Idiopathic cytopenia of undetermined significance (ICUS) and idiopathic dysplasia of uncertain significance (IDUS), and their distinction from low risk MDS

Valent, Peter; Bain, Barbara J.; Bennett, John M.; Wimazal, Friedrich; Sperr, Wolfgang R.; Mufti, Ghulam J.; Horny, Hans‐Peter

doi:10.1016/j.leukres.2011.08.016

Cited by 74 publications

(98 citation statements)

References 22 publications

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“…41,43,44 A substantial proportion of patients with persistent cytopenia lack conclusive morphology and cytogenetics and may presumptively be classified as ICUS. 45,46 The difficulty in diagnosing MDS among AA patients lies in the fact that both conditions often show indistinguishable phenotypes and may even coexist in the same patients, although patients with AA are nevertheless at high risk for MDS development. Many AA patients who ever responded to IST are still cytopenic and, even when a complete response is obtained, recurrence is common.…”

Section: Diagnosing Mds In Aa Patientsmentioning

confidence: 99%

Clonal hematopoiesis in acquired aplastic anemia

Ogawa

2016

Blood

162

130

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Clonal hematopoiesis (CH) in aplastic anemia (AA) has been closely linked to the evolution of late clonal disorders, including paroxysmal nocturnal hemoglobinuria and myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML), which are common complications after successful immunosuppressive therapy (IST). With the advent of high-throughput sequencing of recent years, the molecular aspect of CH in AA has been clarified by comprehensive detection of somatic mutations that drive clonal evolution. Genetic abnormalities are found in ∼50% of patients with AA and, except for PIGA mutations and copy-neutral loss-of-heterozygosity, or uniparental disomy (UPD) in 6p (6pUPD), are most frequently represented by mutations involving genes commonly mutated in myeloid malignancies, including DNMT3A, ASXL1, and BCOR/BCORL1. Mutations exhibit distinct chronological profiles and clinical impacts. BCOR/BCORL1 and PIGA mutations tend to disappear or show stable clone size and predict a better response to IST and a significantly better clinical outcome compared with mutations in DNMT3A, ASXL1, and other genes, which are likely to increase their clone size, are associated with a faster progression to MDS/AML, and predict an unfavorable survival. High frequency of 6pUPD and overrepresentation of PIGA and BCOR/BCORL1 mutations are unique to AA, suggesting the role of autoimmunity in clonal selection. By contrast, DNMT3A and ASXL1 mutations, also commonly seen in CH in the general population, indicate a close link to CH in the aged bone marrow, in terms of the mechanism for selection. Detection and close monitoring of somatic mutations/evolution may help with prediction and diagnosis of clonal evolution of MDS/AML and better management of patients with AA.

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Section: Diagnosing Mds In Aa Patientsmentioning

confidence: 99%

Clonal hematopoiesis in acquired aplastic anemia

Ogawa

2016

Blood

162

130

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“…ICUS is also not a unique or well-defined clinical entity and includes a heterogeneous group of patients, only some of whom have an MDS or AML progression risk. 18 In addition to ICUS, some elderly people have clonally restricted hematopoiesis without cytopenias, sometimes detectable as somatic mosaicism for large chromosomal abnormalities, and the rate at which these patients progress to MDS or other hematologic neoplasms appears to be increased compared with patients without clonal hematopoiesis. [19][20][21] The recent finding of 450 somatic mutations in the healthy blood compartment of a 115-yearold woman is a striking illustration that not all detectable coding mutations are clinically consequential.…”

Section: Epidemiology and Diagnosismentioning

confidence: 99%

“…64,65 This discovery identified TET2 as a regulator of DNA methylation. ASXL1 and EZH2 mutations are now known to affect histone modifications, and collectively, mutations in these genes as well as several others discovered later BLOOD, 30 OCTOBER 2014 x VOLUME 124, NUMBER 18 RECENT…”

Section: Advances In the Genetic Basis Of Mdsmentioning

confidence: 99%

Recent developments in myelodysplastic syndromes

Bejar

Steensma

2014

Blood

154

130

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Once thought to be rare disorders, the myelodysplastic syndromes (MDS) are now recognized as among the most common hematological neoplasms, probably affecting >30 000 patients per year in the United States. US regulatory approval of azacitidine, decitabine, and lenalidomide between 2004 and 2006 seemed to herald a new era in the development of disease-modifying therapies for MDS, but there have been no further drug approvals for MDS indications in the United States in the last 8 years. The available drugs are not curative, and few of the compounds that are currently in development are likely to be approved in the near future. As a result, MDS diagnoses continue to place a heavy burden on both patients and health care systems. Incomplete understanding of disease pathology, the inherent biological complexity of MDS, and the presence of comorbid conditions and poor performance status in the typical older patient with MDS have been major impediments to development of effective novel therapies. Here we discuss new insights from genomic discoveries that are illuminating MDS pathogenesis, increasing diagnostic accuracy, and refining prognostic assessment, and which will one day contribute to more effective treatments and improved patient outcomes.

