Myelodysplastic syndromes: prognostic significance of multilineage dysplasia in patients with refractory anemia or refractory anemia with ringed sideroblasts

Blood ◽  
2002 ◽  
Vol 99 (10) ◽  
pp. 3870-3872 ◽  
Author(s):  
Scott M. Dunkley ◽  
Arumugam Manoharan ◽  
Yiu Lam Kwan
Keyword(s):  
Myelodysplastic Syndromes ◽  
Prognostic Significance ◽  
Refractory Anemia ◽  
Ringed Sideroblasts ◽  
Multilineage Dysplasia

Prevalence and prognostic significance of allelic imbalance by single-nucleotide polymorphism analysis in low-risk myelodysplastic syndromes

Blood ◽  
2007 ◽  
Vol 110 (9) ◽  
pp. 3365-3373 ◽  
Author(s):  
Azim Mohamedali ◽  
Joop Gäken ◽  
Natalie A. Twine ◽  
Wendy Ingram ◽  
Nigel Westwood ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Prognostic Significance ◽  
Low Risk ◽  
Refractory Anemia ◽  
Polymorphism Analysis ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Ringed Sideroblasts ◽  
Multilineage Dysplasia ◽  
Normal Cytogenetics

Abstract Low-risk myelodysplastic syndrome (MDS) with normal cytogenetics accounts for approximately 50% of MDS patients. There are no pathognomonic markers in these cases and the diagnosis rests on cytomorphologic abnormalities in bone marrow and/or peripheral blood. Affymetrix high-resolution single-nucleotide polymorphism (SNP) genotyping microarrays allow detection of cytogenetically cryptic genomic aberrations. We have studied 119 low-risk MDS patients (refractory anemia [RA] = 22; refractory cytopenia with multilineage dysplasia [RCMD] = 51; refractory anemia with ringed sideroblasts [RARS] = 12; refractory cytopenia with multilineage dysplasia with ringed sideroblasts [RCMD-RS] = 12; 5q− syndrome = 16; refractory anemia with excess blasts [RAEB] = 6) using SNP microarrays to seek chromosomal markers undetected by conventional cytogenetics. Loss of heterozygosity (LOH) detected by 50K arrays was verified using 250K and 500K arrays. We demonstrate the presence of uniparental disomy (UPD) in 46%, deletions in 10%, and amplifications in 8% of cases. Copy number (CN) changes were acquired, whereas UPDs were also detected in constitutional DNA. UPD on 4q was identified in 25% of RARS, 12% of RCMD with normal cytogenetics, 17% of RAEB, and 6% of 5q− syndrome cases. Univariate analysis showed deletions (P = .04) and International Prognostic Scoring System (IPSS; P < .001) scores correlated with overall survival; however, on multivariate analysis only IPSS scores retained prognostic significance (P < .001). We show, for the first time, that SNP microarray analysis in low-risk MDS patients reveals hitherto unrecognized UPD and CN changes that may allow stratification of these patients for early therapeutic interventions.

Validation Of a Multi-Diagnostic Approach Including Flow Cytometry To Identify Specific Risk Categories Within Low and Intermediate-1 Risk Myelodysplastic Syndromes Within a Prospective Clinical Trial: A Study On Behalf Of The HOVON89 Study Group

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1521-1521
Author(s):  
Eline M.P. Cremers ◽  
Theresia M. Westers ◽  
Canan Alhan ◽  
Claudia Cali ◽  
Heleen A. Visser-Wisselaar ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Scoring Systems ◽  
Diagnostic Approach ◽  
Refractory Anemia ◽  
Genomic Profiling ◽  
Intermediate Risk ◽  
Ringed Sideroblasts ◽  
Multilineage Dysplasia ◽  
Risk Categories ◽  
Good Risk

