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INTRODUCTION — Peripheral blood cytopenias are common in adults, especially the elderly, and can either be inconsequential or a sign of serious disease. A specific cause for anemia, neutropenia, or thrombocytopenia can be identified in most cases after a careful medical history, targeted physical examination, and appropriate laboratory and imaging tests, supplemented in some circumstances by a bone marrow aspirate and biopsy. (See "Approach to the adult patient with anemia" and "Approach to the adult with unexplained neutropenia" and "Approach to the adult with unexplained thrombocytopenia".)
However, diagnostic uncertainty persists in some patients and cytopenias may remain unexplained even after careful, thorough evaluation . Several terms are used to describe individuals who have cytopenias, clonal mutations in genes known to be associated with hematologic neoplasia, or both, yet who do not meet World Health Organization (WHO) diagnostic criteria for a specific disease entity. These terms are described further below (table 1).
The entities described below are not included in the current WHO classification of tumors of the hematopoietic system, since they are not clearly neoplastic [2,3].
ICUS, CHIP, and CCUS — The following terms have been proposed to describe individuals who have cytopenias, clonal mutations in genes known to be associated with hematologic neoplasia, or both, yet who do not meet World Health Organization (WHO) diagnostic criteria for a specific disease entity (table 1) :
●Idiopathic cytopenia of undetermined significance (ICUS) – Single or multiple blood cytopenias that remain unexplained despite an appropriate evaluation including marrow examination. Excludes patients with a known clonal mutation. (See 'ICUS definition' below.)
●Clonal hematopoiesis of indeterminant potential (CHIP) – Identification of a clonal mutation associated with hematologic neoplasia in an individual who does not yet meet WHO criteria for diagnosis of a hematologic neoplasm. Excludes patients with clinically significant cytopenias. (See 'CHIP definition' below.)
●Clonal cytopenia of undetermined significance (CCUS) – Identification of a clonal mutation in a patient with one or more clinically meaningful unexplained cytopenias, yet who does not meet WHO-defined criteria for a hematologic neoplasm. (See 'CCUS definition' below.)
These three entities are not specific disorders per se. Rather, they are terms that describe patients without a specific hematologic diagnosis in whom cytopenias or clonal mutations represent a possible sign of disease that may manifest more clearly in the future.
Because of their different prognoses, an attempt should be made to distinguish patients with ICUS, CHIP, and CCUS from those who meet WHO criteria for myelodysplastic syndromes (MDS).
Distinction from MDS — Minimal diagnostic criteria for MDS require a meaningful cytopenia (the WHO has proposed cytopenia thresholds for the 2016 MDS reclassification as follows: hemoglobin <10 g/dL, absolute neutrophil count <1.8 x 109/L, or platelet count <100 x 109/L, although these are not evidence-based) and the presence of one or more of the following [3,5-7]:
●Morphologic evidence of significant dysplasia in at least one myeloid lineage (ie, ≥10 percent of erythroid precursors, granulocytes, or megakaryocytes) upon visual inspection of the bone marrow aspirate in the absence of other causes of dysplasia
●5 to 19 percent blast cells with a myeloid phenotype in the marrow
●A recurrent MDS-associated cytogenetic abnormality, such as deletion of the long arm of chromosome 5 [del(5q)] or monosomy 7
Certain acquired karyotypic changes that lack diagnostic specificity (eg, acquired loss of the Y chromosome, trisomy 8, or loss of the long arm of chromosome 20 [del(20q)]) are not sufficient criteria for a diagnosis of MDS .
Securing a diagnosis of MDS may be challenging, especially in the earliest stages of disease when disease-associated blood and marrow cell morphology changes may be subtle. Diagnosis of MDS relies in part on subjective assessment of the degree of hematopoietic cell dysplasia, which has low inter-operator reproducibility. Dysplastic cells in the blood or marrow similar to those found in patients with MDS are commonly encountered in healthy persons aged 50 years and older, further confounding the assessment . (See "Clinical manifestations and diagnosis of the myelodysplastic syndromes".)
