Idiopathic and clonal cytopenias of uncertain significance (ICUS and CCUS)

INTRODUCTION — Peripheral blood cytopenias are common in adults, especially in older adults, and can either be inconsequential or a sign of serious disease. In most cases, clinical evaluation and appropriate testing identify an underlying cause. Some cases of unexplained cytopenias are associated with clonal hematopoiesis (CH; ie, a population of related blood cells with an acquired gene mutation), but there is no other clinical or pathologic evidence of a hematologic malignancy. When cytopenias remain unexplained despite an appropriate evaluation, they may be described as one of the following (table 1):

●Idiopathic cytopenia of undetermined significance (ICUS)

●Clonal cytopenia of undetermined significance (CCUS)

This topic will discuss the diagnosis and management of unexplained cytopenias in adults.

Evaluation of the adult with pancytopenia is discussed separately. (See "Approach to the adult with pancytopenia".)

Clonal hematopoiesis of indeterminate potential (CHIP) refers to CH without associated cytopenias or hematologic malignancy and is discussed separately. (See "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis".)

DEFINITIONS AND DESCRIPTIONS

Cytopenia — Threshold levels for cytopenia may vary depending on age, sex, and race. Individual laboratories typically establish their own reference ranges for normal blood counts and these values should supersede published reference standards, as discussed separately. (See "Approach to the adult with pancytopenia", section on 'Definition'.)

Examples of values that may be considered to represent cytopenias follow:

●Anemia:

•Male: hemoglobin <13.5 g/dL (<135 g/L) or hematocrit <41 percent

•Female: hemoglobin <12.0 g/dL or hematocrit <36 percent

●Leukopenia: <4400 white blood cells/microL (<4.4 x 10⁹/L)

●Thrombocytopenia: <150,000/microL (<150 x 10⁹/L)

Clonal hematopoiesis — Clonal hematopoiesis (CH) refers to a population of blood or bone marrow cells of myeloid lineage that share an acquired (ie, somatic) gene mutation ("gene variant"). This mutation distinguishes the clonal cells from other blood and bone marrow cells which, instead, have the corresponding inherited ("germline") genotype. The normal version of the gene may be referred to as "wild-type." Other useful terms related to clonality are described separately. (See "Genetics: Glossary of terms".)

CH is a characteristic of hematologic malignancies, such as myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), and acute myeloid leukemia (AML). However, CH may also be found in individuals who have no detectable hematologic malignancy. Clinically, CH is most often detected by next-generation sequencing (NGS) of DNA. For clinical purposes, CH is reported when the variant allele frequency (VAF; ie, the percentage of mutated DNA sequencing reads at a given genetic locus) exceeds a given threshold, which varies between laboratories (eg, 2, 5, 10 percent). The VAF roughly corresponds to the size of the clone of hematopoietic cells. DNMT3A, TET2, and ASXL1 are the genes that are most often mutated in CH, and these genes are also commonly mutated in MDS, MPNs, AML, and other hematologic malignancies [1-5]. Further description of detection and characterization of CH is presented separately. (See "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis", section on 'Clonality'.)

Unexplained cytopenia — "Unexplained cytopenia" refers to a condition characterized by peripheral blood cytopenia whose origin is not attributable to causes detectable with conventional tests or due to concomitant diseases. Evaluation of a patient with cytopenias is described separately. (See "Approach to the adult with pancytopenia".)

OVERVIEW — Cytopenias (ie, anemia, leukopenia, and/or thrombocytopenia) are often encountered in adults, and an underlying cause can be identified in most patients. Some patients with unexplained cytopenias have clonal hematopoiesis (CH) with no other clinical or pathologic evidence of a hematologic malignancy. Evaluation of an adult patient with cytopenias and further discussion of CH are presented separately. (See "Approach to the adult with pancytopenia" and "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis", section on 'Clonality'.)

