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Idiopathic cytopenias of undetermined significance (ICUS), clonal hematopoiesis of indeterminate potential (CHIP), and clonal cytopenias of undetermined significance (CCUS)
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Idiopathic cytopenias of undetermined significance (ICUS), clonal hematopoiesis of indeterminate potential (CHIP), and clonal cytopenias of undetermined significance (CCUS)
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jan 2017. | This topic last updated: Aug 10, 2016.

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 [1]. 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 (4th edition, 2008), and will not be formal categories in the 5th edition (scheduled for publication in 2016 to 2017), since they are not clearly neoplastic [2,3].

DEFINITIONS AND DISTINCTION FROM MDS

Definitions — 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) [4]:

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 patients 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 general terms that can be used to describe patients without a specific diagnosis in whom cytopenias or clonal mutations represent a possible sign of disease that may manifest more clearly in the future.

Patients with ICUS, CHIP, and CCUS are distinguished from patients who meet WHO criteria for myelodysplastic syndromes (MDS). This is important because unexplained cytopenias in older adults are commonly due to MDS. For 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 [5].

Although MDS is important to diagnose because the natural history of MDS includes a risk of death from progressive cytopenias or evolution to acute myeloid leukemia (AML), 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 [6]. (See "Clinical manifestations and diagnosis of the myelodysplastic syndromes".)

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 [3,7-9]:

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, including acquired loss of the Y chromosome, trisomy 8, or loss of the long arm of chromosome 20 (del(20q)), are not considered sufficient criteria for a diagnosis of MDS by themselves [9].

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) [10]. 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 [11] 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 [14]. 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) [15]. Patients with ICUS are not known to have a clonal disorder, by definition. This may either be because no clonality testing has been performed (eg, in a resource-poor 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 [7,16]. 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.

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 a Mayo Clinic study, 579 of 2899 patients (20 percent) evaluated for cytopenias with a bone marrow biopsy did not meet criteria for a WHO diagnosis [17]. 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) [18]. 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 the most appropriate frequency of evaluation is unclear. There are no evidence-based practices. 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. More severe cytopenias (eg, hemoglobin <10 g/dL) are more likely to result in a diagnosis compared to those with hemoglobin levels just below the WHO threshold for anemia, and these patients can be followed monthly [10].

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 [1]. (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 [19]. 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 [20]. 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 [19]. Because infinitely deep sequencing will detect acquired mutations in every adult, we proposed defining CHIP as the presence of a mutation with at least 2 percent variant allele frequency (VAF) indicative of a true clonal cell population, but the clinical significance of this cutoff has yet to be confirmed [19]. 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 [20].

CHIP is occasionally discovered when marrow or blood genetic tests are sent for an unrelated reason. As an example, during staging of a non-myeloid neoplasm or clinical trial screening studies for a patient with myeloma or lymphoma, a marrow aspirate may be sent for a molecular analysis that includes a broad array of hematologic neoplasm-associated mutations. 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.

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:

After the BCR/ABL1 fusion was found to be the causative genetic change in chronic myeloid leukemia (CML), sensitive polymerase chain reaction (PCR) techniques detected BCR/ABL1 fusions at low levels in some patients with normal blood counts who never evolved to CML [21].

While translocations of chromosomes 14 and 18 are found in the majority of patients with follicular lymphoma, they have also been detected in healthy people who did not develop lymphoma [22].

JAK2 mutations are detectable in some patients without other features of myeloproliferative neoplasms [23].

Clonal hematopoiesis has also been found to be common in older individuals:

Studies using single nucleotide polymorphism (SNP) array tools have observed an increased frequency of somatic chromosomal mosaicism with age [24].

Some older women with acquired skewing of X chromosome inactivation patterns have acquired TET2 mutations [25].

The best estimate of CHIP incidence comes from an analysis of sequencing data from a series of large genome-wide association studies (GWAS) comparing patients with diabetes mellitus, schizophrenia, and other conditions that explored the frequency with which mutations associated with hematologic neoplasms were found in people without neoplasia [20,26,27]. Remarkably, such mutations 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 [20,26,27].  

CHIP natural history — The presence of a hematologic malignancy-associated mutation is not equivalent to a hematologic malignancy diagnosis. "Indeterminate potential" in the CHIP term describes the stochastic possibility that these clonal states will evolve to a frank neoplasm, a risk estimated at 0.5 to 1 percent per year, similar in magnitude to the rate 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 [28,29]. For reasons that are not yet clear, CHIP is associated with not only an increased risk of hematologic neoplasia but also with higher all-cause mortality.

In one series of 17,182 people unselected for hematologic phenotype, the presence of a somatic mutation was associated with increased risk of developing hematologic malignancy (hazard ratio [HR] 11, 95% CI 3.9-33), 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) [20].

Another series of 12,380 subjects found a similar risk of death associated with mutations (HR 1.4; 95% CI 1.1-1.9) [27]. Work using other GWAS datasets and mouse models is ongoing to try to better understand this association.

Importantly, the estimated risk of progression to a hematologic malignancy associated with CHIP (0.5 to 1 percent per year) is an order of magnitude lower than the risk of progression of WHO-defined myelodysplastic syndromes (MDS) to acute myeloid leukemia (AML). Among lower risk MDS as stratified by the 1997 International Prognostic Scoring System, 19 to 30 percent of patients will go on to develop AML and die from it, whereas in higher risk MDS this proportion is 33 to 45 percent [30].  