Unexplained cytopenias in older adults are commonly due to MDS. As an example, in an Israeli geriatric hospital, 15 percent of cognitively impaired hospitalized patients with unexplained cytopenias at the time of admission were found on subsequent evaluation to have MDS .
Variant allele frequency — Variant allele frequency (VAF) refers to the proportion of sequencing reads for a given gene that include a mutation or polymorphism. In the absence of a copy number variant (ie, duplication or deletion of a copy of the gene), VAF is roughly parallel to the size of the clone bearing the mutation. As an example, since DNMT3A mutations are heterozygous, a DNMT3A R882 mutation at 10 percent VAF would represent 20 percent of the sequenced cells. Germline heterozygous gene variants typically have a VAF of 40 to 60 percent, except for germline variants in X-linked genes in males, which have a VAF of 100 percent.
EPIDEMIOLOGY — The prevalence of ICUS and CCUS is poorly understood. Unlike for defined malignancies, there is no systematic method in place for capturing epidemiologic data for these entities. Further details regarding the incidence of CHIP are presented below. (See 'CHIP incidence' below.)
Data regarding the prevalence of unexplained anemia come from the Third National Health and Nutrition Examination Survey (NHANES III), which was conducted from 1988 to 1994, included data on 33,994 Americans aged two months or older, and used the 1968 World Health Organization (WHO) definition of anemia in adults (ie, hemoglobin <13.0 g/dL in men, <12.0 g/dL in non-pregnant women) . The prevalence of anemia differed by age and gender. Among those 65 years and older, anemia was identified in 11.0 percent of men and 10.2 percent of women, of which 34 percent was unexplained. Among persons aged 85 years and older, the prevalence of anemia was 26.1 percent in men and 20.1 percent in women. In other series, 24 percent of hospitalized patients ≥65 years  and 48 to 59.6 percent of patients residing in skilled nursing facilities [12,13] have been noted to have anemia. (See "Anemia in the older adult".)
In addition, greater use of molecular genetic testing in clinical practice and experimental genome-wide association studies have revealed a high frequency of clonally restricted acquired DNA mutations in the hematopoietic cells of individuals without a diagnosable hematologic neoplasm, including apparently healthy persons with normal blood counts. In one extreme example, a 115-year-old Dutch woman had more than 450 acquired mutations in her hematopoietic cells despite a normal hemogram . As use of genomic assays in clinical practice continues to increase, such mutations will increasingly be encountered.
IDIOPATHIC CYTOPENIAS OF UNDETERMINED SIGNIFICANCE (ICUS)
ICUS definition — The term "idiopathic cytopenia(s) of undetermined significance" (ICUS) has been proposed for patients who have one or more blood cytopenias (usually anemia) that remain unexplained despite appropriate evaluation, including marrow examination (table 1) . By definition, individuals with ICUS are not known to have a clonal disorder. This may either be because no clonality testing has been performed (eg, in a resource-limited setting where such testing is unavailable), or because testing was performed but the assay did not reveal a clonal mutation. Of note, available targetable sequencing assays do not detect all mutations associated with hematologic neoplasia, so a negative result on an assay for somatic mutations does not rule out a clonal disorder.
ICUS is not a specific disorder per se, but rather a general term that can be used to describe patients in whom a cytopenia or cytopenias represent a possible sign of disease, yet a specific diagnosis remains unclear [5,16]. Patients with ICUS have a diverse group of underlying disorders, and an individual patient may have more than one contributing factor to the cytopenia.
ICUS natural history — Little is known about the natural history of ICUS or the rate of subsequent diagnosis of neoplasia, but clearly there is some risk of myelodysplastic syndrome (MDS) or another hematologic malignancy in people with ICUS.
ICUS may take one of several courses over time:
●Reactive non-clonal conditions may prove to be self-limited and eventually resolve without specific cytopenia-directed therapy.