The prevalence of cytopenias rises with age, but the causes are incompletely understood and they likely represent a diverse set of disorders. For some patients, unexplained cytopenias and/or CH may represent an occult malignancy, such as a myelodysplastic syndrome without diagnostic levels of dysplasia or evolving acute myeloid leukemia with a low level of myeloblasts. However, such an assumption is not appropriate for all patients with unexplained cytopenias. Even when CH is detected, the clonal mutation may not actually be responsible for the cytopenias; as an example, the patient could have CH plus a reactive phenomenon, such as the anemia of chronic inflammation.

Unexplained cytopenias and disorders associated with CH may be envisioned as existing on a spectrum that extends from normalcy to overt malignancy. However, most individuals with unexplained cytopenias do not ultimately develop a hematologic malignancy. The epidemiology and classification of conditions of unexplained cytopenias and their distinction from other hematologic disorders are discussed below. (See 'Epidemiology' below and 'Diagnosis' below and 'Differential diagnosis' below.)

Recognition is important because some of these disorders are associated with an increased risk for transformation to hematologic malignancies, and some are associated with cardiovascular complications, as discussed below and separately. (See 'Outcomes' below and "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis", section on 'Outcomes'.)

EPIDEMIOLOGY — The prevalence of cytopenias increases with age, but less than one-third of cases remain unexplained after an appropriate evaluation. The likelihood of finding mutations associated with myeloid malignancies (ie, clonal hematopoiesis; CH) is higher in a cytopenic population compared with an age-matched population [2,5,6].

In a large population-based survey, no cause for anemia could be identified in approximately one-third of older adults; however, the current percentage of unexplained anemia is likely lower because this study (1988 to 1994) predated contemporary cytogenetic and molecular analyses [7]. There is less information about the prevalence of unexplained leukopenia and thrombocytopenia. The prevalence of anemia in association with aging is discussed separately. (See "Diagnostic approach to anemia in adults", section on 'Older adults'.)

In a single institution study, 154 of 683 patients referred for evaluation of unexplained cytopenia were given a provisional diagnosis of ICUS, based on cytopenia in ≥1 lineage that did not meet the criteria for myelodysplastic syndromes and could not be explained by any other hematologic or non-hematologic disease [8]. Among those patients, 56 of 154 (36 percent) carried one or more mutations identified using a panel of 40 myeloid malignancy-associated genes. Patients with these mutations would be classified as CCUS. Descriptions of ICUS and CCUS are provided below. (See 'Diagnosis' below.)

The prevalence of clonal hematopoiesis of indeterminate potential (CHIP; ie, CH with no associated cytopenias) is discussed separately. (See "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis".)

CLINICAL PRESENTATION — Patients with cytopenias may have clinical findings related to anemia, leukopenia, or thrombocytopenia or they may be asymptomatic (eg, cytopenias were detected by routine laboratory tests). The clinical presentation of an individual with cytopenias is described separately. (See "Approach to the adult with pancytopenia", section on 'Initial evaluation'.)

EVALUATION

Evaluation of cytopenias — Evaluation of an adult with cytopenias is discussed separately. (See "Approach to the adult with pancytopenia".)

Who needs clonality testing? — There is no consensus regarding which patients with cytopenias should undergo testing for clonal hematopoiesis (CH). Testing should be performed using next-generation sequencing (NGS), using a panel of leukemia-associated genes or exome sequencing on peripheral blood or bone marrow. (See "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis", section on 'Clonality'.)

In general, we do not test for CH in all patients with unexplained cytopenias. Our approach follows:

●If a bone marrow examination is planned to evaluate cytopenias (eg, to exclude a hematologic malignancy or aplastic anemia) or for staging purposes (eg, for multiple myeloma), a specimen of either blood or marrow should be sent for NGS testing. The decision to perform a bone marrow examination as a component of the evaluation of cytopenias is discussed separately. (See "Approach to the adult with pancytopenia".)

