Distinct clinical outcomes for cytogenetic abnormalities evolving from aplastic anemia

Blood ◽  
2002 ◽  
Vol 99 (9) ◽  
pp. 3129-3135 ◽  
Author(s):  
Jaroslaw P. Maciejewski ◽  
Antonio Risitano ◽  
Elaine M. Sloand ◽  
Olga Nunez ◽  
Neal S. Young
Keyword(s):  
Aplastic Anemia ◽  
Chromosomal Abnormalities ◽  
Bone Marrow Cells ◽  
Chromosome 7 ◽  
Trisomy 8 ◽  
Monosomy 7 ◽  
Cytogenetic Abnormalities ◽  
Constant Rate ◽  
Structural Abnormalities ◽  
Actuarial Risk

Abstract A serious complication of aplastic anemia (AA) is its evolution to clonal hematologic diseases such as myelodysplasia (MDS) and leukemia, which is usually associated with the appearance of a cytogenetic abnormality in bone marrow cells. We present here an analysis of a cohort of 30 patients with otherwise typical AA in whom clonal karyotypic evolution was observed during frequent periodic marrow examinations. The actuarial risk for this complication has been estimated in other studies at around 15% at 5 years. Conversion from normal to abnormal karyotype occurred at a constant rate after initial diagnosis, with about 50% of cases developing within the first 30 months. Transient chromosomal abnormalities were infrequent. Clinically, AA patients with clonal cytogenetic patterns were heterogenous; a variety of karyotypic defects with numerical and structural abnormalities of chromosome 7 accounted for 40% of all cases followed by trisomy 8, structural and numerical abnormalities of chromosome 13, deletion of Y chromosome, and complex cytogenetic abnormalities. Unlike in primary MDS, aberrancies of chromosome 5 and 20 were infrequent. The clinical course depended on the specific abnormal cytogenetic pattern. Most deaths related to leukemic transformation occurred in patients with abnormalities of chromosome 7 or complex cytogenetic alterations or both. Evolution of chromosome 7 abnormalities was seen most often in refractory patients who had failed to respond to therapy. In contrast, trisomy 8 developed in patients with good hematologic responses who often required chronic immunosuppression with cyclosporine A (CsA), and survival was excellent. Although AA patients with monosomy 7 showed a similar prognosis to those with primary MDS, trisomy 8 in AA appears to have a more favorable prognosis than in MDS.

Chromosomal Abnormalities in Philadelphia Chromosome (Ph)-Negative Metaphases Appearing during Imatinib Mesylate (IM) Therapy in Patients (pts) with Newly Diagnosed Chronic Myeloid Leukemia (CML) in Chronic Phase.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1090-1090 ◽  
Author(s):  
Elias Jabbour ◽  
Hagop Kantarjian ◽  
Susan O’Brien ◽  
Srdan Verstovsek ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Chromosomal Abnormalities ◽  
Philadelphia Chromosome ◽  
Chromosome 7 ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Trisomy 8 ◽  
Chromosome Y ◽  
Cytogenetic Abnormalities