Abstract Myelodysplastic syndromes (MDS) constitute a heterogeneous group of hematopoietic stem cell disorders, characterized by ineffective hematopoiesis resulting in cytopenias and variable risk of acute myeloid leukemia (AML). To make an accurate distinction between specific risk categories in MDS, especially in low and intermediate risk MDS, a multi-diagnostic approach is recommended. To verify the efficacy of multiple diagnostic tools in MDS we used the HOVON89 study-cohort (a prospective phase II randomized multicenter study to assess the efficacy of lenalidomide with or without erythropoietin and granulocyte-colony stimulating factor in patients with low-intermediate-1 risk MDS; trial registered at www.trialregister.nl as NTR1825; EudraCT nr.: 2008-002195-10. Inclusion target of the study is 200 low/intermediate-1 risk MDS patients (134 enrolled, inclusion ongoing). We collect data on cytomorphology (CM), conventional cytogenetics (CCG), fluorescence in situ hybridization (FISH) and microarray-based genomic profiling. In addition, we performed flow cytometric (FC) analysis according to European LeukemiaNet guidelines (Van de Loosdrecht et al., Haematologica 2009 and Leukemia 2012). Current CM results (N=98) identified: 8 refractory anemia (RA); 16 refractory anemia with ringed sideroblasts (RARS); 43 refractory cytopenia with multilineage dysplasia with/without ringed sideroblasts (RCMD/RCMD-RS); 16 refractory anemia with excess blast-1 (RAEB-1), 5 chronic myelomonocytic leukemia-1 (CMML-1) and 10 patients with isolated del(5q). CCG analysis (N=101) indicated 2 very good risk, 84 good risk, 13 intermediate risk and 2 poor risk patients according to the IPSS-R risk categories (Greenberg et al., Blood 2012). In addition, interphase FISH analysis (N=72) was normal in 15 patients, in 6 patients the del(5q) was confirmed. From 68 MDS patients data from both CCG and microarray were available. Microarray-based genomic profiling identified genomic abnormalities such as copy neutral loss of heterozygosity and small (<5 Mb) copy number alterations coinciding with a cancer gene in 13 patients with normal CCG. As expected in one patient the balanced translocation t(3;3)(q21;q26) was not identified by microarray-based genomic profiling. FC analysis (N=82) evaluated aberrancies with regard to count, marker expression level and lineage infidelity marker expression on myeloid progenitors, B cell progenitors, maturing myeloid/monocytic and erythroid cells. Current, validated FC-scoring systems identified 60/81 (Della Porta et al., Haematologica 2012) and 61/81 (Wells et al., Blood 2003) patients with MDS. Both scoring systems do not evaluate dyserytropoiesis and dysmegakaropoiesis, thereby possibly not recognizing RA, RARS or RCMD patients with only dyserytropoiesis and dysmegakaropoiesis. We integrated both scoring systems into one score (Van de Loosdrecht et al., Leukemia 2012, and JNCCN 2013). Patients were divided into 3 categories: not likely MDS (A), signs of dysmyelopoiesis (B) and fitting MDS (C). This score diagnosed 69/78 patients as probably or likely MDS by FC (B or C, figure 1). Remarkably, patients scored as ‘category A’ only displayed dyserytropoiesis and/or dysmegakaryopoiesis by CM. FC identified dyserytropoiesis in these patients, however, a consensus erytroid flow score is not yet validated. In addition, FC identified different risk categories within the patient group with no genetic abnormalities (based on CCG, FISH and microarray-based genomic profiling; data not shown). In conclusion, this is the first prospective study in low/int-1 risk MDS that validates FC as a valuable diagnostic tool in MDS (sensitivity of FC in this cohort: 88%). FC only failed to recognize some patients with only dyserytropoiesis and dysmegakaryopoiesis by CM, not evaluated by the current scoring system. Thirteen patients with unilineage dysplasia by CM had multilineage dysplasia by FC. We postulate that RA/RARS patients with multi-lineage dysplasia by FC may have clinical features of RCMD patients and therefore a higher risk on transformation to AML. Clinical follow-up data are expected within 1.5 year. In near future, a multi-diagnostic approach may i) identify risk categories within well defined IPSS-R subgroups, ii) predict risk on transformation and iii) select patients who might benefit from new emerging drugs for low-int-1 risk MDS. Disclosures: No relevant conflicts of interest to declare.

Hemochromatois-Associated Gene Mutations in Patients with Myelodysplastic Syndromes with Refractory Anemia and Ringed Sideroblasts.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1541-1541
Author(s):  
Zachary P. Nearman ◽  
Bianca Serio ◽  
Hadrian Szpurka ◽  
Ilka Warshawsky ◽  
Alan Lichtin ◽  
...  
Keyword(s):  
Clinical Features ◽  
Myelodysplastic Syndromes ◽  
Phenotypic Variability ◽  
Gene Mutations ◽  
Differential Susceptibility ◽  
Control Population ◽  
Refractory Anemia ◽  
Hfe Gene ◽  
Jak2 Mutation ◽  
Ringed Sideroblasts