In contrast, 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

Following patients with CHIP — Patients with CHIP should be followed over time, but the most appropriate frequency of evaluation is unclear and there are no published guidelines. In our practice, we elect to evaluate patients with CHIP every three to six months unless a very high-risk mutation (eg, high variant allele frequency TP53 mutation, or more than two mutations) is present, in which case a monthly blood count may be more appropriate. If a clonal mutation is found in the blood, a bone marrow biopsy is not necessary if blood counts are normal, but bone marrow biopsy is prudent if cytopenias are present.  

With good natural history studies, we may learn that specific mutations and variant allele frequencies 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.

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) has been proposed to describe patients who have clinically meaningful unexplained cytopenias (ICUS) and are also found to have a clonal mutation, yet do not meet World Health Organization (WHO)-defined criteria for myelodysplastic syndromes (MDS) or another hematologic neoplasm (table 1) [19,31].

Most of these cases will be identified when testing for mutations associated with hematologic malignancies is performed as part of the clinical evaluation of patients with unexplained cytopenias [32]. 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 [4,20,33].

CCUS natural history — The progression risk for CCUS is unknown, but it is likely to fall between the CHIP and MDS ranges. While it is tempting is to consider patients with CCUS as having a morphologically occult hematologic neoplasm (for instance, MDS without 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 a hematopoietic clone bearing a mutation to hematopoietic failure. One method of estimating this contribution uses the variant allele frequency (VAF) as a measure of the mutation burden. The VAF is the proportion of sequencing reads with a mutation, which in the absence of a copy number variant is roughly parallel to the size of the clone bearing the mutation. Large clones (VAF >20 percent) seem more likely to be clinically meaningful than small clones (VAF <10 percent), but this may depend on the specific mutant allele [31,32]. In the future, it seems likely that patterns of specific alleles and VAFs will be able to be define a cohort of patients with a progression risk more similar to MDS than CHIP or ICUS.  

One study evaluated 249 consecutive patients with ICUS and 91 patients who met WHO criteria for lower risk MDS, using conventional hematopathology techniques, conventional karyotyping, and a 26-gene mutation panel enriched for MDS-associated genes [33]. Karyotypic abnormalities or point mutations were identified in more than 90 percent of patients with MDS and 40 percent of those with ICUS (and therefore represented CCUS) with the following results:

Among the ICUS cohort, 14 percent had cytogenetic abnormalities, but none of the abnormalities detected were considered specific for MDS; 56 percent of the cytogenetic abnormalities were loss of the Y chromosome and the remaining were mostly trisomy 8 and deletion of 20q.

The distribution of mutations and repertoire of the most commonly detected mutations were similar between ICUS and MDS cases, with the exception of SF3B1, which was overrepresented in MDS compared with ICUS, and SRSF2, which was more common in ICUS. The former is likely because SF3B1 mutations are strongly associated with the presence of ring sideroblasts [34], a striking morphologic alteration in erythroid precursor cells that, if seen, gives hematopathologists additional confidence in making a diagnosis of MDS.

The most commonly observed mutations in both ICUS/CCUS and MDS groups other than SF3B1 were TET2, DNMT3A, and ASXL1.

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) [18]. 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 [20]. 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 the most appropriate frequency of evaluation is unclear and no guidelines have been published. 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 variant allele frequencies 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 following terms have been proposed to describe individuals who have unexplained 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' above.)

While there is a paucity of data regarding the natural history of ICUS, there is clearly a small but undefined risk of myelodysplastic syndrome (MDS) or another hematologic malignancy in people with ICUS. ICUS often resolves over time or is found to be due to a non-myeloid malignancy, immune disorder, or other occult nutritional deficiency. (See 'ICUS natural history' above.)

In our practices, the frequency of follow-up for patients with ICUS depends in part upon the severity of the cytopenias. ICUS with mild cytopenias may be evaluated every three to six months. More severe cytopenias (eg, hemoglobin <10 g/dL) are more likely to result in a diagnosis compared to those with hemoglobin levels just below the WHO threshold for anemia. (See 'Following patients with ICUS' above.)

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' above.)

The presence of a hematologic malignancy-associated mutation is not equivalent to a hematologic malignancy diagnosis. Individuals with CHIP have an estimated risk of progression to a frank neoplasm of 0.5 to 1 percent per year. For reasons that are not yet clear, CHIP is associated with not only an increased risk of hematologic neoplasia but also with higher all-cause mortality. (See 'CHIP natural history' above.)

In our practices, we elect to evaluate patients with CHIP every three to six months unless a very high-risk mutation (eg, high variant allele frequency [VAF] TP53 mutation, or more than two mutations) is present, in which case a monthly blood count may be more appropriate. (See 'Following patients with CHIP' above.)

Clonal cytopenia of undetermined significance (CCUS) – Identification of a clonal mutation in a patients with one or more clinically meaningful unexplained cytopenias, yet 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 the CHIP and MDS ranges. Patients with a high variant allele frequency (eg, VAF >20) and those with certain mutations may be at higher risk of progression. (See 'CCUS natural history' above.)

The frequency of evaluation for patients with CCUS is dependent upon the severity of cytopenia, mutation present, and the mutation burden (eg, VAF). 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. (See 'Following patients with CCUS' above.)

Importantly, these three entities are not specific disorders per se. Rather, they are general terms that can be used to describe patients without a specific diagnosis in whom cytopenias or clonal mutations represent a possible sign of disease that may manifest more clearly in the future.

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