Clonal hematopoiesis of indeterminate potential: clinical relevance of an incidental finding in liquid profiling

Introduction

Liquid profiling uses cell free circulating nucleic acids in the peripheral blood of cancer patients for non-invasive detection of somatic tumor mutations. A number of sequencing and PCR-based molecular techniques have been applied in a plethora of cancers for early tumor detection, residual disease monitoring, detection of therapeutic targets, and guidance of therapy [1]. Thus, liquid profiling has the potential to overcome the necessity of invasive surgery or biopsy to obtain a specimen for genetic tumor profiling and allows serial molecular investigations and follow-up monitoring using peripheral blood only [2]. Somatic mutations detected in cell free DNA (cfDNA) are expected to be derived from the tumor. However, clonal hematopoiesis is a source of biological noise in cfDNA analyses [3]. The high prevalence of large hematopoietic clones in the peripheral blood of healthy individuals was first described in the year 2014 [4], [5], [6]. This condition can be found in >10% of apparently healthy individuals by the age of 70 and was initially termed age-related clonal hematopoiesis (ARCH) [5]. Later on, the term clonal hematopoiesis of indeterminate potential (CHIP) was introduced. CHIP has been defined by the presence of a somatic mutation in a substantial fraction of blood cells (at least 2% variant allele fraction, VAF) in the absence of definitive morphologic, histopathological and clinical evidence for a hematological neoplasm [7]. The currently finalized 5th edition of the World Health Organization Classification of Haematolymphoid Tumours will basically adopt this definition of CHIP as a myeloid precursor lesions defined by clonal hematopoiesis harboring somatic mutations of myeloid malignancy-associated genes detected in the blood or bone marrow at a VAF of ≥2% (≥4% for X-linked gene mutations in males) in individuals without a diagnosed hematologic disorder or unexplained cytopenia [8]. The distinct entity clonal cytopenia of undetermined significance (CCUS) is defined as CHIP detected in the presence of one or more persistent cytopenias that are otherwise unexplained by hematologic or non-hematologic conditions and that do not meet diagnostic criteria for defined myeloid neoplasms [8]. Differences in the clinical presentation and risk of progression between CHIP and CCUS will be discussed in detail below. While CHIP and CCUS are clearly defined, the more unspecific term clonal hematopoiesis – or ARCH when emphasizing on the age-dependent incidence of the condition – refers broadly to the presence of a population of clonal hematopoietic cells in the absence of hematological cancers or other clonal disorders, and does not include any definitions regarding the spectrum of genetic aberrations or the necessary clone size [8].

Since DNA derived from leukocytes represents a large fraction of cfDNA, CHIP-associated somatic mutations are also found in cfDNA and may be detected by liquid profiling [9, 10]. A number of molecular assays used for liquid profiling thus try to overcome this bias and to discriminate tumor-associated from CHIP-associated mutations – e.g., by the paired genotyping of peripheral blood cells together with cfDNA [11], [12], [13]. In addition, differences in the size of cfDNA molecules derived from leukocytes compared to those derived from tumor cells have been suggest for distinguishing carcinoma-derived from CHIP-derived mutations [14, 15]. In contrast to these effort, CHIP is not just a bias in liquid profiling but a finding of potential clinical relevance on its own. This review article summarizes the clinical evidence of CHIP as an incidental finding in liquid profiling with a particular focus on the development of hematologic neoplasms (Figure 1). Non-hematologic conditions associated with CHIP have most recently been reviewed in detail elsewhere [16].

Figure 1:

Clonal hematopoiesis of indeterminate potential (CHIP) is a hematopoietic precursor lesion with an increased risk of progression to mostly myeloid hematopoietic neoplasms and associated with cardiovascular and other non-hematopoietic diseases. Genetic analysis of a gene panel by next generation sequencing (NGS) is necessary to diagnose and monitor CHIP.

Figure modified from Hoermann et al. [24].

