What is Clonal Hematopoiesis?
Clonal hematopoiesis is the acquisition of somatic mutations in hematopoietic stem and progenitor cells (HSPCs) that leads to the disproportionate expansion of mutated blood cell clones, occurring with increasing frequency as people age and representing a premalignant state that increases risk for both hematologic malignancies and cardiovascular disease. 1, 2
Core Definition and Mechanism
Clonal hematopoiesis represents the outsized contribution of expanded clones of HSPCs to blood cell production, where a single hematopoietic stem cell carrying a somatic mutation produces a disproportionate share of circulating blood cells. 2, 3
- The mutations occur in genes commonly associated with myeloid neoplasms, including DNMT3A, ASXL1, TET2, JAK2, TP53, GNAS, PPM1D, BCORL1, and SF3B1. 1
- These are the same initiating mutations found in hematologic malignancies, making clonal hematopoiesis a premalignant condition. 2
Clonal Hematopoiesis of Indeterminate Potential (CHIP)
When clonal hematopoiesis involves a variant allele fraction (VAF) ≥2% in myeloid neoplasm driver genes, occurs in individuals lacking diagnostic criteria for hematologic malignancy, and presents without unexplained cytopenia, it is specifically termed CHIP. 4
- CHIP requires three specific criteria: somatic mutations at VAF ≥2%, absence of diagnostic criteria for defined hematologic malignancy, and absence of unexplained cytopenia. 4
- This distinguishes CHIP from frank myelodysplastic syndrome (MDS) or other hematologic neoplasms. 1, 4
Age-Related Prevalence
The prevalence of clonal hematopoiesis increases dramatically with age, affecting 5-10% of individuals older than 70 years but only approximately 1% of those younger than 50 years. 1
- By age 85 years, more than 30% of individuals demonstrate CHIP. 5
- This age-related increase makes clonal hematopoiesis one of the most common age-associated somatic alterations. 2
Clinical Significance and Risks
Hematologic Malignancy Risk
Clonal hematopoiesis is a strong predictor of subsequent hematologic cancer development, functioning as a precursor state analogous to monoclonal gammopathy of undetermined significance (MGUS). 2, 5
- The risk of progression to hematologic malignancy varies based on specific mutations, VAF, and clinical context. 2
- Patients with advanced age or prior chemotherapy exposure face higher transformation risk. 1, 6
Cardiovascular and Inflammatory Disease
Beyond malignancy risk, clonal hematopoiesis associates with increased cardiovascular events and overall mortality through inflammatory mechanisms. 2, 5
- Mutated blood cells, particularly monocytes/macrophages, release elevated levels of inflammatory cytokines. 2
- This drives accelerated atherogenesis and contributes to various age-related inflammatory disorders. 5
Diagnostic Considerations and Pitfalls
Distinguishing from Germline Variants
A critical pitfall in genetic testing is that variants detected at approximately 50% VAF in blood may represent clonal hematopoiesis rather than germline mutations, particularly in older patients or those who received chemotherapy. 1
- Blood-only sequencing cannot reliably distinguish germline variants from clonal hematopoiesis. 1
- Tumor-normal paired sequencing resolves this ambiguity: variants present in blood but absent or at very low levels in tumor tissue indicate clonal hematopoiesis rather than germline mutation. 1
Clinical Context Matters
Clonal hematopoiesis occurs with higher frequency in patients with lymphoid or solid tumors, particularly after exposure to genotoxic chemotherapy or radiation. 6
- This therapy-related clonal hematopoiesis confers greater risk for therapy-related myeloid neoplasms. 6
- Risk factors include aging, male sex, cigarette smoking, and germline variants in telomere-associated genes like TERT. 5
Management Approach
Surveillance Strategy
For patients with documented clonal hematopoiesis, regular monitoring of blood counts at least every 6 months is recommended. 4
- More rigorous follow-up is warranted when copy-neutral loss of heterozygosity (CN-LOH) spans known myeloid neoplasm-associated genes. 1, 4
- Persistent cytopenias require follow-up for at least 6 months before considering MDS diagnosis. 7
Key Clinical Caveat
The presence of MDS-associated somatic mutations alone does not establish a diagnosis of MDS in the WHO classification—these mutations may represent clonal hematopoiesis without meeting criteria for myeloid neoplasm. 1