●If a prior bone marrow examination to evaluate cytopenias was non-diagnostic but NGS was not performed, we consider it acceptable to perform NGS on peripheral blood. Peripheral blood has high sensitivity for detecting CH (because the clone contributes to circulating blood cells) and in this circumstance, testing of blood may obviate the need to repeat a bone marrow examination.

A judgment to proceed with testing for CH should be a shared decision that is made jointly between the clinician and the patient, as discussed below. (See 'Management' below.)

Findings from CH testing are used to categorize unexplained cytopenias, as described below. (See 'Diagnosis' below.)

DIAGNOSIS

Idiopathic cytopenia of undetermined significance (ICUS) — ICUS (table 1) is diagnosed by:

●Cytopenia in one or more blood lineages that remain unexplained despite appropriate evaluation, as described separately. (See "Approach to the adult with pancytopenia".)

●No evidence of clonal hematopoiesis (CH); if a myeloid malignancy-associated mutation is detected, the variant allele frequency (VAF) should be <2 percent. (See 'Clonal hematopoiesis' above.)

●No other evidence of a hematologic malignancy, according to World Health Organization (WHO) criteria.

For the purpose of diagnosing ICUS, we consider that it is not essential to perform a bone marrow examination to exclude a hematologic malignancy. (See "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis", section on 'Bone marrow examination'.)

Modest dysplasia does not prohibit a diagnosis of ICUS, but if ≥10 percent of peripheral blood cells or bone marrow nucleated cells in one cell line exhibit dysplasia, the condition should be classified as myelodysplastic syndromes, as described separately. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)", section on 'Diagnosis'.)

Because ICUS is defined by cytopenia without a mutation with ≥2 percent VAF, the term encompasses a range of patients, including those who have not yet been tested for clonality (eg, in a setting where such testing is unavailable) as well as patients with CH with VAF <2 percent. It is also important to note that some gene panels do not detect all mutations associated with hematologic malignancies, so a negative result on an assay for somatic mutations of a solid tumor (eg, Foundation One testing) does not rule out CH.

Diagnosis of myelodysplastic syndromes and acute myeloid leukemia are presented separately. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)", section on 'Diagnosis' and "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia", section on 'Diagnosis'.)

Clonal cytopenia of undetermined significance (CCUS) — CCUS (table 1) is diagnosed by:

●Unexplained, clinically meaningful cytopenias

●CH is detected with ≥2 percent VAF of a leukemia-associated gene

●No other evidence of a hematologic malignancy, as described above

DIFFERENTIAL DIAGNOSIS — Various malignant and non-malignant disorders must be considered in the evaluation of a patient with cytopenias. Because of their different prognoses and management, it is important to distinguish patients with ICUS and CCUS from those who meet World Health Organization (WHO) criteria for myelodysplastic syndromes (MDS), various leukemias, aplastic anemia, inherited disorders, and other conditions.

Myelodysplastic syndromes — MDS share certain clinical manifestations (eg, cytopenias) and molecular findings (eg, mutations of myeloid malignancy-associated genes) with ICUS and CCUS (table 1). The distinction between these cytopenic disorders and MDS may require bone marrow examination, including morphology, cytogenetics, and molecular analysis. Diagnosis of MDS requires cytopenia and either morphologic evidence of dysplasia in at least one hematopoietic lineage and/or MDS-specific cytogenetic abnormalities (eg, involving chromosome 5 or 7). Clinical presentation and diagnosis of MDS are presented separately. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)".)

Aplastic anemia/paroxysmal nocturnal hemoglobinuria — Aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) may overlap clinically, and both are associated with cytopenias and/or clonal hematopoiesis (CH). AA can be distinguished from clonal hematopoiesis of indeterminate potential (CHIP) by a bone marrow biopsy, which will reveal substantial hypoplasia, and PNH can be distinguished by flow cytometry that reveals clones of CD59-negative cells in PNH and mutation of PIGA in most cases. Additional details of the clinical presentation and diagnosis of AA and PNH are provided separately. (See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis" and "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria".)

