Clonal Hematopoiesis of Indeterminate Potential

Abstract

Background: Patients with cytopenia are increasingly undergoing molecular genetic tests of periperal blood or bone marrow for diagnostic purposes. These tests can detect genetic mutations that do not have any morphological correlate in hematologic neoplasia such as myelo - dysplastic syndrome (MDS). A new entity was recently defined to lessen the risk of incorrect diagnoses of MDS. This new entity is a potential precursor of myeloid diseases, analogously to monoclonal gammopathy of undetermined significance as a potential precursor of multiple myeloma.

Methods: This review is based on pertinent articles retrieved by a selective search in PubMed employing the terms "clonal hematopoiesis," "acute myeloid leukemia," and "myelodysplastic syndrome."

Results: Clonal hematopoiesis of indeterminate potential (CHIP) is a new entity in which somatic mutations are found in cells of the blood or bone marrow, but no other criteria for hematologic neoplasia are met. Its prevalence rises with age and is roughly 10% among persons aged 70 to 80. It is estimated that, in Germany, about 2.75 million people are affected. The most common mutation is on the DNMT3A gene, followed by TET2 and ASXL1. The rate of transformation to a hematological neoplasia is 0.5-1% per year, and thus about 13 times higher than the incidence of such neoplasias in general. If CHIP is discovered incidentally in a patient with a normal blood count, a complete blood count with differential should be repeated three months later and then at annual intervals.

Conclusion: CHIP must be included in the differential diagnosis of peripheral blood cytopenia. This new entity can help us understand the clinical significance of clonal hematopoiesis.

Figure 1

Stepwise development from polyclonal hematopoiesis (normal, no evidence of somatic mutations) to clonal hematopoiesis of indeterminate potential (CHIP), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). ICUS, idiopathic cytopenia of indeterminate significance. The mutated genes (DNMT3A, ASXL1, TP53) are shown as examples; other genes may be affected, and in a different order.

Figure 2

Age-related prevalence of CHIP (7–9) CHIP, clonal hematopoiesis of indeterminate potential

Figure 3

Frequency of mutated genes in CHIP. The numbers following the gene names give the mutation frequency in percent (– 9). CHIP, clonal hematopoiesis of indeterminate potential

Figure 4

Algorithm for clinical management of CHIP Cytopenia defined as Hb <10 g/dL, platelets <100 000/µL, neutrophils <1000/µL. CHIP, clonal hematopoiesis of indeterminate potential ^*1To acquire samples for cytologic, histologic, cytogenetic, and molecular genetic studies