A common aging-related phenomenon in which hematopoietic stem cells (HSCs) or other early blood cell progenitors contribute to the formation of a genetically distinct subpopulation of blood cells.
This subpopulation in the blood is characterized by a shared unique mutation in the cells’ DNA.
Clonal hematopoiesis (CH) is the sporadic acquisition of somatic mutational changes in hematopoietic stem cells with normal aging.
This subpopulation is derived from a single founding cell and is therefore made of genetic clones of the founder.
A clonal population may occur when a stem or progenitor cell acquires one or more somatic mutations that give it a competitive advantage in hematopoiesis over the stem/progenitor cells without these mutations.
Clonal hematopoiesis may arise without a driving mutation, through mechanisms such as neutral drift in the stem cell population.
Clonal hematopoiesis occurs in people who are completely healthy but has also been found in people with hematologic diseases.
CH increases with age and the age is 65 years more than 10% of healthy people will have clonal hematopoiesis.
CH is linked to environmental factors such as exposure to smoking and chronic infections.
The clonal population may vary in size depending on the person, where it can be less than 2% of the blood or, sometimes close to 100%.
Clonal hematopoiesis incidence rises dramatically with age.
Less than 1% of the population under age 40, and approximately 10-20% of the population over age 70 has observable clonal hematopoiesis.
Oncogenic mutations cause clonal hematopoiesis and is associated with a very high risk of leukemia.
Patients with hematopoiesis also have an increased risk of cardiovascular disease and type two diabetes.
Clonal hematopoiesis can lead to increased coronary atherosclerosis and calcification.
Clonal hematopoiesis has been linked to a more than 10-fold increased risk of developing a blood malignancy, though the overall likelihood is still low.
Among people with CH the incidence of MDS or AML is 0.5 to 1% per year, but not all people with CH will develop MDS or AML.
90% of people with CH will die from other causes especially the increased risk for cardiovascular disease.
Clonal hematopoiesis is virtually absent from the under-40 population, with a sharp uptick in frequency past 60 years of age.
Studies suggests that between 10% and 20% of the population over age 70 have clonal hematopoiesis, meaning that some 2,975,000 seniors over 70 years of age are living with this condition.
There are many different mutations involved in clonal hematopoiesis.
Many patients having clonal hematopoiesis have a mutation in a single gene, though a significant number have mutations in two or more genes.
Clonal hematopoiesis may be ubiquitous in healthy adults, at extremely low levels of less than 0.1% of peripheral blood cells.
It is thought to originate with the hematopoietic stem cells that make blood.
An adult human has approximately 10,000 to 20,000 HSCs.
HSCs are maintained for life and each HSC may acquire about one mutation in a protein-coding exon each decade.
Elderly persons will have a certain amount of genetic mosaicism, or a variety of cells with different unique mutations, within their HSC population.
It is only when the genetic mutation confers a selective advantage on its host or there is another favorable stem cell dynamic that there is a clonal expansion.
A mutation could provide a growth advantage, causing HSCs to divide more rapidly and contribute a larger proportion of the mature blood cells.
A potential mechanism of action is that the mutation makes the HSC-derived progenitor cells less able to differentiate into mature blood cells.
Another possibility is that the mutation makes the progenitor cells and cells derived from them more like stem cells in their ability to keep dividing.
A gradient of epigenetic status may be is created in the HSC and progenitor cells and the cells with the most favorable epigenetics are able to grow out faster than unmutated cells..
A significant proportion of the population who exhibit clonal hematopoiesis have no identifiable mutations in known candidate driver genes.
Clonal hematopoiesis by itself is not considered to be a hematologic cancer, nevertheless, evidence is mounting that this condition may adversely affect human health.
Clonal hematopoiesis as defined by a mutation in a malignancy-associated gene but without evidence of disease, is note to be Clonal Hematopoiesis of Indeterminate Potential (CHIP).
The size of the clonal involvement of 2% of the blood has been tentatively proposed as a cutoff, before influencing health.
Clonal hematopoiesis has been shown to increase blood cancer risk and is correlated with an increased risk of mortality overall, with or without candidate drivers.
Mutations in DNA damage response genes TP 53, CHEK2, and ATM are preferentially selected for in patients with therapy related CH, especially those who received prior platinum, topoisomerase II inhibitors, and or radiation.
Patients with CH and abnormal hematologic processes have poorer prognoses.
It is estimated that just 3 to 4 people per 100,000 will get MDS in a given year, and 4 people per 100,000 will develop AML.
With clonal hematopoiesis the risk of acquiring a hematologic malignancy like MDS or AML is increased more than 10 times.
But, even with clonal hematopoiesis the overall risk for developing a blood cancer, is only about 0.5-1.0% transformation per year.
CH has an increased risk of hematologic malignancy for both myeloid and lymphoid malignancies.
The presence of clonal hematopoiesis has a strong correlation of heart attack/stroke in a patient that smokes, has hypertension, high cholesterol, or is overweight.
Patients with clonal hematopoiesis receiving autologous stem cell transplantation for lymphoma have worse outcomes than patients without clonal hematopoiesis, due to an increase in subsequent therapy-related myeloid neoplasms and increased risk for cardiovascular mortality.
There, presently, is no treatment to slow or target clonal hematopoiesis mutations.
It is compared to the unrelated blood disorders of monoclonal gammopathy of undetermined significance (MGUS) and monoclonal B-cell lymphocytosis (MBL) to which it bears similarities: priming for more advanced hematologic disease combined with a lack of symptoms and overall low risk of progression.
The acquisition of additional mutations can cause clonal hematopoiesis to transform into the related blood disorders MDS and AML.
The risk of developing a myeloid malignancy from CH is gene specific: IDH 1/2, JAK2 and TP 53 have an increased risk of developing AML.
A CH risk score correlates with a cumulative 10 year incidence of myeloid transformation: based on patient age, specific mutations, peripheral blood laboratory values, red cell distribution width and MCV.
The presence of CH in patients with non-myeloid maliignancies who receive anti-neoplastic therapy is associated with an increased incidence of therapy related myeloid malignancies, and adverse clinical outcomes.
CH strongly associated with increased risk of atherosclerotic, cardiovascular disease, especially those with underlying mutations.
While CH and cardiovascular disease are associated with aging, evidence suggest that CH is an independent risk factor for atherosclerotic cardiovascular disease.
The use of anti-inflammatory therapies (canakinumab an anti-IL-one beta monoclonal antibody) as led to decreased recurrent cardiovascular events when compared with placebo in patient with elevated CH.
Inferior long-term clinical outcome is demonstrated in ischemic cardiac failure patients, harboring CHIP mutations.
Certain forms of CH may be associated with the development of autoimmune disease with an association with anti-neutrophil cytoplasmic antibody associated vasculitis.
CH, potentially a driver of systemic inflammation, may be associated with increased risk of diabetes, COPD, chronic liver disease, osteoporosis, gout, infections such as HIV and severe Covid-19.
The presence of CH may protect against Alzheimer’s disease.
The presence of CH in patients undergoing cellular therapy with CAR-T treatments is associated with increased toxcity, and the presence of CH may be associated with an increased risk of graft versus host disease after allogeneic stem cell transplant.
No guidelines regarding screening, monitoring, and management of patients with CH exist, presently.
Individuals with CH should undergo routine cancer screening and vaccinations, and cardiovascular screening for primary prevention of cardiovascular disease, laboratory monitoring for lipid panel, hemoglobin A1c, CBC, and thyroid function tests every 6 to 12 months.