Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis

INTRODUCTION — Clonal hematopoiesis (CH) refers to a genetically distinct subpopulation of myeloid cells, which share an acquired (ie, not inherited) mutation that distinguishes them from other tissues and unaffected hematopoietic cells. CH may be detected in healthy individuals with few or no hematologic manifestations; although clonality is also a feature of myelodysplastic syndromes, acute leukemias, and myeloproliferative neoplasms, these malignancies are generally associated with substantial hematologic findings.

Categories of CH include:

●Clonal hematopoiesis of indeterminate potential (CHIP)

●Clonal cytopenia of undetermined significance (CCUS)

●Aging-related clonal hematopoiesis (ARCH)

CHIP, CCUS, and ARCH are provisionally categorized according to the size of the clonal population and the presence of dysplasia and/or cytopenias (table 1). It is important to recognize these conditions because some are associated with an increased risk for a hematologic malignancy, cardiovascular events, or other conditions.

This topic discusses the pathogenesis, epidemiology, evaluation, diagnosis, and management of CHIP, CCUS, and ARCH.

CCUS, ICUS, and myelodysplastic syndromes/neoplasms are discussed separately. (See "Idiopathic and clonal cytopenias of uncertain significance (ICUS and CCUS)" and "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)".)

Clonality in lymphoid lineages, including monoclonal B cell lymphocytosis, monoclonal gammopathy of undetermined significance (MGUS), and lymphoproliferative disorders are described separately. (See "Monoclonal B cell lymphocytosis" and "Diagnosis of monoclonal gammopathy of undetermined significance".)

CLONALITY

Description and detection — CH refers to a population of blood and/or bone marrow cells that share an acquired mutation. The presence of the mutation distinguishes the hematopoietic clone from unaffected blood cells and non-hematopoietic cells, which instead carry the corresponding unmutated ("wild-type") germline allele.

CH is often detected when next-generation sequencing (NGS) of DNA identifies a shared, acquired mutation in blood or marrow cells. Less commonly, CH is detected by chromosomal analysis (ie, karyotype), fluorescence in situ hybridization (FISH), single-gene polymerase chain reaction (PCR), or other techniques. Sensitivity to detection of CH varies with the detection method, but NGS is generally the most sensitive technique. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications" and "Tools for genetics and genomics: Cytogenetics and molecular genetics".)

Variant allele fraction (VAF) — VAF refers to the percentage of mutated DNA sequencing reads at a given genetic locus. The threshold for VAF is often set at 1, 2, or 5 percent, depending on the testing facility, but the clinical significance of these proportions depends on test characteristics and disease context [1].

The ability to detect a clonal population of cells is a composite of the depth of sequencing (ie, the average number of times a given nucleotide position is sequenced) and the breadth/content of the platform. A common clinical application of NGS in this setting is using a "myeloid gene panel," which includes genes that are frequently mutated in myeloid malignancies. NGS can also be applied on the whole exome (ie, coding sequences of genes) or the whole genome. Detection of somatic mutations and measurement of VAF appear to be similar in paired bone marrow and peripheral blood specimens [2].

Relation of VAF to clone size — VAF roughly parallels the size of the clone (ie, the percentage of blood/marrow cells that bear the mutation).

●Ratio of VAF:clone size – Most autosomal genes are present as two alleles, with one copy on each chromosome of an autosomal pair. In a clone of cells that have one mutated allele and one wild-type allele, the ratio of VAF:clone size would be 1:2. As an example, 10 percent VAF would suggest that 20 percent of the cells are heterozygous for the mutation.

●Caveats:

•The expected 1:2 ratio of VAF:clone size may be affected by duplication or deletion of a copy of the gene. As an example, if the wild-type allele undergoes deletion, the VAF:clone size would be 1:1; conversely, if the wild-type allele undergoes gene duplication, the ratio would be <1:2.

•VAF of 40 to 60 percent may be associated with a large hematopoietic clone, but it may also reflect germline heterozygosity (ie, inheritance of one mutant allele and one wild-type allele). Inherited mutations have been reported with RUNX1, GATA2, DDX41, TP53, DNMT3A, TET2, and other genes [3-6]; some of these germline mutations are associated with cancer predisposition syndromes or other conditions, as discussed separately. (See "Familial disorders of acute leukemia and myelodysplastic syndromes".)