Clonal hematopoiesis is a risk factor for hematologic neoplasms

The definition of CHIP as the presence of a somatic mutation with a VAF ≥2% in genes typically mutated in hematologic neoplasms but without definitive morphologic, histopathological and clinical evidence of such one [7] has two practical implications: First, the 2% VAF cutoff refers to a substantial hematopoietic clone in the peripheral blood. The plethora of data on the clinical relevance of CHIP have been generated using targeted next-generation sequencing (NGS), whole exome sequencing (WES), or whole genome sequencing (WGS) with a moderate analytical sensitivity [4, 5, 17], [18], [19]. While targeted NGS-assays using error-correction methods are capable of detecting much smaller hematopoietic clones down to a VAF of ∼0.1% [20] or even ∼0.01% [21, 22], the clinical significance of these very small clones – not qualifying for CHIP per definition – is currently unclear. In fact, very small clones are nearly ubiquitously detected in healthy individuals [22]. Second, the mutation spectrum of CHIP largely overlaps with that of overt hematologic neoplasms – in particular myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). Most frequent CHIP mutations are found in the genes DNMT3A, TET2, and ASXL1 which encode for epigenetic modifiers and the tyrosine kinase gene JAK2 [23]. While differences in the number, clone size, and mutation pattern between CHIP and overt hematological neoplasms have been described – and will be discussed here in more detail below – the clear discrimination between CHIP and a hematological neoplasm in an individual patient is currently not possible solely based on NGS results but requires a hematologic workup including at least a blood count and differential together with a clinical examination. In addition, if unexplainable blood count abnormalities are found, a complete bone marrow investigation may be required [24, 25].

In many individuals, CHIP clones remain stable over the time. However, progression to hematological neoplasms may occur [26], [27], [28]. Overall, the risk of progression is estimated in the order of 0.5–1% per year [7]. A similar order of magnitude is known for the progression from monoclonal B-cell lymphocytosis (MBL) to chronic lymphocytic leukemia (CLL), or from monoclonal gammopathy of undetermined significance (MGUS) to plasma cell myeloma [29]. Thus, CHIP represents a premalignant condition with a moderate risk of progression to an overt hematologic – mostly myeloid – neoplasm. Overall, the development of a hematologic neoplasm is roughly 10-times higher than in the general population [4, 5]. The risk of progression in individuals with clonal hematopoiesis is profoundly influenced by (1) the presence of accompanying unexplained blood count abnormalities as discussed in detail below – this includes cases with unexplained cytopenia leading to the diagnosis of CCUS [8] but is not restricted to it, and (2) specific gene mutations or patterns of mutations that have been associated with a higher risk of progression or a distinct clinical phenotype. In this regard the term clonal hematopoiesis of oncogenic potential (CHOP) has been introduced for specific disease-driving mutations [26, 27]. For example, BCR:ABL1 is a driver aberration strongly associated with the development of chronic myeloid leukemia (CML), NPM1 mutations are linked to acute myeloid leukemia (AML), KIT D816V is characteristic for systemic mastocytosis, and JAK2 V617F is suggestive for the presence of an MPN [27]. In addition to these mutations closely associated with a distinct clinical presentation, the number and the pattern of somatic mutations are key for the prediction of clonal progression as discussed in detail below.