Abstract Complex interaction between a multitude of genetic variants may be responsible for differential susceptibility to specific diseases, and be responsible for phenotypic variability and heterogeneity of clinical presentations. Such a variability in clinical features confounded for many years investigations into the pathogenesis of myelodysplastic syndromes (MDS). We made a curious observation of increased ferritin levels in some newly diagnosed patients with MDS RARS (refractory anemia with ringed sideroblasts) in whom transfusional iron-overload was unlikely due to very low transfusion burden. Hence, we hypothesized that RARS patients may harbor hemochromatosis-related mutations, which could contribute to the pathophysiology of this particular subset of MDS. We studied a cohort of 109 MDS patients; 42 with RARS, and 67 with other forms of MDS (18 RA, 12 RAEB, 7 RAEB-T, 1 CMML, and 29 MDS/MPD overlap). All patients were genotyped using restriction fragment length polymorphism (RFLP) method, designed to detect presence of C282Y and H63D mutations of the HFE gene. We found significantly higher frequency of heterozygozity for the C282Y mutation in 21% of RARS patients (vs 9% in control population, n=2016, p= 0.017) while H63D genotype was not increased. The possible pathogenic role of this finding in RARS was supported by the normal distribution of mutant HFE alleles in patients with other forms of MDS (5% vs. 9%, p =0.35). Interestingly, 3/7 patients with RA not fulfilling the RARS criteria, but having increased numbers of ringed sideroblasts (<15%) also showed heterozygozity for either C282Y or H63D allele. To correlate the presence of C282Y allele with clinical features of RARS patients, we have performed a subset analysis. Within this group we have included patients with a rather nebulous and rare form of MDS, provisionally subclassified by WHO as RARS with thrombocytosis (RARSt); 7 of these patients (n=10) were found to have either C282Y or H63D allele resulting in a frequency of 30% and 40% of C282Y or H63D allele, respectively. The combined prevalence of either of these alleles in the control population is 33% (vs. 70% in RARSt, p=.01). Previously, we have demonstrated that RARSt patients are characterized by a high prevalence of the V617F JAK2 mutation (Szpurka et al, Blood 2006) suggestive of the pathophysiologic derivation of this syndrome from MPD rather than MDS. Consequently, we have tested the frequency of HFE gene variants associated with hemochromatosis in patients with MPD and Jak2 mutations. Of note is that patients with RARS harbored more C282Y alleles than those with other forms of MDS or MPD with Jak2 mutation (except for those with RARSt; (21% vs 5% and 3%, p =0.036 and .012, respectively). We conclude that hemochromatosis associated mutations may contribute to the pathogenesis of RARS. In patients with MPD and Jak2 mutation, concomitant presence of hemachromatosis-predisposing HFE variants may result in the unusual presentation associated with ringed sideroblasts.

Prognostic Significance of WT1 mRNA and Anti-WT1 Antibody Levels in Peripheral Blood in Patients with Myelodysplastic Syndromes.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3821-3821
Author(s):  
Hideto Tamura ◽  
Kazuo Dan ◽  
Norio Yokose ◽  
Rika Iwakiri ◽  
Masatsugu Ohta ◽  
...  
Keyword(s):  
Immune Response ◽  
Mrna Expression ◽  
Myelodysplastic Syndromes ◽  
Peripheral Blood ◽  
Quantitative Polymerase Chain Reaction ◽  
Mrna Level ◽  
Prognostic Significance ◽  
Refractory Anemia ◽  
Mrna Levels ◽  
Disease Subtype