•VAF near 100 percent may result from a germline polymorphism of an X-linked gene (eg, BCOR, ZRSR2).

•In some cases, CH-associated mutations may be due to somatic mosaicism [3]. (See "Genetics: Glossary of terms", section on 'Mosaicism'.)

With CH, one hematopoietic stem cell (HSC) gives rise to an outsized proportion of blood cells. Normal hematopoiesis in adults is a result of the collective contribution to blood cell production by 50,000 to 200,000 HSCs; if all stem cells were similarly active, an individual HSC would be expected to contribute to 0.002 to 0.0005 percent of blood cell production (ie, the reciprocal of the number of active HSCs) [7].

MOLECULAR FEATURES

CH-associated mutations — The genes that are most frequently mutated in CH are also commonly mutated in myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and myeloproliferative neoplasms (MPN). These genes are often referred to as "leukemia-associated genes" or "leukemia-driver genes" and they are thought to enable expansion of the clone due to a proliferative or survival advantage.

The frequency of specific mutations varies between studies, but the genes that are most often involved are DNMT3A and TET2 [1,8-11].

Genes that are less often associated with CH include ASXL1, JAK2, TP53, SF3B1, SRSF2, CBL, IDH1, IDH2, GNB1, BCOR, U2AF1, GNAS, PPM1D, and BCORL1 [1,8-11]. These genes reflect a broad array of cellular functions, including transcription factors, chromatin modifiers, DNA repair, ribonucleoprotein binding proteins, spliceosome components, signal transduction, and regulators of cellular metabolism, as described separately. (See "Cytogenetics, molecular genetics, and pathophysiology of myelodysplastic syndromes/neoplasms (MDS)", section on 'Gene mutations' and "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia", section on 'Molecular studies'.)

Causes of CH — CH is thought to result from accumulation of mutations throughout an individual's lifetime [12].

Most CH-associated mutations are thought to arise from endogenous mutagenic processes involving impaired DNA repair. As an example, a cytosine-to-thymine (C>T) transition may result from spontaneous deamination of 5-methylcytosine to thymine [9,13-16]. Such nucleotide substitutions accumulate in the genome of hematopoietic stem cells at a rate of approximately 14 mutations per year; mutations in exons have been estimated to accumulate at a rate of approximately 1 every 10 years. Accumulation of mutations with clonal expansion in the absence of malignancy has also been reported in the esophagus, colon, brain, and other tissues [17-19].

Less commonly, CH-associated mutations may be related to environmental mutagens, such as ambient, occupational, diagnostic, or therapeutic radiation; tobacco smoke; air pollutants; and mutagenic drugs (eg, cancer chemotherapy) [20-23]. Rare cases of familial CH were reported in association with a syndrome of long telomeres and heterozygous mutations in POT1 (protection of telomeres 1), which plays a role in telomere maintenance; however, potential contributions of mutated POT1 or aberrant telomeres to familial CH or sporadic CH are presently uncertain [24].

EPIDEMIOLOGY — The prevalence of CH increases with age. Most cases occur sporadically, but family aggregates have been reported.

CH has been reported to account for ≥10 percent of circulating nucleated cells in ≥10 percent of adults in their mid-70s, 20 percent of 90-year-olds, and 30 percent of >100-year-olds [8-10,25,26]. For perspective, the prevalence of unexplained clonal disorders in healthy 70-year-olds is >100-fold higher than the prevalence of myelodysplastic syndromes (MDS) or leukemias [1].

Small clones (eg, variant allele fraction [VAF] ≥0.0001) are almost universally detectable in individuals >40 years [27]. From a study in which an individual's blood cells served as a control for DNA sequencing of a solid tumor, one-quarter of patients had mutations in hematopoietic cells that were not found in the tumor; approximately 5 percent had mutations in leukemia-associated genes [21]. As described above, the prevalence of CH varies with the sensitivity of the detection technique, the genes that are interrogated, and the threshold for defining clonality, as described above. (See 'Clonality' above.)

In some cases, CH has been associated with Hispanic ethnicity, African ancestry, and germline variants of MPL (thrombopoietin receptor), telomere-associated genes, and numerous genes of uncertain biological significance [20,28-32].

EVALUATION — In addition to a history and physical examination, selected patients should undergo testing to exclude a hematologic malignancy, other causes of cytopenias (when present), and/or a germline mutation.