Blood count abnormalities increase the hematologic significance of CHIP

The majority of individuals with CHIP display no blood count abnormalities and a normal leukocyte morphology. While a slight elevation in the red cell size has been described in some studies, an increased red cell distribution width (RDW) is the most consistent blood count feature found in CHIP [5]. In contrast, the presence of an unexplained cytopenia in the context of CHIP-mutations is referred to as clonal cytopenia of unknown significance (CCUS) [7, 8, 26]. CCUS is defined as an unexplained clonal cytopenia not meeting the diagnostic criteria of a hematologic neoplasm – in particular, the criteria of an MDS are not fulfilled. The exclusion of an MDS requires a bone marrow examination including at least cytomorphology and cytogenetics; in addition, histopathology and immunophenotyping are recommended [26]. Patients with CCUS are at a marked risk for progression to an MDS or another hematologic neoplasm. In this regard, CCUS refines the long established conditions of idiopathic cytopenia of unknown significance (ICUS) and idiopathic dysplasia of unknown significance (IDUS) that have been used for patients with unclear conditions not meeting the diagnostic criteria of MDS [30]. Both conditions have been defined primarily based on bone marrow morphology. ICUS is a term used for patients with unexplained persistent cytopenia in the absence of bone marrow dysplasia or other MDS-defining features [30]. IDUS is a term that describes patients who likely have clonal myelopoiesis (based on the morphologic finding of bone marrow dysplasia) without cytopenia that would be diagnostic for MDS [30]. The inclusion of molecular data in this conundrum of myeloid precursor lesions discriminates ICUS into CCUS and non-clonal ICUS [26, 31] (Table 1). Malcovati et al. studied a cohort of patients with traditionally (without molecular data) defined ICUS: Patients with CCUS showed a 14-times higher risk to develop a myeloid neoplasm compared to non-clonal ICUS [32]. CCUS patients were further stratified regarding their mutation pattern: a pattern of splicing factor mutations or multiple gene mutations was associated with a progression risk of ∼20% per year [32]. A subsequent study by Galli et al. investigated clone metrics in 311 patients with ICUS among community-dwelling individuals without hematologic phenotype and patients with overt myeloid neoplasms [33]. Within the ICUS cohort, sole mutations of DNMT3A were not associated with an increased risk for development of a myeloid neoplasm. In contrast, patients harboring mutations in splicing factors genes (SF3B1, SRSF2, or U2AF1), ASXL1, or TET2 were at a substantial risk to develop a myeloid neoplasm. In addition to the mutation pattern, the risk increased with the number of somatic mutations [33]. Overall, selected mutation patterns showed high specificity and positive predictive value (PPV) for the presence of myeloid neoplasm – these patterns included SF3B1 mutations and comutation patterns involving SF3B1, U2AF1, or TP53 with other genes, as well as other comutation patterns [33]. This study indicates that not only the presence of cytopenia but also the mutational pattern and clonal metric of somatic mutations can be used to refine the risk prediction and management of patients with CCUS. Rossi et al. studied the clinical relevance of CHIP in persons aged ≥80 years. Regarding the hematologic outcome, the relevance of CHIP was highest in persons with unexplained cytopenia (30% of cases). Among these individuals, the presence of specific mutation patterns (presence of mutations in splicing factor genes; comutation patterns involving TET2, ASXL1, or DNMT3A; and/or mutations with VAF >9.6%) was associated with a myelodysplastic-like phenotype and a probability of survival comparable to that of overt myeloid neoplasms [34]. In contrast, the presence of any CHIP mutation without stratification for cytopenia had only a low PPV (11%) for the development of a hematologic neoplasm [34]. In another study on patients with chronic idiopathic neutropenia (CIN), the risk of malignant transformation was lower compared to CCUS. Still, the presence of clonal hematopoiesis was identified as a risk factor [35]. In summary, CCUS is a precursor condition for MDS or other myeloid neoplasms with a highly variable risk of disease progression. Clone metrics and mutations patterns enable estimation of disease progression risk and may inform clinical decision making in patients with CCUS [33].

In addition to CCUS, clonal hematopoiesis has also been associated with relevant hematologic end-points in the context of increased blood cell counts. In particular, Cargo et al. studied the impact of clonal hematopoiesis in patients with monocytosis with and without the diagnosis of chronic myelomonocytic leukemia (CMML) [36]. While the detection of somatic mutations is valuable in the diagnosis of CMML, it is of specific interest that the overall survival of individuals with monocytosis and somatic mutations but not meeting the morphologic criteria of CMML was indistinguishable from those with CMML. The authors even concluded that these patients should be managed as such [36]. Subsequently, the term “clonal monocytosis of clinical significance” has been introduced to provide presumptive evidence of myeloid malignancies, specifically of CMML, even in the absence of definitive morphological criteria [36, 37].

