Clonal hematopoiesis of indeterminate potential and clonal cytopenias of undetermined significance: 2023 update on clinical associations and management recommendations

Condition Overview: Clonal hematopoiesis (CH) refers to age-associated expansion of somatic variants in hematopoietic stem and progenitor cells (HSPC). Diagnosis: CH of indeterminate potential (CHIP) is operationally defined as pathogenic variants in HSPCs at a variant allele frequency ≥2%. Clinical Associations: CH is associated with increased occurrence of several hematological conditions such as cytopenias (also called clonal cytopenia of undetermined significance), hematological (predominantly myeloid but also lymphoid) neoplasms, cytosis (including monocytosis), and non-hematological conditions such as atherosclerotic cardiovascular and cerebrovascular disease, ischemic congestive heart failure, venous thromboembolism, type 2 diabetes mellitus, chronic obstructive pulmonary disease, osteoporosis, gout, with a potential protective effect in Alzheimer's disease (AD). Management Recommendations: As of now, there is limited prospective data for CH testing; however, CH detection is becoming increasingly prevalent due to ubiquitous use of somatic and germline NGS testing. This in addition to data suggesting that therapy related myeloid neoplasm (tMN) in many cases is preceded by the detection of CH clones, has led to the establishment of CH clinics at several institutions. At our institution, on a research basis, we currently recommend testing for CH for individuals with persistent (≥4 months) unexplained cytopenias, in patients with malignancies prior to adjuvant cytotoxic chemotherapy and/or radiation or radionuclide therapy, screening prior to autologous hematopoietic stem cell transplantation and chimeric antigen receptor T cell (CAR-T) therapy and to assess as to whether or not, potential germline mosaic variants actually represent CH.