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

Abstract

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. | INTRODUCTIONClonal hematopoiesis (CH) is defined by the detection of somatic variants in hematopoietic stem and progenitor cells, with the potential to expand over time, based on clonal selection pressures. CH was first identified by observing non-random chromosome X-inactivation patterns in the myeloid compartment of healthy women increasing with age, suggesting age-related clonal expansions, 1,2 and confirmed subsequently to be secondary to somatic TET2 mutations, laying the groundwork for future studies in CH involving large numbers of biobanked samples. 3 Interestingly, CH mutations predominantly affect the epigenetic regulator genes (most commonly; DNMT3A, TET2 and ASXL1) and also occur in myeloid neoplasms, suggesting that CH is a neoplastic precursor event, akin to monoclonal gammopathy in plasma

Car-T Cell Therapy in Large B Cell Lymphoma

“…Higher neurological toxicities were preferentially associated with DNMT3A, TET2, and ASXL1 genes. 41 A higher incidence of grade 3 cytokine release syndrome was observed in the CH-positive than in CH-negative patients (17.7% vs 4.2%, respectively). 42 Finally, the 24month cumulative incidence of therapy-related myeloid neoplasms after CAR-T cell therapy was higher in CHpositive than in CH-negative patients (19% vs 4.2%, respectively).…”

“…CH is associated with an increased risk of hematological malignancies, cytopenias, and nonhematological conditions such as atherosclerosis and cardiovascular and cerebrovascular disease. 41 Sinai et al explored 114 LBCL patients undergoing treatment with CAR-T cells (105 with Axi-Cel and with Tisa-Cel) for CH detected in 36.8% of cases. The two most frequently mutated genes were PPMN1D (19/114) and TP53 (13/114).…”

Anemia and Its Connections to Inflammation in Older Adults: A Review

“…Changes associated with clonal hematopoiesis can also lead to aplastic anemias [102]. Along with changes in the cell population in the hematopoietic lineage, the bone marrow undergoes conversion from hematopoietically active red marrow to hematopoietically inactive yellow bone marrow [103].…”