Distinguishing myelodysplastic syndromes (MDS) from idiopathic cytopenia of undetermined significance (ICUS): HUMARA unravels clonality in a subgroup of patients

Schroeder, Thomas; Ruf, Leilani; Bernhardt, A.; Hildebrandt, Barbara; Aivado, Manuel; Aul, Carlo; Gattermann, Norbert; Haas, R.; Germing, Ulrich

doi:10.1093/annonc/mdq233

Cited by 29 publications

(16 citation statements)

References 21 publications

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“…A lack of abnormalities in commonly mutated MDS genes may have prognostic significance. 8,11,36 In conclusion, somatic mutations identified on a commercial myeloid gene sequencing panel indicate the presence of clonal hematopoiesis in a larger-than-expected fraction of patients with clinically meaningful cytopenias. This includes patients with no evidence of dysplasia.…”

Section: Org Frommentioning

confidence: 88%

“…Just as certain chromosomal abnormalities can indicate the presence of clonal hematopoiesis and serve as presumptive evidence of MDS, it was hoped that somatic mutations might help identify clonal ICUS cases that could be considered to have MDS instead. 8,10 This parallels how identification of specific recurrent mutations has redefined the diagnostic criteria for several myeloproliferative neoplasms (MPN). Targeted sequencing of 40 or so genes can identify 1 or more somatic mutations in over 80% of MDS cases.…”

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confidence: 93%

“…Small studies indicate that some patients will go on to develop frank MDS or a related myeloid malignancy such as AML. 8 Others may follow a more indolent course. 9 Clear factors that predict progression have not been discovered.…”

Section: Introductionmentioning

confidence: 99%

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MDS-associated somatic mutations and clonal hematopoiesis are common in idiopathic cytopenias of undetermined significance

Kwok¹,

Hall²,

Witte

et al. 2015

Blood

285

216

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• Over 30% of patients with unexplained cytopenias who do not meet diagnostic criteria for MDS carry MDS-associated somatic mutations.• Clonal cytopenias of undetermined significance are more common than MDS and show comparable variant allele frequencies and blood counts.Establishing a diagnosis in patients suspected of having a myelodysplastic syndrome (MDS) can be challenging and could be informed by the identification of somatic mutations. We performed a prospective study to examine the frequency and types of mutations encountered in 144 patients with unexplained cytopenias. Based on bone marrow findings, 17% were diagnosed with MDS, 15% with idiopathic cytopenias of undetermined significance (ICUS) and some evidence of dysplasia, and 69% with ICUS and no dysplasia. Bone marrow DNA was sequenced for mutations in 22 frequently mutated myeloid malignancy genes. Somatic mutations were identified in 71% of MDS patients, 62% of patients with ICUS and some dysplasia, and 20% of ICUS patients and no dysplasia. In total, 35% of ICUS patients carried a somatic mutation or chromosomal abnormality indicative of clonal hematopoiesis. We validated these results in a cohort of 91 lower-risk MDS and 249 ICUS cases identified over a 6-month interval. Mutations were found in 79% of those with MDS, in 45% of those with ICUS with dysplasia, and in 17% of those with ICUS without dysplasia. The spectrum of mutated genes was similar with the exception of SF3B1 which was rarely mutated in patients without dysplasia. Variant allele fractions were comparable between clonal ICUS (CCUS) and MDS as were mean age and blood counts. We demonstrate that CCUS is a more frequent diagnosis than MDS in cytopenic patients. Clinical and mutational features are similar in these groups and may have diagnostic utility once outcomes in CCUS patients are better understood. (Blood. 2015;126(21):2355-2361 IntroductionMyelodysplastic syndromes (MDS) are clonal bone marrow disorders characterized by inefficient and dysmorphic hematopoietic differentiation, cytopenias of the peripheral blood, and increased risk of transformation to acute myeloid leukemia (AML).1 Establishing a diagnosis of MDS in a cytopenic patient is often challenging as the bone marrow must demonstrate dysplasia in 10% or more of a myeloid cell lineage or a blast proportion of 5% or greater.2 Quantification of these features can be subjective and prone to wide interobserver variation even among expert hematopathologists. 3,4 In cases that do not meet either bone marrow criteria, the presence of certain clonal karyotype abnormalities typical for MDS can serve as presumptive evidence of the diagnosis.2 Finally, other neoplasms and nonclonal causes of cytopenias must also be reasonably excluded. Many patients with otherwise unexplained cytopenias will fail to meet the diagnostic criteria for MDS and instead carry a designation of idiopathic cytopenias of undetermined significance (ICUS). 5-7The natural history of patients with ICUS is largely unknown and appears to be highly variable. Sma...

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Section: Org Frommentioning

confidence: 88%

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confidence: 93%

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MDS-associated somatic mutations and clonal hematopoiesis are common in idiopathic cytopenias of undetermined significance

Kwok¹,

Hall²,

Witte

et al. 2015

Blood

285

216

View full text Add to dashboard Cite

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“…In a subset of patients, progression to MDS or even AML is observed after a variable time period [21, 24, 26]. In other ICUS patients, a lymphoproliferative or mast cell neoplasm may develop.…”

Section: Idiopathic Cytopenia Of Unknown Significancementioning

confidence: 99%

ICUS, IDUS, CHIP and CCUS: Diagnostic Criteria, Separation from MDS and Clinical Implications

Valent

2018

Pathobiology

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Various myeloid neoplasms, including the myelodysplastic syndromes (MDS), bear a certain risk of progression to secondary acute myeloid leukemia (sAML). The evolution from low-risk to high-risk MDS and finally to sAML suggests that leukemogenesis is a multistep process. However, even before an overt neoplasm, such as an MDS, develops, “prediagnostic” clonal conditions may be identified. With the advent of large-scale genomic screens, such conditions may be detected quite frequently and early in apparently healthy individuals. Recent data suggest that these conditions increase with age and are indeed associated with an increased risk of the occurrence of MDS or another myeloid neoplasm. In other patients, unexplained cytopenia may be detected and may precede MDS. More recently, diagnostic criteria for potential pre-MDS conditions, including idiopathic cytopenia of uncertain significance and clonal hematopoiesis with indeterminate potential, have been proposed. The current article provides an overview of pre-MDS states and related criteria through which these conditions can be discriminated from each other and from MDS. In addition, the clinical implications and management of pre-MDS states are discussed.

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“…Myelodysplastic syndrome (MDS) is a heterogeneous group of diseases characterized by ineffective and dysplastic hematopoiesis and pancytopenia in the peripheral blood (1) . Minimal diagnostic criteria for MDS have been discussed by several working groups.…”

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confidence: 99%

Myelodysplastic syndrome versus idiopathic cytopenia of undetermined significance: the role of morphology in distinguishing between these entities

Santos¹,

Gonçalves²,

Duarte³

2013

Revista Brasileira De Hematologia E Hemoterapia

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Distinguishing myelodysplastic syndromes (MDS) from idiopathic cytopenia of undetermined significance (ICUS): HUMARA unravels clonality in a subgroup of patients

Cited by 29 publications

References 21 publications

MDS-associated somatic mutations and clonal hematopoiesis are common in idiopathic cytopenias of undetermined significance

MDS-associated somatic mutations and clonal hematopoiesis are common in idiopathic cytopenias of undetermined significance

ICUS, IDUS, CHIP and CCUS: Diagnostic Criteria, Separation from MDS and Clinical Implications

Myelodysplastic syndrome versus idiopathic cytopenia of undetermined significance: the role of morphology in distinguishing between these entities

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