Abstract The development of chromosomal abnormalities in the Ph-negative metaphases during IM therapy of CML has been recognized mostly in pts who failed prior therapy. Prior exposure to cytarabine has been suggested to be a predisposing factor. This phenomenon has not been yet assessed to date in patients with newly diagnosed CML and treated with IM. This is different from clonal evolution where the abnormalities are observed in the Ph-positive metaphases. We assessed the frequency and the significance of this event among 258 newly diagnosed pts with CML receiving IM (800 mg/d n=207, 400 mg/d n=51) as first line of therapy between March 2001 and April 2005. After a median follow-up of 30 months (range, 6–48 months), 19 pts (7%) developed 21 chromosomal abnormalities in Ph-negative metaphases. Thirteen (62%) of these abnormalities have been seen in 2 or more metaphases. The median time from the start of IM to appearance of abnormalities was 18 months (range, 3–36 months). The most common cytogenetic abnormalities were: loss of chromosome Y (n=7, 33%), trisomy 8 (n=3, 14%), and deletion of chromosome 7 (n=2, 10%). Excluding loss of chromosome Y abnormalities, the incidence was 5%. All pts achieved a major (Ph < 35%) cytogenetic (CG) response (complete cytogenetic response [CCGR] in 17 [89%] pts). Major molecular response (BCR-ABL/ABL ratio <0.05) was observed in 13 (68%) pts (including 2 with complete molecular response). In all but 4 pts these events have been transient and disappeared after a median of 4 months (range, 3–9 months). In 4 pts (loss of chromosome Y n=3, trisomy 8 n=1), they persisted for a median of 13+ months (range, 6+–24+ months). One pt developed acute myeloid leukemia (associated with -7); none of the other pts has any feature of myelodysplasia. After a median follow-up of 13 months (range, 1–42 months), 17 of the 19 pts are alive. One pt died after allogeneic stem cell transplantation, and one died after 6 months of CCGR from myocardial infarction. One pt lost response to IM. The remaining 16 pts are in major CG response at the last follow-up. We conclude that: 1) cytogenetic abnormalities occur in Ph-negative cells in a small fraction of patients (7%; 5% if loss of Y excluded) in newly diagnosed CML on IM; 2) in the majority of cases, they are transient with no clear clinical consequences; 3) in rare instances (loss of chromosome 7 only in our study) they could reflect the emergence of a new malignant clone necessitating and a close follow-up.

Comparison of Clinical Outcomes Between Pediatric Aplastic Anemia and Refractory Cytopenia of Childhood

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1498-1498
Author(s):  
Asahito Hama ◽  
Atsushi Manabe ◽  
Daisuke Hasegawa ◽  
Kazue Nozawa ◽  
Atsushi Narita ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Clinical Outcomes ◽  
Who Classification ◽  
Chromosomal Abnormalities ◽  
Response Rates ◽  
World Health ◽  
Trisomy 8 ◽  
Monosomy 7 ◽  
Cell Lineages

Abstract In the diagnosis of childhood bone marrow failures (BMFs), differentiating aplastic anemia (AA) from hypoplastic myelodysplastic syndrome (MDS) is challenging. The 2008 World Health Organization (WHO) classification has proposed a provisional entity, "refractory cytopenia of childhood (RCC)". The spectrum of patients with RCC is wide, ranging from patients with severe hypocellular bone marrow (BM) and mild dysplasia to those with normocellular BM and distinct dysplasia meeting the criteria for refractory cytopenia with multilineage dysplasia (RCMD) defined for adults with MDS. Currently, it is recommended that children who meet the criteria for RCMD should be classified as RCC in the WHO classification until the number of lineages involved has been fully evaluated with regard to their relative importance as prognostic factors. Until now, few studies have addressed the question whether the current WHO classification reflects clinical outcomes of childhood BMFs. To determine the clinical differences among AA, RCC, and RCMD, we compared clinical outcomes for patients with AA, RCC, and RCMD in Japan. From February 2009 to December 2013, 252 patients were registered to the central morphology review system of the Japanese Society of Hematology and Oncology and were diagnosed with BMFs. Peripheral blood (PB) and BM smears were reviewed by two pediatric hematologists, and BM trephine biopsies were reviewed by a hematopathologist. RCC is defined as persistent cytopenia with <2% and <5% blasts in PB and BM, respectively. BM aspirate smears show dysplastic changes in >2 cell lineages or >10% within one cell lineage. On the other hand, the criteria of RCMD is defined as persistent cytopenia with <1% and <5% blasts in PB and BM, respectively. BM smears show >10% dysplastic changes in >2 cell lineages. Patients with inherited BMFs were excluded by family history and physical examination. Further, Fanconi anemia was excluded by chromosome fragility test　and Dyskeratosis congenita was screened by measuring the telomere length of the peripheral lymphocytes by flowcytometry. Out of 252 patients, 63 were classified as AA, 131 as RCC, and 58 as RCMD. Median ages in AA, RCC, and RCMD groups were 10, 8, and 7 years, respectively (p=0.07). The median of leukocyte, neutrophil, reticulocyte, and platelet count, and mean corpuscular volume were significantly lower in AA than in RCC and RCMD groups (p<0.01). Chromosomal abnormalities were detected in 1 patient with AA (trisomy 8), 3 patients with RCC (trisomy 8, n=2; other, n=1), and 9 patients with RCMD (trisomy 8, n=5; monosomy 7, n=1; other, n=3) at the time of diagnosis (p<0.01). Out of 252 patients, 82 (AA, n=3; RCC, n=46; RCMD, n=33) were observed without any treatments (watch and wait, WW). 5-year overall survival (OS)/failure free survival (FFS) rates in WW group were 67%/67% in AA, 98%/54% in RCC, and 100%/69% in RCMD patients (p<0.01/p=0.97). Immunosuppressive therapy (IST) with rabbit antithymocyte globulin and cyclosporine was performed in 110 (AA, n=39; RCC, n=57; RCMD, n=14) patients. Six months after the IST, the response rates to the IST were not significantly different among AA (40%), RCC (63%), and RCMD (64%) (p=0.08). The development of additional chromosomal aberrations was found in 2 patients with RCC, and 1 with RCMD. The 5-year OS/FFS rates in IST group were 89%/36% in AA, 94%/38% in RCC, and 93%/23% in RCMD patients (p=0.64/p=0.86). Stem cell transplantation (SCT) as a first line therapy was performed in 19 patients with AA, 10 with RCC, and 5 with RCMD. The rejection was found in 2 patients with RCC and 3 with RCMD. Although 5-year OS rates in patients who underwent SCT were not different among 3 groups (p=0.26), FFS rate (30%) in patients with RCMD was significantly lower than in those with AA (100%) and RCC (78%) (p<0.01). In conclusion, we could not find any clinical relevance of separating RCC from AA because response rates to IST and the development of clonal evolution did not significantly differ between AA and RCC. The entity of RCMD should be adopted to childhood MDS classification because children with RCMD exhibited a distinct characteristic of morphology and a frequent chromosomal aberration at the time of diagnosis. The optimal treatment strategy including preconditioning regimen of SCT should be established for children with acquired BMFs based on the BM cellularity and morphological classification. Disclosures Kojima: SANOFI: Honoraria, Research Funding.

