Causes and consequences of clonal hematopoiesis

Abstract

Clonal hematopoiesis (CH) is described as the outsized contribution of expanded clones of hematopoietic stem and progenitor cells (HSPCs) to blood cell production. The prevalence of CH increases dramatically with age. CH can be caused by somatic mutations in individual genes or by gains and/or losses of larger chromosomal segments. CH is a premalignant state; the somatic mutations detected in CH are the initiating mutations for hematologic malignancies, and CH is a strong predictor of the development of blood cancers. Moreover, CH is associated with nonmalignant disorders and increased overall mortality. The somatic mutations that drive clonal expansion of HSPCs can alter the function of terminally differentiated blood cells, including the release of elevated levels of inflammatory cytokines. These cytokines may then contribute to a broad range of inflammatory disorders that increase in prevalence with age. Specific somatic mutations in the peripheral blood in coordination with blood count parameters can powerfully predict the development of hematologic malignancies and overall mortality in CH. In this review, we summarize the current understanding of CH nosology and origins. We provide an overview of available tools for risk stratification and discuss management strategies for patients with CH presenting to hematology clinics.

Graphical abstract

Figure 1.

Nosology of CH. CH is the expansion of a clonal population of HSPCs. Many instances of CH are caused by unknown drivers and can be referred to as CHUD (dotted branch). When molecular drivers of CH are known, they can be further subclassified as initiating events of myeloid malignances (myeloid CH) or lymphoid malignancies (lymphoid CH). Myeloid CH is classified as CH caused by somatic mutations in myeloid malignancy-driver genes at VAF ≥ 2%. The term CHIP is used in the absence of cytopenias, and CCUS is used when cytopenias are present. Mosaic chromosomal alterations (mCAs) can also be drivers of myeloid CH (m-MCA). Lymphoid CH is subdivided into CH caused by mutations in drivers of lymphoid malignancy with a VAF ≥ 2% (L-CHIP) or mCA that reflect chromosomal abnormalities driving lymphoid malignancies (L-mCA). Ever-improving sensitivity of next-generation sequencing has led to an increasing identification of low-abundance (VAF < 2%) clones, which some have referred to as micro-CH. The clinical significance of these low-abundance clones remains to be fully elucidated.

Figure 2.

Context-dependent expansion of CH genotypes. Several lines of evidence suggest molecular abnormalities driving CH are acquired early in life. Detection of CH is rare for individuals aged <50 years. The ability to detect CH increases with age, corresponding to a decline in HSPC diversity. Male sex, inherited germ line predisposition, systemic inflammation, chemotherapy/radiation therapy exposure, and smoking each select for distinct CH genotypes.

Figure 3.

Malignant and nonmalignant consequences of CH. COPD, chronic obstructive pulmonary disease.

Figure 4.

Current management strategies for CH. Patients with CHIP/CCUS are typically identified incidentally as routine screening for CHIP/CCUS is not currently recommended outside of the context of a well-designed clinical research study. We advise the use of the CHRS to risk stratify patients with CHIP/CCUS into high-, intermediate-, and low-risk groups. All patients with cytopenia should be offered a bone marrow biopsy and cytogenetic profile to rule out underlying MDS. Patients at high risk may be followed up every 3 to 6 months depending on cytopenia burden and the rate of clinical change. Bone marrow biopsies and NGS should be repeated for clinical changes that may indicate progression. These patients are most likely to derive benefit from therapeutic intervention clinical trials designed to prevent malignant transformation and, if interested, may be considered for these studies. Less frequent monitoring is indicated for patients at intermediate and low risk. Bone marrow biopsies should not be performed outside of initial workup of cytopenia or to investigate clinical changes that may be indicative of progression. These patients are statistically unlikely to derive benefit from therapeutic clinical trials designed to prevent malignant transformation, and these patients should not be routinely considered as candidates for these studies. All patients may derive benefit from healthy lifestyle modifications such as smoking cessation, reduction of visceral fat burden, and exercise. Patients with CVD risk factors may derive benefit from preventive cardiology evaluation and/or enrollment on clinical trials to prevent CVD outcomes. A complete review of symptoms should be performed on all patients with CCUS to evaluate for systemic immune and autoinflammatory disease, including VEXAS syndrome. CBC + D, complete blood count with differential; NGS, next-generation sequencing.

Figure 5.

CHRS: a tool to predict risk of myeloid malignancy in CHIP/CCUS. (Top) Table of prognostic features and corresponding scores assigned in CHRS, and (bottom) cumulative incidence of hematologic malignancy among 470 960 participants in the UK Biobank stratified based on CHRS status. Top panel: From Weeks et al. Prediction of Risk for Myeloid Malignancy in Clonal Hematopoiesis. New England Journal of Medicine Evidence. 2023;2(5). Copyright ©(2023) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.