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“…MDS may be morphologically occult until the time of leukemic transformation; persistent unexplained cytopenias that could represent MDS but defy diagnosis despite extensive investigation have been termed ''idiopathic cytopenias of undetermined significance'' (ICUS) [12,13].…”

Section: Discussionmentioning

confidence: 99%

An extreme example of focal bone marrow involvement in acute myeloid leukemia

et al. 2012

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A 59-year-old man presented to the Emergency Department (ED) with a 2 month history of progressive fatigue, dyspnea, and exertional chest pain. For 9 years, he had had chronic, mild fluctuating cytopenias of uncertain etiology. A bone marrow biopsy of the left iliac crest at the onset of the cytopenias demonstrated aplasia, but a followup biopsy of the contralateral iliac crest 2 months later revealed a hypercellular marrow with mild erythroid hyperplasia and no dysplasia. Given these discrepant results, an extensive investigation for potential causes of cytopenias was undertaken, but failed to yield a specific diagnosis. Several subsequent bone marrow biopsies from both iliac crests showed only a severely hypocellular marrow with a normal male karyotype, but a sternal aspirate performed 8 years prior to presentation was hypercellular and without morphologic abnormalities. Four months prior to ED presentation, the patient had a normal complete blood count (CBC).On presentation to the ED, CBC revealed hemoglobin of 7.8 g/dL, hematocrit of 21.7%, white cell count of 0.81 3 10 9 /L (absolute neutrophil count 190/mm 3 ), and platelets of 103 3 10 9 /L. Peripheral blood smear showed evidence of dysplasia, with poikilocytosis, anisocytosis, basophilic stippling, and hypogranular neutrophils, but no circulating blasts. Bone marrow aspirate and biopsy of the left iliac crest was performed, which was again hypocellular and non-diagnostic, but a few suspicious blasts were observed. Due to the patient's unusual history, [18 F] fluorodeoxyglucose positron emission tomography (FDG-PET) was performed, with concurrent non-contrast helical computed tomography (CT) to enable anatomic correlation and attenuation correction of the PET images.FDG-PET/CT revealed scattered, patchy high-intensity FDG uptake in the sternum, part of the right ilium and pelvis, and 8 of 24 vertebral bodies, as seen in the coronal section PET image in Fig. 1A. The remainder of the marrow, including the left iliac crest (Fig. 1B) was markedly photopenic, in keeping with the findings of a hypocellular marrow on previous aspirates. Figure 1C,D demonstrates different FDG uptake in two adjacent vertebrae, showing how the T12 vertebral body (Fig. 1C) is highly FDG-avid, while the L1 vertebral body (Fig. 1D) is not. Normal marrow shows low metabolic activity on FDG-PET and appears nearly black.Bone marrow aspirates targeted to FDG-avid areas of the right ilium and sternum showed 51% and 56% blasts, respectively, with a myeloid phenotype (expressing CD34, dim CD45, HLA-DR, and the myeloid markers CD13, Image 1. Panels A-D depict FDG uptake in several vertebral bodies and patchy areas of the pelvic bones, including the right iliac crest, on PET/CT scanning of a patient with focal involvement by AML. Other vertebral bodies (panel D) and the left iliac crest are photopenic, and the left iliac crest was hypocellular (panel G) and non-diagnostic upon biopsy. Panels E and F depict a cellular marrow with myeloblasts, obtained from a PET-avid area of the pelvis; panel G...

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Idiopathic cytopenia of undetermined significance (ICUS) and idiopathic dysplasia of uncertain significance (IDUS), and their distinction from low risk MDS

Cited by 74 publications

References 22 publications

Clonal hematopoiesis in acquired aplastic anemia

Clonal hematopoiesis in acquired aplastic anemia

Recent developments in myelodysplastic syndromes

An extreme example of focal bone marrow involvement in acute myeloid leukemia

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