Fas-mediated apoptosis is important in regulating cell replication and death in trisomy 8 hematopoietic cells but not in cells with other cytogenetic abnormalities

Blood ◽  
2002 ◽  
Vol 100 (13) ◽  
pp. 4427-4432 ◽  
Author(s):  
Elaine M. Sloand ◽  
Sonnie Kim ◽  
Monika Fuhrer ◽  
Antonio M. Risitano ◽  
Ryotaro Nakamura ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Fas Ligand ◽  
Chromosomal Abnormalities ◽  
Bone Marrow Cells ◽  
Active Role ◽  
Trisomy 8 ◽  
Normal Cells ◽  
Monosomy 7 ◽  
Fresh Bone ◽  
Fas L

Increased apoptosis of hematopoietic progenitor cells has been implicated in the pathophysiology of cytopenias associated with myelodysplastic syndromes (MDSs), and inhibition by immunosuppression may account for the success of this treatment in some patients. We examined bone marrow and peripheral blood of 25 patients with chromosomal abnormalities associated with MDS (monosomy 7, trisomy 8, and 5q−) for evidence of apoptosis. When fresh bone marrow was examined, the number of apoptotic and Fas-expressing CD34 cells was increased in patients with trisomy 8, but decreased in monosomy 7, as compared with healthy control donor marrow. Fas expression was increased in the trisomy 8 cells and decreased in the monosomy 7 cells when compared with normal cells from the same patient. Trisomy 8 cells were more likely to express activated caspase-3 than were normal cells. For bone marrow cells cultured with Fas agonist or Fas antagonist, the percentage of cells with trisomy 8 was significantly decreased in most cases after Fas receptor triggering and increased by Fas ligand (Fas-L) antagonist (P < 0.01), suggesting increased Fas susceptibility of cells with trisomy 8. No such changes were seen in cultures of cells with 5q− or monosomy 7. Fas antagonist facilitated the expansion of cells with trisomy 8 only. Cells with trisomy 8 appear to be more susceptible to Fas-mediated apoptosis. Clinical data demonstrating the responsiveness of some patients with trisomy 8 to anti–thymocyte globulin (ATG) and cyclosporine (CsA) would favor an active role of the immune system in this syndrome.