Abstract Abstract 3821 Poster Board III-757 (INTRODUCTION) The Wilms tumor gene (WT1) message is overexpressed in tumor cells from various solid cancers as well as hematologic malignancies including myelodysplastic syndromes (MDS). We reported previously that WT1 mRNA expression in peripheral blood mononuclear cells (PBMCs) as well as bone marrow (BM) cells increased with the aggressiveness of MDS disease subtype as defined by the French-American-British (FAB) classification and that a humoral immune response, IgG- or IgM-type anti-WT1 antibody (Ab) expression, was detected in sera from most MDS patients. In this study, we investigated whether WT1 mRNA expression and anti-WT1 Ab titers in PB were associated with prognosis in MDS patients by examining their long-term follow-up data. (METHODS AND RESULTS) (1) WT1 mRNA expression in PBMCs was examined in 80 patients: 35 with refractory anemia (RA); 5 with RA with ringed sideroblasts (RARS); 24 with RA with excess blasts (RAEB); 5 with RAEB in transformation (RAEB-t); and 11 with acute myeloid leukemia transformed from MDS (AML-MDS). Levels of WT1 mRNA expression were assessed using the real-time quantitative polymerase chain reaction [Tamaki H, et al, Leukemia 1999]. WT1 mRNA levels increased with the aggressiveness of disease subtype (mean: RA, 220.9; RARS, 129.4; RAEB, 5,554.3; RAEB-t, 14,284.0; AML-MDS, 56,272.7 copies/μg) and with the aggressiveness of the International Prognostic Scoring System (IPSS) category (mean: low, 114.5; intermediate-1, 360.8; intermediate-2, 12,041.6; high, 7,357.9 copies/μg) in these patients. (2) IgG- and IgM-type anti-WT1 Ab titers were determined using the dot-blot assay [Elisseeva OA, Blood 2002] in sera from 45 of the 80 patients: 15 RA; 3 RARS; 18 RAEB; 3 RAEB-t; and 6 AML-MDS. IgM and IgG WT1 Abs were detected in 31 (79.5%) and 34 (87.2%) MDS patients, and 5 (83.3%) and 6 (100%) AML-MDS patients, respectively. WT1 Abs levels were not correlated with FAB subtype, IPSS, or WT1 mRNA expression in PBMCs. (3) When patients were divided into three groups based on the WT1 mRNA level (fewer than 100 copies/μg, 100 to 10,000 copies/μg, and more than 10,000 copies/μg), their survival rates differed significantly (P = 0.0186): survival was worse in those with increased WT1 mRNA levels. Specifically, a high WT1 mRNA level was a strong predictor of rapid AML transformation even if adjusted by the IPSS (P = 0.0005). Furthermore, patients with high levels of either IgM or IgG WT1 Abs had significantly better survival compared with those whose IgM and IgG WT1 Abs values were both low (P = 0.0007) even when adjusted by the IPSS (P = 0.0019). (CONCLUSIONS) This study showed for the first time that high WT1 mRNA expression and high WT1 Ab titers in PB affected the prognosis of MDS patients negatively and positively, respectively, suggesting that an optimal immune response against WT1 may beneficial. Recently, clinical trials of WT1 peptide-based immunotherapy have been conducted for various malignancies including MDS. Our data presented here may provide a rationale for anti-WT1 immunotherapy in MDS. Disclosures: No relevant conflicts of interest to declare.

scholarly journals SF3B1 mutations are prevalent in myelodysplastic syndromes with ring sideroblasts but do not hold independent prognostic value

Blood ◽  
2012 ◽  
Vol 119 (2) ◽  
pp. 569-572 ◽  
Author(s):  
Mrinal M. Patnaik ◽  
Terra L. Lasho ◽  
Janice M. Hodnefield ◽  
Ryan A. Knudson ◽  
Rhett P. Ketterling ◽  
...  
Keyword(s):  
World Health Organization ◽  
Myelodysplastic Syndromes ◽  
Prognostic Value ◽  
Univariate Analysis ◽  
World Health ◽  
Refractory Anemia ◽  
Multilineage Dysplasia ◽  
Ring Sideroblasts ◽  
Health Organization ◽  
Risk Categorization

SF3B1 mutations were recently reported in myelodysplastic syndromes (MDSs), especially in the presence of ring sideroblasts (RSs). We sought to define the interaction between SF3B1 mutations, morphology, karyotype, and prognosis in MDS with more than or equal to 15% RS (MDS-RS). We studied 107 patients with MDS-RS, including 48 with refractory anemia with RS (RARS), 43 with refractory cytopenia with multilineage dysplasia (RCMD)-RS, 11 with refractory anemia with excess blasts-1 (RAEB1)–RS, and 5 with RAEB2-RS. SF3B1 mutations were detected in 53 (∼ 50%) patients: 35 RARS (73%), 16 RCMD-RS (37%), and 2 RAEB1-RS (18%). In univariate analysis, the presence of SF3B1 mutations was associated with better overall (P < .01) and leukemia-free (P < .01) survival; however, in both instances, significance was completely accounted for by World Health Organization morphologic risk categorization. In other words, when RARS and RCMD-RS were analyzed separately, there was no additional prognostic value from the presence or absence of SF3B1 mutations.

scholarly journals Hemochromatosis-associated gene mutations in patients with myelodysplastic syndromes with refractory anemia with ringed sideroblasts

2007 ◽  
Vol 82 (12) ◽  
pp. 1076-1079 ◽  
Author(s):  
Zachary P. Nearman ◽  
Hadrian Szpurka ◽  
Bianca Serio ◽  
Ilka Warshawksy ◽  
Karl Theil ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Gene Mutations ◽  
Refractory Anemia ◽  
Ringed Sideroblasts

