What is Clonal Hematopoiesis (CH) of Indeterminate Potential (CHIP)?

Clonal Hematopoiesis of Indeterminate Potential (CHIP)

Clonal hematopoiesis of indeterminate potential (CHIP) is defined as the presence of somatic clonal mutations in myeloid neoplasm driver genes detected in blood or bone marrow at a variant allele fraction of ≥2% in individuals who lack diagnostic criteria for a hematologic malignancy or unexplained cytopenia. 1

Definition and Characteristics

• CHIP refers to the clonal expansion of hematopoietic stem cells that have acquired one or more somatic mutations, providing them with a growth advantage compared to wild-type hematopoietic stem cells 2
• The term specifically requires:
  • Presence of somatic mutations in genes associated with myeloid neoplasms at a variant allele fraction (VAF) ≥2% 1
  • Absence of diagnostic criteria for a defined hematologic malignancy 1
  • Absence of unexplained cytopenia 1
• CHIP is distinguished from clonal cytopenia of unknown significance (CCUS), which shares the presence of somatic mutations but also includes cytopenia 1

Common Genetic Mutations in CHIP

• Approximately 80% of CHIP cases involve mutations in specific genes 3:
  • Epigenetic regulators: DNMT3A, TET2, ASXL1 3, 4
  • DNA damage repair genes: PPM1D, TP53 3, 5
  • Regulatory tyrosine kinase: JAK2 1, 3
  • mRNA spliceosome components: SF3B1, SRSF2 1, 3
• These mutations are also commonly found in myeloid neoplasms but alone are not diagnostic of myelodysplastic syndrome (MDS) or other hematologic malignancies 1

Epidemiology and Risk Factors

• CHIP prevalence increases significantly with age 4, 6
• Prevalence ranges from 10% to 30% in solid tumor patients 4
• Associated risk factors include:
  • Advanced age 4, 6
  • Smoking and obesity 3
  • Previous exposure to cytotoxic therapies (chemotherapy and radiotherapy) 1, 3
  • Inflammatory conditions 3
  • HIV infection 3

Clinical Significance and Associated Risks

• CHIP carries a 0.5-1.0% annual risk of progression to hematologic malignancy 3
• It is associated with a two-fold increased risk of cardiovascular disease independent of traditional risk factors 3, 5
• CHIP is linked to:
  • Increased mortality risk (adjusted HR 1.45-1.64 in individuals without cardiometabolic disease) 6
  • Higher risk of coronary artery disease, myocardial infarction, and venous thromboembolic disease 3
  • Poorer prognosis in patients with aortic stenosis and heart failure 3
  • Potential impact on cancer treatment outcomes (both immunotherapy and chemotherapy) 4

Diagnostic Considerations

• CHIP can be detected through:
  • Next-generation sequencing (NGS) of blood or bone marrow samples 1
  • Cell-free DNA (cfDNA) analysis, where it is often an incidental finding 4
• Distinguishing CHIP-related variants from tumor-derived variants in cfDNA can be challenging 1
• The gold standard for differentiating CHIP from tumor-derived mutations is comparison of plasma-derived cfDNA with DNA from peripheral blood mononuclear cells 1

Clinical Management

• Regular monitoring of blood counts is recommended at least every 6 months 1
• More frequent monitoring may be appropriate based on clinical expertise 1
• Clonal copy number-neutral loss of heterozygosity (CN-LOH) spanning known myeloid neoplasm-associated genes warrants a more rigorous follow-up schedule for early detection of myelodysplastic disease 1
• No specific interventions are currently recommended for CHIP alone, but management of associated cardiovascular risk factors may be beneficial 3, 5

Relationship to Other Conditions

• CHIP is part of a spectrum of indolent myeloid hematopoietic disorders that includes:
  • Idiopathic cytopenia of unknown significance (ICUS) 1
  • Idiopathic dysplasia of unknown significance (IDUS) 1
  • Clonal cytopenia of unknown significance (CCUS) 1
• CHIP has been included in the updated WHO classification of hematolymphoid tumors 2