High-Resolution Genomic Arrays Facilitate Detection of Novel Cryptic Chromosomal Lesions in MDS.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 370-370
Author(s):  
Christine L. O’Keefe ◽  
Ramon Tiu ◽  
Lukasz Gondek ◽  
Aaron Viny ◽  
Karl Theil ◽  
...  
Keyword(s):  
High Resolution ◽  
Chromosomal Abnormalities ◽  
Bone Marrow Cells ◽  
Genomic Analysis ◽  
Normal Karyotype ◽  
Chromosome 7 ◽  
Comparative Genomic ◽  
Stem Loop ◽  
Monosomy 7 ◽  
Normal Cytogenetics

Abstract The evolution of abnormal hematopoietic clones characterized by acquired chromosomal abnormalities is the central event in the pathogenesis of MDS. Defective chromosomes have significant clinical implications in the management of MDS and suggest the presence of an inherent chromosomal instability. As karyotypic lesions are not found in all MDS patients, it is possible that in some the dysplastic clone may evolve without a chromosomal defect or, more likely, the resolution of routine metaphase cytogenetics is not sufficient to detect smaller lesions; in many instances lack of growth precludes the analysis. Array-based comparative genomic hybridization (A-CGH) allows for a high-resolution genomic scan that circumvents some of the limitations associated with the use of conventional cytogenetics. We hypothesized that high-resolution genomic analysis of genetic gains and losses by A-CGH may detect cryptic lesions, particularly in patients with negative/non-informative cytogenetics that may be of clinical/scientific significance. We examined bone marrow cells from 39 MDS patients (18 RA/RARS, 11 RAEB-t, 6 CMML and 4 secondary AML) and 11 controls using a 2632 BAC microarray and CGH. Dye swapping on duplicate arrays assured reproducibility of the CGH results, confirmed globally by a high resolution 50K SNP microarray in 4 patients and by microsatellite analysis in others. By traditional cytogenetics 19 patients had chromosomal lesions, 18 were normal and 2 tests non-informative. When A-CGH was applied, a normal karyotype was found in only 15% of patients in comparison to 46% by metaphase cytogenetics. Of note is that both cases with uninformative cytogenetics showed an abnormal CGH result and in several patients (N=11) with an abnormal karyotype additional lesions were found. Karyotypic results were confirmed in 7 cases; discordant analysis may be due to a lower proportion of dysplastic cells in marrow. Irrespective of the genomic area affected, when we studied the raw number of lesions more advanced forms of MDS (RAEB-t/AML) were evenly distributed between patients subdivided on sheer number of lesions (0, 1–17, &gt;17). Many hotspots of genomic instability shared between patients were identified. For example, 1p26.3, 10q26 and 4p16 lesions were found in 2 or more patients. Interestingly, these regions contain genes of potential pathologic significance, including tubulin gamma complex associated protein 2 (TUBGCR2) and histone stem-loop binding protein (SLBP). Cryptic lesions on chromosome 7 (e.g. 7p21, 7q31) were identified in 5 patients with normal cytogenetics. These patients suffered from severe cytopenias, consistent with the prognosis of monosomy 7 and highlighting a consensus defect on chromosome 7. Certain chromosomes were rarely or never affected, implying that a more targeted array might be designed for clinical use. A-CGH Cytogenetics Unsuccessful Normal Abnormal Unsuccessful (N=2) 0 0 2 Normal (N=18) 0 3 15 Abnormal (n=19) 0 3 16 In summary, our study highlights the superior level of resolution of A-CGH as compared to metaphase analysis in the diagnosis of MDS. A prospective analysis is underway to determine the prognostic value of CGH-detected lesions and their pathophysiologic significance.