Clinical and laboratory evaluation for myelodysplastic syndromes, acute leukemias, and myeloproliferative neoplasms are described separately. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)" and "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia" and "Overview of the myeloproliferative neoplasms".)

Clinical settings — CH may be encountered in a variety of clinical settings and is usually detected by next-generation sequencing (NGS) of DNA, as described above. (See 'Description and detection' above.)

Settings in which CH may be encountered include:

●Evaluation for cytopenia or another blood disorder

●Bone marrow examination for staging of multiple myeloma, lymphoma, or a non-hematopoietic neoplasm

●Testing for an inherited hematologic condition or genetic predisposition to cancer in a relative

●Screening evaluation of a potential donor for hematopoietic cell transplantation (HCT)

●Genetic testing associated with a clinical trial

●Testing for plasma circulating cell-free DNA (cfDNA) or a paired blood sample for diagnostic solid tumor sequencing

●Other testing, including direct-to-consumer (DTC) genetic testing

●Evaluation for premature cardiovascular events (see "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk", section on 'Older adults')

Further testing — Further testing in a patient with CH is guided by the clinical setting, presence of hematologic findings, the nature of previous testing, and the size of the hematopoietic clone.

Excluding a germline mutation — We generally test dermal fibroblasts (or another non-hematopoietic somatic tissue) to exclude a germline mutation in cases when the variant allele frequency (VAF) is ≥25 percent or with a strong family history of cancer. As described above, VAF in that range may be due to genomic heterozygosity (ie, inheritance of one mutant allele and one wild-type allele) or somatic mosaicism. (See 'Relation of VAF to clone size' above.)

Bone marrow examination — We perform a bone marrow examination when cytopenias or other hematologic findings (eg, circulating blasts), would otherwise prompt the procedure (eg, to exclude a hematologic malignancy or aplastic anemia). In some situations, molecular findings alone (eg, TP53 mutation, ≥2 mutations in the hematopoietic clone) might prompt a shared decision between the clinician and the affected individual to perform a bone marrow examination because of a higher risk for a hematologic malignancy.

The role of a bone marrow examination and/or other evaluation of cytopenias is discussed separately. (See "Approach to the adult with pancytopenia", section on 'Subsequent evaluation'.)

CLASSIFICATION OF CLONAL HEMATOPOIESIS — Classification of CH is based on the variant allele frequency (VAF) and the presence of cytopenias and/or cellular dysplasia (table 1).

Clonal hematopoiesis of indeterminate potential (CHIP) — CHIP has been defined as:

●VAF ≥2 percent (≥4 percent for X-linked gene mutations in males) of an acquired mutation of a leukemia-associated gene; the most common mutations affect DNMT3A, TET2, and/or ASXL1, but other recurrently mutated genes are also listed above. (See 'CH-associated mutations' above.)

●Normal peripheral blood counts. The diagnosis of CHIP specifically excludes patients with clinically significant cytopenias; such patients should instead be diagnosed with clonal cytopenia of uncertain significance (CCUS). (See 'Clonal cytopenia of uncertain significance (CCUS)' below.)

●No clinical or pathologic evidence for a World Health Organization (WHO)-defined hematologic malignancy [1].

A bone marrow examination is not required to diagnose CHIP, but it may be performed to exclude a hematologic malignancy, as described above. (See 'Bone marrow examination' above.)

Modest degrees of dysplasia and abnormalities of mean cell volume (MCV) or red cell distribution width (RDW) do not exclude the diagnosis of CHIP. However, if ≥10 percent of blood or bone marrow nucleated cells of one cell lineage exhibit dysplasia or if there is a disease-defining mutation, the condition should be classified as a myelodysplastic syndrome/neoplasm (MDS) or as acute myeloid leukemia (AML), according to the findings. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)", section on 'Diagnosis' and "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia".)

Clonal cytopenia of uncertain significance (CCUS) — CCUS (table 1) is defined by:

●VAF ≥2 percent of an acquired mutation of a leukemia-associated gene. (See 'CH-associated mutations' above.)

●Unexplained cytopenia (ie, below the lower limit of normal for that laboratory) of at least one blood lineage, after an appropriate evaluation, as described separately. This is defined as Hb <13 g/dL in males and <12 g/dL in females for anemia, absolute neutrophil count <1.8 ×10⁹/L for leukopenia, and platelets <150 × 10⁹/L for thrombocytopenia. (See "Approach to the adult with pancytopenia".)

