Dr. Weeks continued that “the other side of it, though, is that those cells that have these mutations can also accelerate the risk of developing nonmalignant diseases like cardiovascular disease.”
This, Dr. Gondek explained, is because the mutations will be retained when the stem cells become monocytes or macrophages and, by either silencing or activating individual genes, they can make the cells more pro-inflammatory.
The result is that CHIP is associated with a marked increased risk for arteriosclerotic events such as stroke, myocardial infarction, decompensated heart failure, and cardiogenic shock, and worse outcomes after these events.
Researchers have shown that CHIP-related somatic mutations are associated with a twofold increased risk for coronary heart disease, a more than 2.5-fold increased risk for ischemic stroke, and a fourfold greater risk for myocardial infarction. A study from earlier this year found that CHIP also increases the risk for heart failure with preserved ejection fraction more than twofold.
There is even evidence to suggest that CHIP is associated with more severe acute kidney injury (AKI) and greater post-AKI kidney fibrosis.
The consequence is that individuals with CHIP face a 40% increased risk for all-cause mortality over 8 years.
No CHIP Test Yet
All of which has led for some to call for CHIP testing.
However, there are currently no screening programs for CHIP and no plans to introduce any. “So most CHIP is actually being diagnosed incidentally, when patients get genetic testing for some other indication,” said Dr. Weeks.
“The patients that we see in our CHIP clinic at Dana-Farber have genetic testing because they have low blood counts,” she continued, “and somebody’s trying to figure out: Do you have MDS?”
Other patients have genetic testing due to a family history of other cancers, “and so they’re getting hereditary cancer panels to determine if they have Lynch syndrome, or other hereditary syndromes,” which are picking up gene mutations associated with CHIP.
In other cases, study protocols are identifying CHIP “in various research contexts, and then as a follow-up, some of those patients end up with our clinic,” added Dr. Weeks.
Due to the associated risks for CHIP, “obviously everyone wants to know whether they are at risk for hematologic malignancy, or not,” said Dr. Gondek. To those ends, Dr. Weeks and colleagues developed the clonal hematopoiesis risk score (CHRS).
Published by NEJM Evidence in 2023, the score takes a range of predictive variables, such as age, number of mutations and their degree of associated risk, the variant allele fraction, and a series of blood indices to define patients as low-, intermediate-, or high-risk.
“A little over half” of high-risk individuals “will develop a blood cancer” such as MDS or acute myeloid leukemia (AML)” over the next 10 years, Weeks explained, while “for your intermediate risk folks, in that same time period, 7%-8% of them will develop a blood cancer.”
In low-risk individuals, the 10-year risk for MDS or AML is just 1%.
Dr. Weeks noted the “caveat that there are environmental factors or patient-specific issues that might increase your risk that are not considered in the calculator,” such the presence of hereditary cancer syndromes, “or if you’re getting chemotherapy for other cancers.”
From a cardiology point of view, Dr. Ballantyne said that, above all, “cardiologists need to be aware that some of these people are at increased risk for cardiovascular events.” This prompted a team including Dr. Weeks and Dr. Ballantyne to study whether the CHRS can also predict cardiovascular risk.
They found that people designated low-risk on the score faced an 8% increased risk for all-cause mortality vs individuals without CHIP during a median follow-up of 7 years. This rose to a 12% increase in intermediate-risk individuals.
And those deemed high-risk had a 2.5-fold increased risk for early mortality and a threefold higher risk for cardiovascular death.
Dr. Weeks noted: “We have not done a dedicated study to define a cardiovascular disease-specific calculator for CHIP,” but in the meantime, the CHRS is a “very reasonable way to estimate what someone’s risk of progression or adverse events is for cardiovascular disease.”
For clinicians, however, the key question becomes: What can be done to mitigate the risks, particularly in high-risk individuals?
For malignant conditions, the approach is to monitor patients, although “we and other centers are in the process of developing various interventional clinical trials to test various agents on their ability to improve blood counts, as well as to mitigate the risk of progression to overt blood cancer,” said Dr. Weeks.
Treat CHIP Like Lipoprotein(a)?
As for cardiovascular risk, Dr. Ballantyne believes that, because CHIP is an unmodifiable risk factor, an example to follow could be lipoprotein(a) (LP[a]).
“We don’t have a therapy specifically to target LP(a) yet, but we do know that the things that benefit in general,” he said, such as “taking a statin, lowering blood pressure into the optimal zone, diet ,and exercise.”
“What we do in our clinic, and what others have been doing,” Dr. Weeks added, “is for every patient who comes in and is diagnosed with CHIP, we are referring them to preventative cardiology for very aggressive preventative management.”
Finally, both Dr. Ballantyne and Dr. Weeks agree that there are many potential innovations on the horizon.
“It’s pretty exciting in terms of beginning to understand some of the links between aging, cardiovascular disease, and cancer that we had not been thinking about,” Dr. Ballantyne said.
On the malignant side, Dr. Weeks is already working on a prospective study to determine how the risks associated with CHIP evolve when patients undergo chemotherapy and radiation for other cancers.
“That will be really exciting and will help us to develop a specific calculator in that context,” she said, adding that a cardiovascular-specific calculator “is also coming down the line.”
Dr. Weeks declared relationships with Abbvie, Vertex, and Sobi. Dr. Ballantyne declared a relationship with Ten Sixteen Bio, and funding from the National Heart, Lung, and Blood Institute. No other relevant financial relationships were declared.
A version of this article appeared on Medscape.com.