Clinical Implications of Abnormal Cytogenetics at Diagnosis of Aplastic Anemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 986-986
Author(s):  
Sung-Yong Kim ◽  
Jong-Wook Lee ◽  
Byung-Sik Cho ◽  
Ki-Seong Eom ◽  
Yoo-Jin Kim ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Immunosuppressive Therapy ◽  
Clinical Implications ◽  
Trisomy 8 ◽  
Hematopoietic Stem ◽  
Monosomy 7 ◽  
Normal Peripheral Blood ◽  
Cytogenetic Abnormalities ◽  
Secondary Mds ◽  
Normal Cytogenetics

Abstract Because cytogenetic abnormalities of aplastic anemia at diagnosis have been reported fairly infrequently, their clinical implications have not known yet. A retrospective study was performed of the cytogenetics findings and clinical courses in patients with typical morphological and clinical features of aplastic anemia from a single institution for the years 1995 through 2005. The results of chromosome analysis of 610 patients were evaluable. Of the evaluable patients, 584 (95.7 %) had normal karyotypes and 26 (4.3 %) had abnormal karyotypes at diagnosis. The most frequent abnormality was trisomy 8 (n=13) followed by deletion 1q (n=5) and monosomy 7/deletion 7q (n=5). Other chromosome abnormalities were isochromosome 17q (n=1), trisomy 15 (n=1) and monosomy 21 (n=1). Among the 584 patients with typical aplastic anemia and no cytogenetic abnormalities, only two developed MDS/AML during the follow-up period, while 5 (19.2%) of 26 patients with typical aplastic anemia and abnormal cytogenetics subsequently developed MDS/AML. The incidence of secondary MDS/AML was statistically higher in abnormal cytogenetics group compared with normal cytogenetics group (p&lt;0.001). The incidence of secondary MDS/AML was not influenced by immunosuppressive therapy (IST) (p=0.715). The patients with trisomy 8 responded poorly to immunosuppressive therapy (IST) and showed statistically significant lower response rate compared with the patients with other cytogenetics (p=0.033). However, response rates of IST were not statistically different in the patients with normal cytogenetics group and the patients with abnormal cytogenetics other than trisomy 8 (p=1.000). Four patients with abnormal cytogenetics received allogeneic hematopoietic stem cell transplantations (allo-HSCT) with the same conditioning as the patients with normal cytogenetics. Three of them are still alive with normal peripheral blood counts. One of them died of acute GVHD and infection after successful engraftment. Our analysis suggested that cytogenetic abnormalities at diagnosis of aplastic anemia could be a risk factor for development of secondary MDS/AML and the patients with trisomy 8 at diagnosis of aplastic anemia might hardly respond to IST. Outcomes of allo-HSCT for aplastic anemia with abnormal cytogenetics probably are not different compared with aplastic anemia with normal cytogenetics.

Inflammation Caused by Allogeneic Lymphocytes Results in Aneuploidy in Bone Marrow Mononuclear Cells (BMMNC)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3112-3112
Author(s):  
Elaine M Sloand ◽  
Hesed Padilla-Nash ◽  
Megan Furnari ◽  
Rodrigo Calado ◽  
Ling Casey ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Telomere Length ◽  
Genomic Instability ◽  
Chromosomal Abnormalities ◽  
Bone Marrow Cells ◽  
Trisomy 8 ◽  
Monosomy 7 ◽  
Transplant Patients ◽  
Marrow Cells ◽  
Allogeneic Lymphocytes

