Clonal Hematopoiesis (CH)

James Brogan

Background

  • Clonal hematopoiesis (CH) refers to the expansion of blood cells derived from a single hematopoietic stem cell (HSC) with somatic mutations
  • CH can be driven by point mutations or structural variants
  • CH is common in the elderly and is a premalignant state, as the somatic mutations detected in CH can lead to myeloid neoplasms such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML)

Spectrum of CH-Related Disorders

  • Clonal hematopoiesis of indeterminate potential (CHIP): the presence of somatic mutations in leukemia driver genes at a VAF of ≥ 2% without meeting the criteria for hematologic malignancy
  • CHIP is associated with a 0.5% to 1% annual risk of progression to hematologic malignancy and increases the risk of cardiovascular events due to a proinflammatory state
  • Clonal cytopenia of undetermined significance (CCUS): the combination of unexplained cytopenia(s) and somatic mutations without marrow dysplasia or other diagnostic criteria for hematologic malignancies
  • CCUS carries a higher risk of progression to myeloid neoplasms compared to CHIP, particularly in cases featuring high-risk mutations
  • Idiopathic cytopenia of undetermined significance (ICUS): the presence of one or more cytopenias with no identifiable mutation or other cause

Presentation

  • Patients with CHIP are often asymptomatic and identified incidentally during genetic testing
  • CCUS patients present with unexplained cytopenias but do not meet criteria for MDS or other hematologic malignancies
  • CHIP and CCUS are associated with an increased risk of progression to myeloid neoplasms and non-hematologic complications such as cardiovascular disease (atherosclerosis, myocardial infarction and stroke) and renal disease
  • Clinical pearl: consider CH-related disorders in patients with premature or unexplained cardiovascular disease, as the inflammatory effects of clonal hematopoiesis can accelerate atherosclerosis independent of traditional risk factors

Evaluation

  • Routine screening with next-generation sequencing (NGS) is not currently recommended for asymptomatic individuals
  • Genetic testing may be considered in patients with unexplained cytopenias or during the evaluation for other hematologic conditions
  • Screening for CH-related disorders typically involves NGS to detect somatic mutations in genes such as DNMT3A, TET2, and ASXL1
  • Additional tests may include cytogenetic analysis and flow cytometry to rule out other hematologic malignancies
  • Risk calculators, such as the Clonal Hematopoiesis Risk Score (CHRS), can stratify patients into low, intermediate or high risk

High-Risk Features for Progression from Clonal Hematopoiesis to Myeloid Neoplasm

Category

Risk Factor

Significance
Demographics Age ≥ 65 years Older patients have higher risk of progression
Hematologic parameters Red cell distribution width ≥ 15% Indicates altered erythropoiesis Mean cell volume ≥ 100 femtoliters Macrocytosis suggests
Mean cell volume ≥ 100 femtoliters Macrocytosis suggests dyserythropoiesis
Presence of any cytopenia Suggests early bone marrow dysfunction
Mutation characteristics Variant allele frequency ≥ 20% Higher allele frequency suggests greater clonal dominance
≥ 2 mutations in leukemia driver genes Multiple mutations indicate more advanced clonal evolution
Specific mutations Splicing factor mutations (SRSF2, SF3B1, ZRSR2) Associated with higher risk of progression to MDS/AML
TP53 mutations Associated with myeloid neoplasms secondary to cancer treatment and poor outcomes
IDH1/2 mutations Higher risk of progression to AML
Clinical context Prior chemotherapy or radiation exposure Therapy-related CH has higher progression risk
Serial monitoring Increasing variant allele frequency over time Suggests active clonal expansion
Acquisition of new mutations Indicates ongoing genomic instability

Risk Stratification and Prognosis per CHRS

Risk Category

Percentage of CH Patients

10-Year Risk of Myeloid Neoplasm
Low risk 90% ~0.6%
Intermediate risk 9% ~8%
High risk 1% ~30%

Management 

  • Patients with CH-related disorders should undergo periodic CBC and clinical evaluation; however, there are no current guidelines for the frequency of evaluation
  • Those with CCUS require closer surveillance due to a higher risk of progression to hematologic malignancy
  • Lifestyle modifications and management of cardiovascular risk factors are crucial
  • Currently, there are no FDA-approved therapies for CH-related disorders
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