●Some individuals with ICUS will ultimately be found to have MDS or another myeloid neoplasm that is not diagnosable at the time of initial presentation using World Health Organization (WHO) diagnostic criteria. (See "Clinical manifestations and diagnosis of the myelodysplastic syndromes", section on 'Pathologic features'.)
●Occult non-myeloid neoplasms or non-neoplastic disorders may become overt with time.
●Some patients have persistent unexplained cytopenias that last for years.
Retrospective studies have noted a variable risk of MDS among individuals with ICUS. As examples:
●In 248 of 683 (36 percent) consecutive individuals who were referred for evaluation of unexplained cytopenias, no detectable somatic mutations were found among 40 genes that are recurrently mutated in myeloid malignancies . In patients with ICUS (ie, those who had no such clonal abnormalities and no cytogenetic abnormalities or morphologic findings diagnostic of MDS), the negative predictive value for development of a myeloid neoplasm was 0.84 (CI 95% 0.79-0.89).
●In another study, 579 of 2899 patients (20 percent) who were evaluated for cytopenias with a bone marrow biopsy did not meet criteria for a WHO diagnosis . Follow-up data were available on only 49 percent of the 182 patients with normal marrows in this series; in most patients, the cytopenias either resolved or were ultimately attributable to a non-MDS diagnosis (eg, a rheumatological disorder, cirrhosis, or lymphoid neoplasm). Several patients in the series with non-diagnostic marrows eventually developed a myeloid malignancy, but the risk could not be quantified due to lack of long-term follow-up on many patients.
●A study from the United Kingdom assessed 69 patients who had previously undergone a non-diagnostic marrow biopsy and were subsequently diagnosed with MDS or acute myeloid leukemia (AML) . These 69 patients represented <2 percent of 4875 marrow aspirates performed during the study period to evaluate patients with cytopenias by a regional hematology service in northern England. Unfortunately, the proportion of patients with non-diagnostic marrows in this series who had persistent unexplained cytopenias, cytopenias that resolved spontaneously, or were diagnosed with another disorder is unknown.
Following patients with ICUS — Patients with ICUS should be followed over time, but there are no evidence-based guidelines and the optimal frequency of evaluation is unclear. In our practices, the frequency of follow-up depends in part upon the severity of the cytopenias. ICUS with mild cytopenias may be evaluated with blood counts every three to six months. Patients with more severe cytopenias (eg, hemoglobin <10 g/dL) can be followed monthly, because they are more likely to result in a diagnosis compared to those with hemoglobin levels just below the WHO threshold for anemia .
ICUS often resolves over time or is found to be due to a non-hematopoietic disorder or a non-myeloid malignancy. Therefore, when following patients longitudinally, clinicians should remain vigilant for the possibility of diagnoses other than MDS, including low-grade lymphoproliferative disorders (eg, splenic marginal zone lymphoma or T cell large granular lymphocyte disorders), immune disorders, or other occult nutritional deficiencies . (See "Approach to the adult patient with anemia" and "Anemia in the older adult".)
CLONAL HEMATOPOIESIS OF INDETERMINATE POTENTIAL (CHIP)
CHIP definition — The term "clonal hematopoiesis of indeterminate potential" (CHIP) is used to describe individuals who have a clonal mutation associated with hematologic neoplasia, yet do not meet World Health Organization (WHO) criteria for diagnosis of a hematologic neoplasm . Individuals with CHIP usually have normal complete blood counts, normal erythrocyte indices or mild red cell macrocytosis without anemia, or minimal and clinically insignificant cytopenias .