Abstract Patients with aplastic anemia and other autoimmune diseases such as rheumatoid arthritis are more likely to develop myelodyplasia when compared to healthy controls. Inflamed tissue from Barrett’s esophagus, areas of bronchitis, healing burn tissue, and bowel with ulcerative colitis commonly show increased numbers of tetraploid and aneuploid cells, suggesting that inflammation may have a role in promoting genomic instability. We recently demonstrated the common occurrence of aneuploid cells in the 15 buccal smears of transplant patients with graft versus host disease involving the oral mucosa but not in transplant patients without GVSH when these cells were examined by fluorescence in situ hybridization (FISH). Aneuploidy could be reproduced in 5 normal keratinocyte cultures following incubation with allogeneic HLA-mismatched lymphocytes. Oxidative stress and repeated cell division with telomere shortening may play a role in producing karyotypic abnormalities. Alternatively, in the AA bone marrow factors such as increased cytokine expression and the presence of cytotoxic T cells in marrow may lead to a relatively improved survival of cells with certain chromosomal abnormalities. In this respect, we previously demonstrated survival advantages for trisomy 8 and monosomy 7 relative to diploid cells (Proc Natl Acad Sci2006; 10314483: Blood. 2007;109(6):2399). In order to more thoroughly assess the role played by inflammation in producing aneuploidy, we examined five samples of normal bone marrow co-cultured for two weeks with allogeneic, autologous lymphocytes (effector to target ratio of 2:1), or with interferon alone (1000 u/mL); media was changed after 24 hours and FISH was performed using probes to chromosomes 7,8 and 20 after two weeks. Slides were read by three different individuals blinded to the identity of the slides. All bone marrow samples with allogeneic lymphocyte and with interferon but not those cultured with autologous lymphocytes showed significant numbers of aneuploid cells; Aneuploidy was most prominent in bone marrow treated with allogeneic lymphocytes (monosomy 7 mean control=1%±1%; treated=11±2%; p=0.01; trisomy 8 control=0±0%; treated=6±1%; p=0.06; deletion 20 control=1±1%; treated=14%; p=0.01; N=5). In order to ensure that these changes were not secondary to apoptosis-related DNA disintegration and to determine if aneuploidy occurred in cells capable of self renewal, bone marrow cells were exposed to allogeneic lymphocytes and to interferon g (1000 units/mL) in short-term methylcellulose culture for two weeks; we subsequently picked cells from hematopoietic colonies, pooled these cells, and stained them with annexin-FITC. Cells were sorted by flow cytometry and annexin-negative cells were subjected to FISH using centromeric probes to chromosome 8, 7 and 20. These isolated cells, derived from single progenitors, still demonstrated significant numbers of trisomy 8, monosomy 7, and deletion (20) by FISH (Fig. 1). Spectral karyotyping (SKY) analysis demonstrated chromosomal abnormalities in 13/25 (52%) of cells and prominent telomeric fusion in many metaphase preparations (Fig II). In order to determine whether telomeric shortening could play a role in fusion of chromosomes and subsequently aneuploidy, we measured telomere length by Southern hybridization: bone marrow cells cultured with allogeneic lymphocytes showed a 20% decline in telomere length relative to control populations. These in vitro data suggest that inflammatory changes may be associated with genomic instability, possibly secondary to accelerated telomere attrition in response to regeneration. Fig 1 Fig 1. Fig 2 Fig 2.

Classification of Childhood Bone Marrow Failure Syndrome Based On Revised WHO Classification.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4212-4212
Author(s):  
Asahito Hama ◽  
Ayami Yoshimi ◽  
Shinsuke Hirabayashi ◽  
Hideki Muramatsu ◽  
Nobuhiro Nishio ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Immunosuppressive Therapy ◽  
Who Classification ◽  
Chromosomal Abnormalities ◽  
Response Rates ◽  
Trisomy 8 ◽  
Monosomy 7 ◽  
Cell Lineages ◽  
Increased Risk