Inherited disorders — It is increasingly recognized that inherited bone marrow disorders may first present in adulthood. There may be accompanying somatic physical abnormalities (eg, premature graying of the hair, abnormalities of fingernails or skeleton, frequent warts), the history and prior laboratory studies may document a prolonged period of cytopenias, and there may be other affected family members. Inherited disorders are confirmed by detection of a mutation in blood/marrow cells with a similar variant allele frequency (VAF) in other somatic tissues (eg, fibroblasts). Evaluation of inherited hematopoietic disorders in adults is described separately. (See "Approach to the adult with pancytopenia", section on 'Other patient scenarios'.)

Other causes of pancytopenia — Various causes of pancytopenia and individual cytopenias must be considered in the adult with cytopenias, including autoimmune illnesses and vitamin deficiencies, and should be excluded based on evaluation, as described separately. (See "Approach to the adult with pancytopenia".)

CHIP — Clonal hematopoiesis of indeterminate potential (CHIP) manifests similar leukemia-associated mutations to those seen with CCUS (table 1). CHIP is distinguished based on the absence of cytopenias, as discussed separately. (See 'Cytopenia' above and "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis", section on 'Classification of clonal hematopoiesis'.)

OUTCOMES — Patients with unexplained cytopenias have a modest but poorly-defined risk of progression to myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). The risk of progression is greater with CCUS (ie, detectable leukemia-associated mutations) than in patients with ICUS (ie, no detectable mutations) and the risk of transformation may be affected by specific gene mutations. Patients with CCUS may also be at increased risk for cardiovascular complications, as occurs with clonal hematopoiesis of indeterminate potential (CHIP). (See "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis", section on 'CHIP outcomes'.)

The natural histories of ICUS and CCUS are not well-defined but may take one of several courses:

•Cytopenias are self-limited and eventually resolve without specific therapy

•Unexplained cytopenias persist for years

•MDS, another myeloid neoplasm, another cancer, or a non-neoplastic disorder becomes overt with time

Patients with CCUS with VAF ≥10 percent have a higher probability of developing a myeloid neoplasm compared to patients with ICUS. In a single institution retrospective study, compared to ICUS, the hazard ratio (HR) for development of MDS or AML with CCUS was 13.9 (95% CI 5.4-35.9) and 5- and 10-year cumulative probabilities of progression were 82 versus 9 percent and 95 versus 9 percent, respectively [8]. In this study, individuals with spliceosome gene mutations or mutations in TET2, ASXL1, or DNMT3A combined with additional mutations, had a 95 percent five-year cumulative probability of developing a myeloid neoplasm. The likelihood of disease progression appears to be higher with larger clones (ie, higher VAF) and with multiple mutations.

The natural history of individuals with clonal hematopoiesis of indeterminate potential (ie, clonal hematopoiesis with no cytopenias) is discussed separately. (See "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis", section on 'Outcomes'.)

MANAGEMENT — There are no evidence-based guidelines or consensus protocols for monitoring patients with unexplained cytopenias, and the optimal frequency of evaluation is unclear. In general, the protocol for follow-up depends on the severity of the cytopenias and associated symptoms and/or complications, the extent and nature of clonal hematopoiesis (CH; reflected by a higher variant allele frequency [VAF]), and concerns on the part of patient and clinician. We generally follow patients with CCUS more frequently than those with ICUS.

Our approach follows:

●The frequency of follow-up is primarily informed by the severity of the cytopenias. For patients with mild, asymptomatic, and uncomplicated cytopenias, evaluation should include interval history, focused physical examination, and complete blood count (CBC) every three to six months. Patients with more severe or symptomatic cytopenias can be seen more often, as guided by clinical judgment.