We define CHIP as the presence of a mutation with at least 2 percent variant allele frequency, but the clinical significance of this cutoff for presumed clonality has yet to be confirmed . The most common mutations that meet the criteria for CHIP are mutations in DNMT3A, TET2, JAK2, SF3B1, ASXL1, TP53, CBL, GNB1, BCOR, U2AF1, CREBBP, CUX1, SRSF2, MLL2, SETD2, SETDB1, GNAS, PPM1D, and BCORL1 . CHIP has also been called age-related clonal hematopoiesis (ARCH) because of the higher prevalence in older persons, although it can be seen at any age .
CHIP is occasionally discovered when marrow or blood genetic tests are sent for an unrelated reason. As an example, bone marrow may be analyzed for mutations of genes associated with hematologic neoplasms while staging multiple myeloma, lymphoma, or a non-hematopoietic neoplasm. Occasionally, mutations more typically associated with myeloid neoplasia such as ASXL1 or DNMT3A may be noted at low levels in these patients without morphological evidence for a second, myeloid neoplasm.
CHIP incidence — The incidence of CHIP increases with age. The best estimates of CHIP incidence come from genome-wide association studies (GWAS; eg, in patients with diabetes mellitus, schizophrenia, and other conditions) in which mutations characteristically associated with hematologic neoplasms were found in 10 percent of those age 70 years or greater and in more than 30 percent of those who reached 100 years of age, despite the absence of detectable hematologic disorders [21-23].
In addition, it has long been recognized that rare individuals who are apparently healthy can have mutations in the blood or marrow that are associated with hematologic malignancies. As examples:
●BCR/ABL1 fusions were found in some patients with normal blood counts who never evolved to chronic myeloid leukemia .
●Translocations of chromosomes 14 and 18, which are found in the majority of patients with follicular lymphoma, have also been detected in healthy people who did not develop lymphoma .
●JAK2 mutations are detectable in some patients without other features of myeloproliferative neoplasms .
Clonal hematopoiesis has also been found to be common in older individuals:
●Studies using single nucleotide polymorphism (SNP) array tools have observed an age-associated increased frequency of somatic chromosomal mosaicism .
●Some older women with acquired skewing of X chromosome inactivation patterns have acquired TET2 mutations .
CHIP natural history — Detection of a mutation typically associated with hematologic malignancies (ie, CHIP) is not equivalent to a diagnosis of a hematologic malignancy; the phrase, "indeterminate potential" in the CHIP acronym simply describes the possibility that these clonal states may evolve to a frank neoplasm.
However, CHIP is associated with an increased risk of evolution to a hematologic malignancy. As an example, in one series of 17,182 people unselected for hematologic phenotype, the presence of CHIP was associated with increased risk of developing a hematologic malignancy (hazard ratio [HR] 11, 95% CI 3.9-33) .
Development of an overt hematologic malignancy following a diagnosis of CHIP is estimated at 0.5 to 1 percent per year; this incidence is similar in magnitude to the rates at which monoclonal B cell lymphocytosis (MBL) or monoclonal gammopathy of undetermined significance (MGUS) evolve to non-Hodgkin lymphoma, myeloma, or another plasma cell or lymphoid neoplasm [29,30].
Importantly, the estimated risk of progression to a hematologic malignancy following a diagnosis of CHIP is an order of magnitude lower than the risk of progression to acute myeloid leukemia (AML) from a myelodysplastic syndrome (MDS). Among patients with lower risk MDS, the risk of progression to AML is 19 to 30 percent, whereas this proportion is 33 to 45 percent in patients with higher risk MDS .
Only a minority of patients with CHIP will progress to a frank neoplasm. There are several potential reasons that cells bearing such neoplasia-associated clonal mutations fail to result in cancer. As examples:
●Clearance of clonal cells or suppression of their expansion by a host immune response
●Occurrence of the mutation in a cell without transformative potential
●Lack of acquisition of "second hit" lesions critical for frank neoplasia development prior to the extinction of the clonal cells
Increased all-cause mortality and cardiovascular risk — In addition to its possible evolution to hematologic malignancies, CHIP is associated with increased all-cause mortality and heightened risk of cardiovascular diseases. Examples of this association include the following:
●In one series of more than 17,000 people, the presence of CHIP was associated with increased all-cause mortality (HR 1.4, 95% CI 1.1-1.8) and increased risk of incident coronary heart disease (HR 2.0, 95% CI 1.2-3.4) and ischemic stroke (HR 2.6, 95% CI 1.4-4.8) .