Abstract Abstract 4212 The WHO classification revised in 2008 proposes the term, “refractory cytopenia of childhood (RCC)” for children with myelodysplastic syndrome (MDS) and a low blast count. This condition is characterized by persistent cytopenia with < 5% blasts in the bone marrow and < 2% blasts in the peripheral blood. Dysplastic changes must be recognized in more than two cell lineages, or exceed 10% in a single cell line on bone marrow aspirate smears. To differentiate between RCC and aplastic anemia (AA) is challenging, especially when the bone marrow is hypoplastic and chromosomal abnormalities are undetectable. Aplastic anemia can progress to MDS and some patients with RCC respond to immunosuppressive therapy, suggesting that the two conditions have an overlapping pathophysiology. The spectrum of RCC ranges from mild cytopenia to cytogenetic abnormalities of monosomy 7, which carries an increased risk for disease progression. However, few studies have attempted to differentiate the two diseases. To compare the clinical and biological features of AA and RCC, we retrospectively reviewed bone marrow smears from 140 patients registered for the childhood AA-97 study. The smears were classified as AA (no morphologically dysplastic changes in any hematopoietic cell lineages), AA-RCC borderline (< 10% dysplastic changes only in erythroid lineage) and RCC groups. Disease severity was classified as non-severe (n = 32), severe (n = 43) and very severe (n = 65). Aplastic anemia was idiopathic in 116 patients and associated with hepatitis in 24. Two patients had chromosomal abnormalities at presentation. The AA, AA-RCC borderline and RCC groups comprised 96 (67%), 20 (16%) and 24 (17%) patients, respectively. Bone marrow smears in the RCC group frequently presented megaloblastoid changes in cells of erythroid lineage and the pseudo-Pelger-Huet anomaly in those of myeloid lineage. Dysplastic changes in the megakaryocytic lineage were rare. The median ages were 9, 9 and 11 years in the AA, AA-RCC borderline and RCC groups, respectively. The AA group included most of the patients with hepatitis-associated AA and those with very severe AA. On the other hand, 6 (9%), 7 (16%) and 11 (35%) patients in the RCC group had very severe, severe and with non-severe disease, respectively. Four patients in the AA group developed new chromosomal abnormalities: trisomy 8 (n = 2) and monosomy 7 (n = 2). Two patients with monosomy 7 progressed to acute myeloid leukemia (AML). Three patients in the RCC group developed new chromosome abnormalities; 2 had trisomy 8 and 1 had ? X. None of the patients in the RCC group developed MDS or AML. The response rates for immunosuppressive therapy with cyclosporine and antithymocyte globulin were 55%, 50% and 67% in the AA, AA-RCC borderline and RCC groups, respectively. To determine whether the two diseases are truly different entities, response rates to immunosuppressive therapy, the frequency of clonal evolution and the genetic background should be prospectively compared between AA and RCC in a larger patient cohort. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Interphase cytogenetic analysis of in vivo differentiation in the myelodysplasia of Down syndrome

Blood ◽  
1994 ◽  
Vol 84 (7) ◽  
pp. 2278-2282 ◽  
Author(s):  
A Zipursky ◽  
H Wang ◽  
EJ Brown ◽  
J Squire
Keyword(s):  
Down Syndrome ◽  
Chromosomal Abnormalities ◽  
Chromosome 8 ◽  
Chromosome 7 ◽  
Leukemic Cells ◽  
Trisomy 8 ◽  
Monosomy 7 ◽  
Megakaryoblastic Leukemia

Abstract In Down syndrome, acute megakaryoblastic leukemia (AMKL) occurs frequently during the first 4 years of life and is usually preceded by a period of myelodysplasia (MDS), often associated with chromosomal abnormalities. Archival peripheral blood and/or bone marrow films of six patients with Down syndrome and MDS whose leukemic cells contained monosomy 7 or trisomy 8 were studied to determine whether the abnormal precursors produce mature cells in vivo. Using fluorescence in situ hybridization (FISH) of interphase nuclei with chromosome-specific centromere probes for either chromosome 7 or 8, we were able to determine which cells had one, two, or three signals indicative of one, two, or three no. 7 or 8 chromosomes. In five patients with trisomy 8, 80% to 100% (94.5% +/- 6.2%) of the megakaryoblasts had three signals using a chromosome 8 probe; in one patient with monosomy 7, 96.5% of the megakaryoblasts had one signal using a chromosome 7 probe. In all six patients, the myeloid and lymphoid series did not have evidence of the chromosomal abnormality present in the blasts. In three of five patients with trisomy 8, three signals were observed in 27%, 33%, and 41% of normoblasts, respectively. These data are evidence that the abnormal cell in MDS is a progenitor cell with the potential of forming cells of megakaryocyte and erythroid lineages.

scholarly journals Interphase cytogenetic analysis of in vivo differentiation in the myelodysplasia of Down syndrome