●No clinical or pathologic evidence for another defined hematologic malignancy neoplasm [1].

Exclusion of a hematologic malignancy for the purpose of diagnosing CCUS is described separately. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)" and "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia".)

CCUS is discussed in more detail separately. (See "Idiopathic and clonal cytopenias of uncertain significance (ICUS and CCUS)".)

Aging-related clonal hematopoiesis (ARCH) — ARCH is a loosely-defined term that refers to the presence of a detectable hematopoietic clone of any size (generally <2 percent VAF), without other evidence of a WHO-defined hematopoietic malignancy (table 1) [1].

When the VAF is ≥2 percent, the condition should be classified as either CHIP or CCUS (table 1). (See 'Clonal hematopoiesis of indeterminate potential (CHIP)' above and 'Clonal cytopenia of uncertain significance (CCUS)' above.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of CH includes hematologic malignancies and other conditions that are associated with clonality. Indeed, clonality is a feature of a spectrum of disorders that range from the various types of CH to myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), acute myeloid leukemia (AML), and other hematologic malignancies.

In some cases, CH must be distinguished from an inherited (ie, germline) gene mutation, as discussed above. (See 'Excluding a germline mutation' above.)

Hematologic malignancies — Mutation of a leukemia-associated gene is a characteristic feature of hematologic malignancies. Compared with CH, hematologic malignancies (eg, MDS, AML, MPN) generally have a higher variant allele frequency (VAF), are more likely to have ≥2 mutations, and dysplasia and/or other morphologic abnormalities are usually more prominent (table 1).

Bone marrow examination (including morphology, flow cytometry, cytogenetics, and molecular evaluation) may be needed to distinguish hematologic malignancies from CH. Clinical manifestations and diagnosis of MDS, AML, and MPNs are discussed separately. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)", section on 'Diagnosis' and "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia", section on 'Diagnosis' and "Overview of the myeloproliferative neoplasms", section on 'The classic myeloproliferative diseases'.)

Aplastic anemia/paroxysmal nocturnal hemoglobinuria — Aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) clinically overlap with one another and both disorders are associated with clonality and variable degrees of cytopenias. AA/PNH can be distinguished from CH by bone marrow biopsy (which will reveal substantial hypoplasia for AA), flow cytometry (which will reveal clones of CD59 negative cells in PNH), and genetic testing (eg, mutation of PIGA in most cases of PNH). Additional details of the clinical presentation and diagnosis of AA and PNH are provided separately. (See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis", section on 'Evaluation' and "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria", section on 'Diagnosis and classification'.)

Inherited disorders — Inherited disorders are usually detected in childhood, but some cases are first recognized in adulthood; adults with inherited syndromes may display only subtle hematologic or other abnormalities.

Importantly, a heterozygous germline mutation may be difficult to distinguish from an acquired mutation, especially when the VAF is close to 50 percent. As discussed above, an inherited disorder is distinguished by testing dermal fibroblasts or other somatic tissue for the mutation; an individual with a germline abnormality should have approximately the same VAF in blood/marrow as in other tissues. (See 'Relation of VAF to clone size' above.)

Presentation and diagnosis of familial hematologic syndromes are discussed separately. (See "Familial disorders of acute leukemia and myelodysplastic syndromes".)

OUTCOMES

CHIP outcomes — Clonal hematopoiesis of indeterminate potential (CHIP) is associated with decreased overall survival, increased risk for a hematologic malignancy, and a greater risk for cardiovascular complications, compared with age-matched members of the general population without CHIP [9,10,28,33,34]:

●Inferior survival – Compared with the general, age-matched population, CHIP is associated with increased all-cause mortality [9,12,33]. A retrospective review of 5132 individuals, with a median follow-up of 96 months, identified increased mortality in association with a CHIP-associated mutation (hazard ratio [HR] 1.4; 95% CI 1.1-1.8) [9]. Increased mortality was observed in those ≥70 years old, but not in younger individuals. Another series of 12,380 subjects found a similar risk of death in association with CHIP (HR 1.4, 95% CI 1.1-1.9) [10]. Most of the excessive mortality in individuals with CHIP was associated with coronary heart disease and ischemic stroke, rather than hematologic malignancies, as described below.