●Another series of 12,380 subjects found a similar risk of death associated with CHIP mutations (HR 1.4, 95% CI 1.1-1.9) .
●Analysis of nearly 8,000 subjects (in two prospective and two retrospective studies) found that carriers of CHIP had a risk of myocardial infarction that was two- to fourfold greater than non-carriers .
Following patients with CHIP — Patients with CHIP should be followed over time, but there are no evidence-based guidelines and the optimal frequency of evaluation is unclear. It is our practice to evaluate patients with CHIP every three to six months; however, we evaluate patients more frequently (eg, monthly blood counts) in the setting of a very high-risk mutation (eg, high variant allele frequency [VAF] TP53 mutation) or when two or more mutations are detected. If a clonal mutation is found in the peripheral blood in the setting of normal blood counts, a bone marrow biopsy is not necessary. However, it is our practice to perform a bone marrow biopsy if cytopenias are present to assess the possibility of MDS or another disorder. (See 'Variant allele frequency' above.)
With good natural history studies, we may learn that specific mutations or levels of VAF in the setting of CHIP have a similar natural history to MDS.
At present, a diagnosis of CHIP has no therapeutic implications, and there are no data to suggest that an intervention is beneficial. However, the hazard ratio (HR) for cardiovascular mortality associated with CHIP is similar in magnitude to that associated with dyslipidemia or smoking. These findings underscore the importance of screening for traditional cardiac risk factors (hyperlipidemia, hypertension, diabetes mellitus, and smoking) and aggressive management of these risk factors in patients with CHIP. In the future, clinicians may be able to intervene with therapy to clear mutant hematopoietic clones and practice a form of "preventive hematology" in a similar fashion to the use of lipid-lowering agents or aspirin to prevent primary cardiovascular events.
CLONAL CYTOPENIAS OF UNDETERMINED SIGNIFICANCE (CCUS)
CCUS definition — The term "clonal cytopenias of undetermined significance" (CCUS) describes patients who have unexplained cytopenias and are also found to have a clonal mutation, yet do not meet World Health Organization (WHO)-defined criteria for myelodysplastic syndromes (eg, MDS) or another hematologic neoplasm (table 1) [20,33].
Most cases of CCUS will be identified when mutation testing is performed as part of the clinical evaluation of patients with unexplained cytopenias . The likelihood of finding myeloid neoplasia-associated mutations is much higher in a cytopenic population compared with the age-matched population with normal blood counts [4,21,35].
CCUS natural history — The progression risk for CCUS is unknown, but it is likely to fall between the CHIP and MDS ranges.
Examples of the incidence of CCUS are provided by the following studies:
●Approximately two-thirds of nearly 700 consecutive patients who were undergoing evaluation for unexplained cytopenias (mostly anemia) were found to have CCUS, based on the detection in peripheral blood granulocytes of at least one somatic mutation with an allele frequency ≥0.1 among 40 genes that are recurrently mutated in myeloid malignancies .
The presence of one such mutation or ≥2 mutations had positive predictive values for diagnosis of a myeloid neoplasm of 0.86 and 0.88, respectively. Individuals with spliceosome gene mutations, or those with mutations in TET2, ASXL1, or DNMT3A that were combined with additional mutations, had a 95 percent five-year cumulative probability of developing a myeloid neoplasm.
●Another study found that 42 of 120 patients (35 percent) undergoing evaluation for cytopenias at a reference laboratory had CCUS (ie, a clonal abnormality in one of 22 MDS-associated genes, or a clonal chromosomal abnormality that was not diagnostic of MDS), 17 percent met morphologic and/or karyotypic criteria for MDS, and the remainder would be categorized as having ICUS .
