CHIP/CCUS Natural History Protocol

Description

Clonal Hematopoiesis of Indeterminate Potential (CHIP) has been defined as the presence of a somatic pathogenic variant associated with hematological malignancy, with an allele fraction of at least 2%, without morphological evidence of bone marrow dysplasia or neoplasia. Such variants are small, occur in leukocytes and are found in a substantial proportion of the healthy aging population using next generation sequencing (NGS). They are thought to represent a pre-neoplastic phase of hematological malignancy, particularly myeloid disorders such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). They are considered by some to be analogous to monoclonal B cell lymphocytosis (MBL), or monoclonal gammopathy of uncertain significance (MGUS) as precursors for chronic lymphocytic leukemia (CLL) and myeloma respectively, and, with a similar rate of progression of 0.5%-1% per year.

CHIP is strongly associated with advancing age with a prevalence of up to 10% in those >65 years of age compared to 1% in those <50 years of age, and has also been associated with an increased atherosclerotic risk, and an increase in overall mortality. Despite this association, most people with CHIP are denoted healthy and do not progress to hematological malignancy. Those with low blood counts in association with a – termed clonal cytopenias of undetermined significance (CCUS) – do show a significantly higher rate of progression to myeloid malignancy, more analogous to patients with low risk MDS, though they are currently not classified as such as they lack the morphological dysplasia or defining chromosomal abnormalities.

The optimal follow-up and management of CHIP and CCUS is not yet established – evidence has suggested that factors such as which specific variant, how many variants are present, and the frequency at which these variants increase can help us to delineate high and low risk status. Some recent data has shown that the presence of CHIP is associated with increased levels of inflammation. In depth, investigation should provide further insight into the pathogenesis and progression of this process. The establishment of a natural history protocol will allow patients with CHIP and CCUS to be followed prospectively in a clinical setting. This protocol will have many collaborators from different institutes providing expertise including National Human Genome Research Institute (NHGRI), National Heart, Lung and Blood Institute (NHLBI), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the Department of Laboratory Medicine (DLM).