An increase of thrombocytes, erythrocytes, and/or granulocytes is a hallmark of MPN like essential thrombocythemia (ET), polycythemia vera (PV), or primary myelofibrosis (PMF). Mutations in JAK2, MPL, or CALR are characteristic for these patients and represent a diagnostic criterion of MPN [38]. Thus, if JAK2, MPL, or CALR mutations are discovered as an incidental finding, the presence of an MPN needs to be considered. While the diagnosis of an MPN is highly likely in patients with characteristic blood count alterations and presence of these driver mutations, it has been shown that JAK2 V617F and CALR mutations in the general population are also linked to a distinct blood count profile even if the diagnostic criteria for MPN are not met. Further evidence shows that MPN-mutations and MPN-associated bone marrow changes can precede the elevation of blood cell counts, suggesting that MPN might be underdiagnosed by current criteria of blood count alterations [39, 40]. While the typical driver mutations JAK2, MPL, or CALR are highly specific for MPN, the detection of other less specific somatic mutations may also assist in the diagnosis of so called triple-negative MPN [41]. This is particularly the case for ET or PMF while nearly all patients with PV harbor JAK2 mutations [42]. In line, the presence of clonal hematopoiesis in patients with unexplained erythrocytosis has been associated with cardiovascular morbidity and mortality but not necessarily with a marked hematological progression beyond that of CHIP [43].

Hematologic significance of CHIP without blood count abnormalities

While the risk of progression to an overt hematologic neoplasm can be very high in the combination of clonal hematopoiesis and a blood count abnormality not meeting the diagnostic criteria of a hematologic neoplasm, this is not the case for the majority of individuals with CHIP. Overall, the risk of progression is moderate with approximately 1% per year. A large study on individuals of the UK Biobank characterized myeloid and lymphoid CHIP based on the mutation profile and studied genetic risk factors for progression [44]. Myeloid CHIP was more common in the population and was characterized by mutations in the typical CHIP genes DNMT3A, TET2 and ASXL1, while lymphoid CHIP showed a more evenly distributed profile of a number of affected genes. Both myeloid and lymphoid CHIP were associated with an increased risk for the development of hematologic malignancies of the respective lineage (hazard ration 7.0 and 4.2 respectively). In addition to NGS-based characterization of single and small nucleotide variants (SNVs), the authors used SNP-array profiles to study mosaic chromosomal alterations (copy number variants, CNVs; and copy-neutral loss of heterozygosity, LOH). Mosaic chromosomal alterations were found as an independent risk factor for development of a hematologic neoplasm and amplified the risk among individuals with both a CHIP variant and a mosaic chromosomal alterations (hazard ratio 102.6 for myeloid malignancies, and 66.9 for lymphoid malignancies) [44]. Abelson et al. studied CHIP in patients with a subsequent development of AML (on average 6.3 years before diagnosis) and proposed a model to predict AML development based on clinical data and mutation profiles [45]. Pre-AML cases had more mutations per sample, higher VAF, indicating greater clonal expansion, and showed enrichment of mutations in splicing factor genes, JAK2, RUNX1, TP53, IDH1, and IDH2. This study indicates that precursor lesions of AML could potentially be found many years before disease onset [45]. However, the sensitivity and specificity of the model do currently not justify a CHIP-based screening for AML and other rare hematologic diseases in the general population [24].

In summary, CHIP represents a premalignant condition often preceding the development of a myeloid or more rarely a lymphoid neoplasm [24]. NGS is widely used to detect clonality in patients with unexplained blood count abnormalities and to diagnose, prognoses, and predict response to treatment in patients with suspected or diagnosed hematologic malignancies. The incidental finding of CHIP-associated somatic mutations in liquid profiling can reveal a hitherto undetected myeloid or lymphoid neoplasm. More often, the hematologic workup does not reveal an underlying leukemia or lymphoma but a hematologic precursor lesion with a variable risk of progression. The risk of progression is highest in patients with an additional unexplained blood count abnormality, in particular CCUS. In addition, the mutation pattern and clonal characteristic of CHIP can be used to identify patients with high risk of hematologic progression.