When these CCUS specimens were combined with a cohort 249 similar specimens, the most common genetic abnormalities included TET2, DNMT3A, TP53, SF3B1, and ASXL1 . The spectrum of mutations was comparable to that of MDS specimens, with the exception of SF3B1, which was overrepresented in MDS, and SRSF2, which was more common in CCUS. The former is likely because SF3B1 mutations are strongly associated with the presence of ring sideroblasts , a striking morphologic alteration in erythroid precursor cells that, if seen, gives hematopathologists additional confidence in making a diagnosis of MDS.
While it is tempting is to consider patients with CCUS as having a morphologically occult hematologic neoplasm (eg, MDS without diagnostic levels of dysplasia), such an assumption is not appropriate since the clonal mutation may not actually be responsible for the cytopenias. As an example, the patient could have CHIP plus a reactive phenomenon such as the anemia of chronic inflammation.
Using currently available diagnostic tests, it can be difficult to be certain of the contribution of the mutation-bearing hematopoietic clone to cytopenias. One method of estimating this contribution uses the variant allele frequency (VAF) as a measure of the mutation burden. Large clones (eg, VAF >20 percent) seem more likely to be clinically meaningful than small clones (eg, VAF <10 percent), but this may depend on the specific mutant allele [33,34]. In the future, it seems likely that patterns of specific alleles and VAFs will define a cohort of patients with a progression risk more similar to MDS than CHIP or ICUS. (See 'Variant allele frequency' above.)
Information regarding the impact of VAF comes from the United Kingdom study described above which assessed 69 patients who had previously undergone a non-diagnostic marrow biopsy and were subsequently diagnosed with MDS or acute myeloid leukemia (AML) . The VAF was higher in patients who developed MDS or AML. When compared with a CHIP population, the mutations detected in this series had significantly greater median VAF (ie, 40 versus 9 to 10 percent) and occurred more commonly together with additional mutations (≥2 mutations, 64 versus 8 percent). Most CHIP mutations, in contrast, have a VAF of <10 percent and are single mutations . Therefore, there appears to be a higher risk of hematologic malignancy development if multiple mutations with higher VAF are present.
Following patients with CCUS — Bone marrow biopsy should be performed to evaluate patients with cytopenias and clonal mutations. Patients with CCUS should be followed over time, but no evidence-based guidelines have been published and the optimal frequency of evaluation is unclear. Evaluation may need to be more frequent with CCUS than for ICUS or CHIP, especially if there are multiple mutations with a high VAF. In our practices, we evaluate patients every three months unless there is a very high-risk mutation (eg, high VAF TP53 mutation, or more than two mutations) or severe cytopenia (eg, hemoglobin <10 g/dL), in which case a monthly blood count may be more appropriate.
With good natural history studies, we may learn that specific mutations and VAF have a similar natural history to MDS diagnosed by conventional means, thus allowing diagnosis of MDS without the morphologic dysplasia that is currently required for the diagnosis in the absence of karyotypic abnormalities.
SUMMARY AND RECOMMENDATIONS
●A specific cause for anemia, neutropenia, or thrombocytopenia can be identified in most cases after a careful medical history, targeted physical examination, and appropriate laboratory and imaging tests, supplemented in some circumstances by a bone marrow aspirate and biopsy.
●The entities described in this topic are not specific hematologic diseases per se. Rather, these terms describe patients in whom cytopenias or clonal mutations (or both) are present, yet World Health Organization (WHO) diagnostic criteria for a specific disease entity are not met (table 1).
●Idiopathic cytopenia of undetermined significance (ICUS) – Idiopathic cytopenia of undetermined significance (ICUS) describes cytopenias that remain unexplained despite an appropriate evaluation, including marrow examination. ICUS excludes patients with a known clonal mutation. (See 'ICUS definition' above.)