Even without a mutation involving leukemia-driver gene, individuals with CH were reported to have higher rates of all-cause mortality compared to patients without CH [28].

●Increased hematologic malignancies – Although only a small fraction of individuals with CHIP will develop a hematologic malignancy, CHIP is associated with an increased risk for transformation to myelodysplastic syndromes/neoplasms (MDS), myeloproliferative neoplasms (MPNs), or acute myeloid leukemia (AML). Rates of progression appear to vary with the specific mutations, the number of mutations, and the size of the hematopoietic clone [34].

The risk of evolution to AML has been estimated to be 0.5 to 1 percent per year [35]. As an example, CHIP was associated with an increased risk for developing a hematologic malignancy (HR 11.1, 95% CI 3.9-32.6) compared with individuals without CHIP based on whole exome sequencing of 17,182 people [9]. The prevalence of CHIP in 70-year-olds is at least 100-fold greater than the prevalence of MDS or AML, which indicates that the majority of individuals with CHIP do not go on to develop an overt hematologic malignancy [1]. For perspective, the risk of development of a hematologic malignancy in an individual with CHIP is an order of magnitude lower than the risk of progression from MDS to AML. Development of a hematologic malignancy following a diagnosis of CHIP is similar in magnitude to the rates at which monoclonal B cell lymphocytosis (MBL) or monoclonal gammopathy of undetermined significance (MGUS) evolve to non-Hodgkin lymphoma, myeloma, or another plasma cell or lymphoid neoplasm [36,37].

●More cardiovascular complications – CHIP is associated with an increased risk of cardiovascular diseases and worse outcomes in patients with heart failure. Examples of this association include:

In a series that included >17,000 people, CHIP was associated with an increased risk of coronary heart disease incidents (HR 2.0, 95% CI 1.2-3.4) and ischemic stroke (HR 2.6, 95% CI 1.4-4.8) [9]. In a separate analysis of nearly 8000 subjects from two prospective and two retrospective studies, carriers of CHIP had a risk of myocardial infarction that was two- to fourfold greater than non-carriers [33].

Survivors of myocardial infarction with CHIP have increased mortality and worsened heart failure outcomes [35,38].

The mechanism of increased cardiovascular events appears to be inflammation in the endothelium driven by clonally-derived monocytes/macrophages. Testing for CH in patients with premature or unexpected cardiovascular complications is discussed separately. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk" and "Overview of secondary prevention of ischemic stroke".)

CCUS outcomes — Clonal cytopenia of uncertain significance (CCUS) is associated with increased risk for progression to a hematologic malignancy, as described separately. (See "Idiopathic and clonal cytopenias of uncertain significance (ICUS and CCUS)", section on 'Outcomes'.)

ARCH outcomes — Outcomes for individuals with aging-related clonal hematopoiesis (ARCH) are not well-defined.

MANAGEMENT

Monitoring — Monitoring of the patient with CH should be individualized. We generally evaluate individuals every three to six months with an interval history, directed physical examination, and complete blood count (CBC) and differential. We suggest not routinely repeating DNA sequencing and not routinely repeating a bone marrow examination, unless there is another indication.

There is no optimal protocol or evidence-based guideline for monitoring an individual with CH. The nature and frequency of monitoring is influenced by the level of variant allele fraction (VAF), presence of cytopenias, and concerns of the clinician and affected individual. We may modify the frequency of visits and/or CBCs in individuals with certain clinical and genetic characteristics or an elevated CHRS score (a prognostic model to estimate risk for development of a myeloid malignancy).

Features that we consider in establishing a monitoring protocol include:

●High-risk mutations (SF3B1, SRSF2, ZRSR2, JAK2, TP53, RUNX1, FLT3, IDH1, or IDH2).

●VAF ≥20 percent.

●≥2 distinct mutations.

●Age ≥65 years.

●Altered RBC indices (RDW ≥15 percent or MCV >100 fL).

●Cytopenias, especially if associated with clinical findings (eg, cardiorespiratory compromise, infections, bleeding/bruising) and/or other associated cardiovascular risk factors.

Management of CH with associated cytopenias (eg, clonal cytopenia of uncertain significance [CCUS]) is discussed separately. (See "Idiopathic and clonal cytopenias of uncertain significance (ICUS and CCUS)", section on 'Management'.)