CHIP increases the risk of treatment-related myeloid neoplasms in patients with solid cancer

The finding of CHIP can be of special interest in patients diagnosed with a solid cancer. First, chemotherapy and/or radiation is associated with an increased prevalence of CHIP [46, 47]. In particular, cancer therapy with radiation, platinum and topoisomerase II inhibitors was found to preferentially select for mutations in DNA damage response genes TP53, PPM1D, and CHEK2 [48]. PPM1D mutations are characteristic for treatment-related myeloid neoplasms (t-MN) and have been shown to drive clonal hematopoiesis in response to cytotoxic chemotherapy in preclinical models [49]. In addition, chemotherapy and/or radiation may promote the progression to a t-MN in the context of preexisting CHIP clones. In a study of 9,437 patients with cancer exposed to cancer therapy, of whom 75 developed t-MN, the hazard ratio was highest for mutations in TP53 and for mutations in spliceosome genes (SRSF2, U2AF1 and SF3B1). A model for the risk of t-AML or t-MDS by clinical and CHIP-mutational characteristics in patients with solid tumors even indicated that the risk to develop t-MN in the highest risk category of CHIP could exceed the predicted absolute benefit in overall survival of adjuvant chemotherapy in a subgroup of women with early-stage breast cancer [48]. A retrospective genetic association study of high-grade ovarian cancer patients found an association of pretreatment TP53-mutated CHIP clones with the development of t-MN after poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitor treatment [50]. In contrast, Miller et al. observed no expansion of hematopoietic clones or selection for clones at high risk for malignant transformation in patients who received immune checkpoint inhibitors [51]. Currently, no clinical guidelines call for screening for CHIP in patients with solid cancer [52]. However, the association of CHIP and cancer provides a rational for future studies to include this information in risk-adapted treatment decisions [48].

Clonal hematopoiesis is as a risk factor for non-hematologic diseases

In addition to the hematologic risk, CHIP has been associated with a number of non-malignant diseases as recently reviewed in detail [16]. In brief, CHIP has been linked to atherosclerotic cardiovascular disease, ischemic heart failure, chronic obstructive pulmonary disease, and autoimmune disorders [53]. First hints of a potential association of non-malignant diseases have already been discussed in the first studies reporting ARCH/CHIP. The presence of CHIP was associated with a slightly increased all-cause mortality that was rather explained by a moderate increase of cardiovascular mortality than by the increase of hematologic neoplasm that was substantial in relative but not in absolute numbers for the total cohort [5]. Further well balanced case-control studies (matched for traditional cardiovascular risk factors, including age, sex, type 2 diabetes status, and smoking history) confirmed a significant association of CHIP with coronary heart disease [18]. The cardiovascular risk was highest for individuals with JAK2 mutations compared to mutations in the commonly affected CHIP genes DNMT3A, TET2, and ASXL1. Furthermore, only clones with a VAF >10% were clearly associated with cardiovascular risk [18]. The outstanding effect of JAK2 V617F as a typical MPN-driver mutation in CHIP carriers on the cardiovascular risk was confirmed in subsequent studies [54]. In summary, the hazard ratio for cardiovascular disease in CHIP carriers is comparable to that of hyperlipidemia or cigarette smoking [29]. Importantly, the data on CHIP and cardiovascular disease go beyond association studies and indicated a causative link between proinflammatory myeloid cells carrying the CHIP mutations and atherosclerosis as well as cardiac dysfunction in vitro and in vivo [18, 55], [56], [57], [58]. In line with this mechanistic inflammation hypothesis, CHIP has been associated with increased levels of C-reactive protein in patients [59], and a germline variant in the IL-6 receptor that reduces IL-6 signaling was found to attenuate the cardiovascular risk in CHIP carriers [60]. In contrast, Heyde et al. proposed that CHIP could be a symptom rather than a cause of atherosclerosis. They found that hematopoietic stem cell division rates are increased in mice and humans with atherosclerosis resulting in accelerated somatic evolution of hematopoietic stem cell carrying CHIP mutations and thus in the emergence of detectable CHIP clones in patients [61]. While the mechanisms behind the association of CHIP and cardiovascular disease are still not fully understood, it is possible that inflammation promotes CHIP and vice versa resulting in a vicious cycle of atherosclerosis and clonal evolution [62].