There is a small but undefined risk of evolution to myelodysplastic syndrome (MDS) or another hematologic malignancy following a finding of ICUS. This condition may resolve over time or may be found to be associated with a non-myeloid malignancy, immune disorder, occult nutritional deficiency, or another condition. (See 'ICUS natural history' above.)
Follow up of patients with ICUS is guided, in part, by the severity of cytopenias. (See 'Following patients with ICUS' above.)
●Clonal hematopoiesis of indeterminant potential (CHIP) – Clonal hematopoiesis of indeterminant potential (CHIP) describes detection of a somatic mutation that is typically associated with a hematologic neoplasm in an individual who does not meet WHO criteria for diagnosis of a hematologic malignancy. CHIP excludes patients with clinically significant cytopenias. (See 'CHIP definition' above.)
The presence of a hematologic malignancy-associated mutation is not equivalent to a diagnosis of a hematologic malignancy. Individuals with CHIP have an estimated risk of progression to a frank neoplasm of 0.5 to 1 percent per year, but also have higher all-cause mortality and increased incidence of cardiovascular diseases. (See 'CHIP natural history' above.)
Follow up of patients with CHIP is guided, in part, by the nature and number of associated mutations and the mutation burden (ie, variant allele frequency [VAF]). (See 'Following patients with CHIP' above.)
●Clonal cytopenia of undetermined significance (CCUS) – Clonal cytopenia of undetermined significance (CCUS) describes identification of a clonal mutation in a patient with unexplained cytopenias who does not meet WHO-defined criteria for a hematologic neoplasm. (See 'CCUS definition' above.)
The progression risk for CCUS is unknown, but it is likely to fall between those of CHIP and MDS, and is greater than for ICUS. Patients with a high variant allele frequency and those with certain mutations may be at higher risk of progression. (See 'CCUS natural history' above.)
Follow up of patients with CCUS is dependent upon the severity of cytopenias, the nature of the mutation(s), and the mutation burden (eg, VAF). (See 'Following patients with CCUS' above.)
- Valent P. Low blood counts: immune mediated, idiopathic, or myelodysplasia. Hematology Am Soc Hematol Educ Program 2012; 2012:485.
- Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, Fourth Edition, IARC Press, Lyon 2008.
- Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127:2391.
- Steensma DP. Cytopenias + mutations - dysplasia = what? Blood 2015; 126:2349.
- Valent P, Horny HP. Minimal diagnostic criteria for myelodysplastic syndromes and separation from ICUS and IDUS: update and open questions. Eur J Clin Invest 2009; 39:548.
- Valent P, Horny HP, Bennett JM, et al. Definitions and standards in the diagnosis and treatment of the myelodysplastic syndromes: Consensus statements and report from a working conference. Leuk Res 2007; 31:727.
- Brunning RD, Orazi A, Germing U, et al. Myelodysplastic syndromes/neoplasms, overview. In: WHO Classification of Tumours of the Haematopoietic and Lymphoid Tissues, Fourth edition, Swerdlow SH, Campo E, Harris NL, et al (Eds), IARC Press, Lyon 2008. p.89.
- Bain BJ. The bone marrow aspirate of healthy subjects. Br J Haematol 1996; 94:206.
- Beloosesky Y, Cohen AM, Grosman B, Grinblat J. Prevalence and survival of myelodysplastic syndrome of the refractory anemia type in hospitalized cognitively different geriatric patients. Gerontology 2000; 46:323.
- Guralnik JM, Eisenstaedt RS, Ferrucci L, et al. Prevalence of anemia in persons 65 years and older in the United States: evidence for a high rate of unexplained anemia. Blood 2004; 104:2263.
- Joosten E, Pelemans W, Hiele M, et al. Prevalence and causes of anaemia in a geriatric hospitalized population. Gerontology 1992; 38:111.