Counseling — Counseling is an important aspect of management of CH. The emotional burden of potential cancer-associated mutations and the small risk of developing a hematologic malignancy in blood cells should be discussed. It is also important to emphasize that CH-associated mutations are acquired, and that the mutation does not affect relatives.

Modification of risk factors for cardiovascular complications is discussed separately. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".)

CH in potential transplant donors — There is controversy about the suitability of an individual with CH as a donor for allogeneic hematopoietic cell transplant (HCT) [39,40]. Some institutions screen older potential donors for CH, as discussed separately. (See "Donor selection for hematopoietic cell transplantation", section on 'Matched sibling donors'.)

Recipient outcomes after receiving a transplant from a donor with CH involving DNMT3A or TET2 are similar or superior to those from a donor without CH [29,41]. By contrast, the presence of CH involving MDS-associated genes, such as TP53 or splicing factors, has been linked directly to development of donor cell leukemia [41].

SUMMARY

●Description – Clonal hematopoiesis (CH) refers to a genetically distinct subpopulation of myeloid cells that share an acquired (ie, not inherited) mutation, which distinguishes them from other tissues and unaffected hematopoietic cells. CH may be detected in healthy individuals with few or no hematologic manifestations; although hematologic malignancies (eg, myelodysplastic syndromes/neoplasms, acute leukemias, myeloproliferative neoplasms) also exhibit clonality, they are generally associated with substantial hematologic findings.

Categories of CH (table 1) include:

•Clonal hematopoiesis of indeterminate potential (CHIP)

•Clonal cytopenia of undetermined significance (CCUS)

•Aging-related clonal hematopoiesis (ARCH)

●Clonality – (See 'Clonality' above.)

•Detection – CH is usually detected by next-generation sequencing (NGS) of DNA, but clonality is occasionally recognized by other molecular, cytogenetic, or immunophenotypic techniques. (See 'Description and detection' above.)

•Variant allele fraction (VAF) – The percentage of mutated DNA sequencing reads at a given genetic locus, which roughly parallels the size of the hematopoietic clone. (See 'Relation of VAF to clone size' above.)

●CH-associated mutations – The genes that are most frequently mutated in CH are also commonly mutated in hematologic malignancies; they are often referred to as "leukemia-associated genes" or "leukemia-driver genes." (See 'CH-associated mutations' above.)

The most frequently mutated leukemia-associated genes in CH are DNMT3A and TET2. Other genes are less-often associated with CH, but the frequency of specific mutations varies among studies.

●Epidemiology – The prevalence of CH increases with age. Most cases arise in a sporadic pattern, but there are reports of rare aggregates in families. (See 'Epidemiology' above.)

●Evaluation – (See 'Evaluation' above.)

•Clinical settings – CH may be encountered in a variety of clinical settings in which testing reveals a subpopulation of myeloid cells that share an acquired (ie, non-germline) mutation. Examples of clinical settings are provided above. (See 'Clinical settings' above.)

•Further testing – In selected cases, further testing should be performed to exclude an inherited condition (ie, germline mutation) or a hematologic malignancy.

●Classification – Classification of CH is based on the VAF and the presence of cytopenias and/or cellular dysplasia (table 1).

●Differential diagnosis – Includes hematologic malignancies and other conditions associated with clonality, including myelodysplastic syndromes/neoplasms, myeloproliferative neoplasms, acute myeloid leukemia, and aplastic anemia/paroxysmal nocturnal hemoglobinuria. In some cases, CH must be distinguished from inherited disorders (ie, germline mutation). (See 'Differential diagnosis' above.)

●Outcomes – CHIP is associated with inferior overall survival, a modestly increased risk for developing a hematologic malignancy, and increased cardiovascular events. (See 'CHIP outcomes' above.)

●Management – Monitoring of the individual with CH should be individualized. Counseling about risks and reassurance about outcomes are important aspects of management. (See 'Management' above.)

We generally evaluate individuals every three to six months with an interval history, directed physical examination, and complete blood count (CBC) and differential. We suggest not routinely repeating DNA sequencing and not routinely repeating a bone marrow examination, unless there is another indication.

ACKNOWLEDGMENTS

The UpToDate editorial staff acknowledges the contributions of Stanley L Schrier, MD as Section Editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.

The UpToDate editorial staff acknowledges David P Steensma, MD, who contributed to earlier versions of this topic review.