In addition to atherosclerosis, CHIP has also been associated with reduced survival after transcatheter aortic valve implantation [63], and pulmonary arterial hypertension [64]. A number of studies reported an association of CHIP with ischemic and non-ischemic heart failure and described worse long-term survival and re-hospitalization due to heart failure, accelerated heart failure progression, and reduced left ventricular ejection fraction [17, 65], [66], [67], [68], [69]. In addition, CHIP could be linked to incident heart failure in large population databases [70]. CHIP was also found to be associated with an increased risk of stroke, particularly with hemorrhagic and small vessel ischemic stroke [71].

Furthermore, CHIP has been associated with a number of immune disorders and autoinflammatory diseases including rheumatoid arthritis [72], systemic sclerosis [73], osteoarthritis leading to total hip arthroplasty [74], and systemic lupus erythematosus [75]. The incidence of CHIP was increased in patients infected with HIV, and CHIP as well as HIV infection were independently associated with increases in blood parameters and biomarkers associated with inflammation [76]. Further investigations associated CHIP in HIV infected patients with a lower CD4 nadir and increased residual HIV transcriptional activity [77]. Controversial results have been reported on the association of CHIP with SARS-CoV-2 infections. While smaller studies found no association between CHIP and severity of COVID-19 [78, 79], Bolton et al. described a signification association with severe COVID-19 outcomes [80]. In patients with chronic kidney disease, CHIP has been associated with adverse outcomes and worsening of kidney function [81, 82]. Miller et al. found that CHIP was associated with the development and severity of chronic obstructive pulmonary disease independent of age and cumulative smoke exposure [83]. In summary, CHIP has been associated with a number of non-hematologic diseases. If and how information on CHIP can be used for prevention and management of these diseases remains to be seen.

Management of CHIP

While screening for CHIP is currently not recommended in the general population, CHIP is increasingly diagnosed as an incidental finding. There is currently an ongoing discussion about the practical management of patients with CHIP and CCUS, especially with regard to the patient’s initial information about implications by physicians or other caregivers. While CCUS is most often diagnosed in the context of the hematologic workup of unexplained cytopenia in which the detection of a clonal condition is typically not unexpected for the physician and the patient, CHIP is more often diagnosed as pure incidental finding in individuals undergoing sequencing analysis for an unrelated medical or scientific purpose. In this situation it is recommended to inform the patients about the potential of the discovery of clonal hematopoiesis as an incidental finding within the process of the informed consent to the analysis and to ensure the appropriate communication and follow-up investigation if it is indeed detected.

The management of CHIP includes both hematologic and cardiovascular risk assessment [25]. From a hematologic point of view it is important to communicate that the risk for development of a hematological neoplasm is minor for the vast majority of CHIP carriers. In particular, individuals with small DNMT3A mutated clones without additional mutations and without blood count abnormalities typically do not require a close hematologic monitoring after the initial hematologic examination. A closer monitoring with serial blood counts and differential counts has been suggested for clones with a larger VAF (>10%), mutations in high-risk genes, or mutations in multiple genes [25]. Genetic aberrations considered high-risk for the diagnosis or development of hematologic neoplasms in CHIP carriers are: mutations in splicing factor genes (e.g., SF3B1, SRSF2, U2AF1), TP53, PPM1D, RUNX1, IDH1, IDH2, MPN-driver genes (JAK2, MPL, CALR), or mosaic chromosomal alterations. Patients with clonal hematopoiesis and unexplained cytopenia are diagnosed as CCUS if an underlying occult hematologic neoplasm can be excluded. The exclusion of an MDS in this patient group typically requires a bone marrow examination to evaluate at least blast cell content, dysplasia and cytogenetic aberrations [26] (Table 1). Molecular follow-up investigations revealing clonal evolution may be useful when progression is suspected. However, prospective clinical data are currently not sufficient for recommendation of general follow-up intervals of molecular analysis in CHIP and CCUS in the absence of progressive blood count abnormalities or other signs or symptoms of progression.