When following patients longitudinally, the clinician 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), ongoing infections, immune or endocrine disorders, or occult nutritional deficiencies that may emerge as a cause for cytopenias.

●We generally follow patients with CCUS more frequently than those with ICUS, especially if they are at higher risk for transformation to a myeloid malignancy, based on high-risk somatic mutations. As examples, we might obtain a CBC and differential count every three months for patients with mutation of TP53, ≥2 mutations, and/or a higher VAF (eg, ≥20 percent). We suggest not routinely repeating next-generation sequencing testing due to the expense and because at present there are no indications for intervention based on changes in VAF. We also suggest not routinely repeating a bone marrow examination in the absence of another indication to perform the procedure, such as worsening cytopenias.

It is important to emphasize that CH-associated mutations are acquired (ie, not heritable) and to recognize the emotional burden to patients of knowing they have potential cancer-associated mutations in blood cells. It is important to discuss the risk of developing a hematologic malignancy and the importance of modifying risk factors for cardiovascular complications, as discussed separately. It is unclear whether cytopenias modify the cardiovascular risk seen with clonal hematopoiesis of indeterminate potential. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".)

SUMMARY

●Description – Unexplained cytopenias are common in adults, especially older adults, and can either be inconsequential or a sign of serious disease. In some cases, unexplained cytopenias are associated with clonal hematopoiesis (a population of related blood cells with an acquired gene mutation) but no other clinical or pathologic evidence of a hematologic malignancy. In most cases, an underlying cause for cytopenias can be identified after an appropriate evaluation. The diagnostic evaluation of cytopenias is described separately. (See "Approach to the adult with pancytopenia".)

●Epidemiology – The prevalence of cytopenias, with or without associated mutations in a leukemia-associated genes rises with increasing age of the population. (See 'Epidemiology' above.)

●Evaluation – Criteria for cytopenias and methods for detecting clonality are described above. (See 'Definitions and descriptions' above.)

There is no consensus regarding which patients with cytopenias should have a bone marrow examination, including next-generation sequencing of a panel of genes that are most often associated with myeloid malignancies.

●Diagnosis – Diagnosis of conditions associated with unexplained clonality (table 1) follows:

•Idiopathic cytopenia of undetermined significance (ICUS) – ICUS is diagnosed based on the presence of one or more cytopenias that are unexplained despite an appropriate evaluation and no evidence of clonal hematopoiesis, either because no clonality testing has been performed, or because such testing did not detect clonality, as described above. (See 'Idiopathic cytopenia of undetermined significance (ICUS)' above.)

•Clonal cytopenia of undetermined significance (CCUS) – CCUS is diagnosed based on unexplained clinically meaningful cytopenias plus the presence of clonal hematopoiesis, yet the bone marrow does not meet criteria for myelodysplastic neoplasms/syndromes (MDS), leukemia, or another hematologic neoplasm. Most cases of CCUS are identified when mutation testing is performed as part of the clinical evaluation of patients with unexplained cytopenias. (See 'Clonal cytopenia of undetermined significance (CCUS)' above.)

●Differential diagnosis – The differential diagnosis of unexplained cytopenia syndromes includes various malignant and non-malignant disorders with similar clinical presentations, including MDS, acute myeloid leukemia, aplastic anemia/paroxysmal nocturnal hemoglobinuria, autoimmune disorders, or other diseases. (See 'Differential diagnosis' above.)

●Progression – There is a modest, but poorly defined risk of progression to myelodysplastic syndromes or leukemias and the risk is greater in patients who have associated mutations (ie, CCUS) than in patients without mutations (ie, ICUS). (See 'Outcomes' above.)

●Monitoring – There are no guidelines or consensus protocols for monitoring patients with unexplained cytopenias. In general, follow-up depends on the severity of cytopenias, the presence and severity of symptoms or complications, degree of clonality, and concerns on the part of patient and clinician. (See 'Management' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David P Steensma, MD, who contributed to earlier versions of this topic review.