Blood ◽  
1994 ◽  
Vol 84 (7) ◽  
pp. 2278-2282
Author(s):  
A Zipursky ◽  
H Wang ◽  
EJ Brown ◽  
J Squire
Keyword(s):  
Down Syndrome ◽  
Chromosomal Abnormalities ◽  
Chromosome 8 ◽  
Chromosome 7 ◽  
Leukemic Cells ◽  
Trisomy 8 ◽  
Monosomy 7 ◽  
Megakaryoblastic Leukemia

In Down syndrome, acute megakaryoblastic leukemia (AMKL) occurs frequently during the first 4 years of life and is usually preceded by a period of myelodysplasia (MDS), often associated with chromosomal abnormalities. Archival peripheral blood and/or bone marrow films of six patients with Down syndrome and MDS whose leukemic cells contained monosomy 7 or trisomy 8 were studied to determine whether the abnormal precursors produce mature cells in vivo. Using fluorescence in situ hybridization (FISH) of interphase nuclei with chromosome-specific centromere probes for either chromosome 7 or 8, we were able to determine which cells had one, two, or three signals indicative of one, two, or three no. 7 or 8 chromosomes. In five patients with trisomy 8, 80% to 100% (94.5% +/- 6.2%) of the megakaryoblasts had three signals using a chromosome 8 probe; in one patient with monosomy 7, 96.5% of the megakaryoblasts had one signal using a chromosome 7 probe. In all six patients, the myeloid and lymphoid series did not have evidence of the chromosomal abnormality present in the blasts. In three of five patients with trisomy 8, three signals were observed in 27%, 33%, and 41% of normoblasts, respectively. These data are evidence that the abnormal cell in MDS is a progenitor cell with the potential of forming cells of megakaryocyte and erythroid lineages.

scholarly journals Clinico-Hematological and cytogenetic spectrum of adult myelodysplastic syndrome The first retrospective cross-sectional study in Iranian patients

2021 ◽  
Author(s):  
Mostafa Paridar ◽  
Kazem Zibara ◽  
Seyed Esmaeil Ahmadi ◽  
Abbas Khosravi ◽  
Maral Soleymani ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Cross Sectional Study ◽  
Cytogenetic Abnormality ◽  
Sectional Study ◽  
Trisomy 8 ◽  
Cross Sectional ◽  
Iron Storage ◽  
Monosomy 7 ◽  
Female Ratio ◽  
Cytogenetic Abnormalities

Abstract Background Myelodysplastic syndrome (MDS), a heterogeneous group of hematopoietic malignancy, has been shown to present different cytogenetic abnormalities, risk factors, and clinico-hematological features in different populations and geographic areas. Herein, we determined the cytogenetic spectrum and clinico-hematological features of Iranian MDS patients for the first time. Methods This prospective cross-sectional study was conducted on 103 patients with MDS in Ahvaz, southwest of Iran, from 2014 to 2018. Clinical presentations, complete blood counts (CBC), and bone marrow (BM) biopsy samples were assessed. Perls' staining was used to evaluate BM iron storage. The cytogenetic evaluation was performed using the conventional G banding method on the BM. Results Patients’ median age was 62.3 (ranged from 50–76), and the majority were male (72.8%). The most common clinical symptom at the time of admission was fatigue (n = 33) followed by pallor (n = 27). The most common subgroup was MDS-Multi Lineage Dysplasia (MDS-MLD) (n = 38, 36.8%), followed by MDS-Single Lineage Dysplasia (MDS-SLD) (n = 28, 18.4%). A normal karyotype was observed in 59 patients (57.3%), while 44 patients (42.7%) had cytogenetic abnormalities. Trisomy 8 (+ 8) was the most common cytogenetic abnormality (n = 14) followed by dell 17p (n = 9) and monosomy 7 (-7) (n = 7). Twelve patients (11.65 %) were transformed to AML. Conclusion Our data betokened that among our MDS patients, Trisomy 8 is the predominant cytogenetic abnormality, and MDS-MLD and MDS-SLD are the most common of subtypes. Noteworthy, the male: female ratio was slightly higher in Iran than in previous reports from other parts of the world. Our study is the first report of the clinical, hematological, and cytogenetic spectrum of MDS patients in Iran

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