In addition to the hematologic progression, CHIP has been associated with a plethora of non-hematologic diseases of which cardiovascular diseases are currently best understood and clinically established [53]. CHIP represents a previously unrecognized major risk factor for atherosclerosis and cardiovascular disease and can thus help to identify individuals at high risk of cardiovascular disease despite the absence of traditional risk factors [24]. It has been recommended to offer all CHIP patients a consultation with a cardiologist and/or primary care physician for individualized risk assessment and counseling to generate awareness among patients and to mitigating the overall cardiovascular risk by using guideline-concordant primary and secondary cardiovascular prevention [84]. It has to be emphasized that there are currently no guidelines or evidence-based recommendations specifically addressing the reduction of cardiovascular risk in individuals with CHIP [84].

The discovery of CHIP in patients with early-stage, surgically resected solid cancer raises the question to weight the benefit of adjuvant therapy to reduce recurrence rates against the risk of development of a t-MN. The current evidence is not sufficient to recommend a change of the practice based on the presence of CHIP. Still, it has been recommended to counsel the patient and the oncologist on the increased risk of t-MN after cytotoxic therapy in individuals with preexisting TP53 mutated CHIP [84]. Further studies are needed to generate evidence for an individualized treatment approach taking the information on CHIP into account.

Future perspectives

NGS-based detection of clonal hematopoiesis has become a diagnostic standard in the hematologic workup of patients with suspected myeloid neoplasms. In contrast, testing for CHIP is currently not recommended in the general population. Still, the number of incidental findings of CHIP in sequencing studies including liquid profiling is steadily increasing. Thus, the management of CHIP is an emerging topic that needs to be included in personalized medicine strategies in patients with solid neoplasms [85]. Strategies for the communication, risk assessment and follow-up monitoring are needed for sequencing assays with a high likelihood to detect CHIP in routine diagnostics or clinical studies. While a universal notification of patients about all hematopoietic clones is still a matter of discussion, it is at least recommended when clinical or mutational features associated with higher risk of hematologic malignancy are present [86]. Furthermore, it has been suggested to take the patient’s life expectancy, personal preferences, and local cultural context into account for the decision whether or not to notify individuals about CHIP. In addition, it would be preferable to inform the patient about CHIP as a potential incidental finding and to discuss the patient’s preference for the notification of incidental finding when obtaining the informed consent for genetic testing [86].

The ideal management of individuals diagnosed with CHIP requires a highly multidisciplinary setting including hematology/oncology, cardiology, internal medicine, clinical pathology/laboratory medicine, clinical genetics, and bioinformatics [84]. The individualized care should consider additional features such as comorbidities, life expectancy, and other traditional cardiovascular risk factors [87]. While such CHIP clinics have been established in a number of U.S. centers [84], similar structures and collaborations are needed in Germany. Further clinical research in this area is needed to move from the descriptive nature of association studies to interventional trials aiming to mitigate the hematologic and cardiovascular risk of individuals with CHIP and to provide robust evidence for personalized therapeutic decisions. It is tempting to speculate that reduction of sequencing costs and turn-around-time will justify a regular examination for the presence of hematopoietic cell clones in the future [87]. In summary, CHIP is a potential incidental finding in liquid profiling with clinical relevance for hematological and cardiovascular diseases.