Increased Bone Marrow Erythroid Precursors Is Associated with Shorter Survival in Low-Grade Myelodysplastic Syndromes.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2371-2371
Author(s):  
Hesham M. Amin ◽  
Sherry A. Pierce ◽  
Hagop M. Kantarjian ◽  
Michael J. Keating ◽  
Emil J. Freireich ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndromes ◽  
Prognostic Significance ◽  
Refractory Anemia ◽  
International Prognostic Scoring System ◽  
Low Grade ◽  
Nucleated Red Blood Cells ◽  
Erythroid Precursors ◽  
History Of

Abstract According to the FAB and WHO classifications, the diagnosis of acute erythroid leukemia is based on the numbers of nucleated red blood cells and myeloid blasts in the bone marrow. The WHO classification recognizes two types of acute erythroid leukemia; M6A with 51–80% erythroid precursors and with 20% or more of the non-erythroid precursors being myeloid blasts; and M6B with more than 80% of the nucleated cells in the bone marrow consisting of erythroid precursors, regardless of the percentage of the myeloid blasts. Previous studies have shown that many cases of acute erythroid leukemia arise in patients with a history of myelodysplastic syndrome and in other cases acute erythroid leukemia is associated with significant dysplastic features. The significance of the number of erythroid precursors is not well known in the myelodysplastic syndromes. In the present study, we included 617 consecutive patients with low-grade myelodysplasia (482 patients with refractory anemia [RA] and 135 patients with refractory anemia with ringed sideroblasts [RARS]). Among this group, 82 patients with 50% or more of erythroid precursors had shorter survival compared with 535 patients with less than 50% erythroid precursors (P &lt; .01; Figure 1). The shorter survival in those with 50% or more of erythroid precursors may reflect the tendency of these patients to have worse International Prognostic Scoring System (IPSS) scores. Thus, among the patients with less than 50% erythroid precursors and primary MDS, 35% were IPSS low, 52% IPSS intermediate 1, and 13% IPSS intermediate 2. For the patients with 50% or more of erythroid precursors, the corresponding proportions were 14%, 57%, and 29%, respectively (P &lt; .001). As a result of the association between IPSS and the percentage of erythroid precursors, the percentage of erythroid precursors had no effect on survival within individual IPSS groups. Similarly, the percentage of erythroid precursors had no prognostic significance in patients with refractory anemia with excess blasts (RAEB) or chronic myelomonocytic leukemia (CMML). Our findings demonstrate that in low-grade dysplasia (RA and RARS) the number of erythroid precursors may represent an important prognostic marker. These findings implicate that the percentage of erythroid precursors should be considered in the classification of the low-grade myelodysplastic syndromes. A multivariate analysis will be performed to ascertain the relative effects of IPSS score and the percentage of erythroid precursors on prognosis in patients with low-grade myelodysplasia. Figure Figure

The WHO classification of MDS does make a difference

Blood ◽  
2004 ◽  
Vol 103 (9) ◽  
pp. 3265-3270 ◽  
Author(s):  
Robert B. Howe ◽  
Anna Porwit-MacDonald ◽  
Robert Wanat ◽  
Ramin Tehranchi ◽  
Eva Hellström-Lindberg
Keyword(s):  
Median Survival ◽  
Who Classification ◽  
Therapeutic Response ◽  
World Health ◽  
Refractory Anemia ◽  
Ringed Sideroblasts ◽  
Additional Information ◽  
Multilineage Dysplasia ◽  
Health Organization

Abstract The purpose of this study was to determine the facility and reliability of the World Health Organization (WHO) classification of myelodysplastic syndromes (MDSs) with several observers reviewing the same diagnostic specimens. We also wanted to determine if the WHO classification provided additional information about predictability of clinical response outcome. To accomplish these goals we reviewed 103 previously diagnosed cases of low-risk MDS. We found 92% interobserver agreement (P &lt; .001). Sixty-four of these patients had been entered into clinical trials using growth factors by the Nordic MDS Study Group. The WHO classification reliably predicted therapeutic response to the combination of granulocyte colony-stimulating factor (G-CSF) and erythropoietin (Epo). The response rate differed significantly between refractory anemia with ringed sideroblasts (RARS) and refractory anemia with multilineage dysplasia and ringed sideroblasts (RCMD/RS) with regard to therapeutic response (75% versus 9%; P = .003). Also, in the group of patients with less than 5% marrow blasts, there was a difference in median survival between patients with unilineage dysplasia (51% surviving at 67 months) and those with multilineage dysplasia (median survival, 28.5 months; P = .03). (Blood. 2004;103:3265-3270)

Sign in / Sign up

Export Citation Format

Share Document