- Robinson B, Artz AS, Culleton B, et al. Prevalence of anemia in the nursing home: contribution of chronic kidney disease. J Am Geriatr Soc 2007; 55:1566.
- Artz AS, Fergusson D, Drinka PJ, et al. Prevalence of anemia in skilled-nursing home residents. Arch Gerontol Geriatr 2004; 39:201.
- Holstege H, Pfeiffer W, Sie D, et al. Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis. Genome Res 2014; 24:733.
- Wimazal F, Fonatsch C, Thalhammer R, et al. Idiopathic cytopenia of undetermined significance (ICUS) versus low risk MDS: the diagnostic interface. Leuk Res 2007; 31:1461.
- Valent P, Bain BJ, Bennett JM, et al. Idiopathic cytopenia of undetermined significance (ICUS) and idiopathic dysplasia of uncertain significance (IDUS), and their distinction from low risk MDS. Leuk Res 2012; 36:1.
- Malcovati L, Gallì A, Travaglino E, et al. Clinical significance of somatic mutation in unexplained blood cytopenia. Blood 2017; 129:3371.
- Hanson CA, Hoyer JD, Zakko L, et al. Is idiopathic cytopenia of undetermined significance (ICUS) a valid clinical concept? A longitudinal clinicopathological study. Leuk Res (Abstracts of the 10th International Symposium on Myelodysplastic Syndromes, Abstract P089) 2009; 33, Supplement 1:S109.
- Cargo CA, Rowbotham N, Evans PA, et al. Targeted sequencing identifies patients with preclinical MDS at high risk of disease progression. Blood 2015; 126:2362.
- Steensma DP, Bejar R, Jaiswal S, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood 2015; 126:9.
- Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 2014; 371:2488.
- Xie M, Lu C, Wang J, et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med 2014; 20:1472.
- Genovese G, Kähler AK, Handsaker RE, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med 2014; 371:2477.
- Biernaux C, Loos M, Sels A, et al. Detection of major bcr-abl gene expression at a very low level in blood cells of some healthy individuals. Blood 1995; 86:3118.
- Limpens J, Stad R, Vos C, et al. Lymphoma-associated translocation t(14;18) in blood B cells of normal individuals. Blood 1995; 85:2528.
- Nielsen C, Birgens HS, Nordestgaard BG, Bojesen SE. Diagnostic value of JAK2 V617F somatic mutation for myeloproliferative cancer in 49 488 individuals from the general population. Br J Haematol 2013; 160:70.
- Laurie CC, Laurie CA, Rice K, et al. Detectable clonal mosaicism from birth to old age and its relationship to cancer. Nat Genet 2012; 44:642.
- Busque L, Patel JP, Figueroa ME, et al. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat Genet 2012; 44:1179.
- Goldin LR, McMaster ML, Caporaso NE. Precursors to lymphoproliferative malignancies. Cancer Epidemiol Biomarkers Prev 2013; 22:533.
- Kyle RA, Therneau TM, Rajkumar SV, et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med 2006; 354:1362.
- Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89:2079.
- Jaiswal S, Natarajan P, Silver AJ, et al. Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease. N Engl J Med 2017; 377:111.
- Malcovati L, Cazzola M. The shadowlands of MDS: idiopathic cytopenias of undetermined significance (ICUS) and clonal hematopoiesis of indeterminate potential (CHIP). Hematology Am Soc Hematol Educ Program 2015; 2015:299.
- Bejar R. Myelodysplastic Syndromes Diagnosis: What Is the Role of Molecular Testing? Curr Hematol Malig Rep 2015; 10:282.
- Kwok B, Hall JM, Witte JS, et al. MDS-associated somatic mutations and clonal hematopoiesis are common in idiopathic cytopenias of undetermined significance. Blood 2015; 126:2355.
- Malcovati L, Karimi M, Papaemmanuil E, et al. SF3B1 mutation identifies a distinct subset of myelodysplastic syndrome with ring sideroblasts. Blood 2015; 126:233.