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.

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

scholarly journals Refractory anemia with ringed sideroblasts associated with marked thrombocytosis harbors JAK2 mutation and shows overlapping myeloproliferative and myelodysplastic features

Leukemia ◽  
2006 ◽  
Vol 20 (9) ◽  
pp. 1641-1644 ◽  
Author(s):  
S A Wang ◽  
R P Hasserjian ◽  
J M Loew ◽  
E V Sechman ◽  
D Jones ◽  
...  
Keyword(s):  
Refractory Anemia ◽  
Jak2 Mutation ◽  
Ringed Sideroblasts

Clinical significance of HFE gene mutations in patients with refractory anemia with ring sideroblasts (RARS).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e18556-e18556
Author(s):  
Rama Nanah ◽  
Mrinal Patnaik ◽  
Naseema Gangat ◽  
Darci Zblewski ◽  
Rong He ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Hereditary Hemochromatosis ◽  
Gene Mutations ◽  
Refractory Anemia ◽  
Heterozygous Mutation ◽  
Hfe Gene ◽  
C282y Mutation ◽  
H63d Mutation ◽  
Ring Sideroblasts ◽  
Hfe Gene Mutations

e18556 Background: RARS is a subtype of myelodysplastic syndromes (MDS) defined by < 5% blasts and ≥15% ring sideroblasts (WHO 2008). Hereditary hemochromatosis is a disorder characterized by dysregulations in iron absorption, largely associated with C282Y and H63D mutations of the HFE gene. Iron levels are elevated in both disorders and pathophysiologic correlations were suggested. HFE gene mutations were previously found higher in MDS compared to controls (50% vs 36%) ( Nearman et al, Am J Hematol 2007). Methods: A total of 168 RARS patients’ data from 1994 to 2015 at Mayo Clinic were reviewed after appropriate IRB approval was obtained. All cases had their bone marrow slides reviewed at our center. We searched patients’ records retrospectively to Identify those tested for HFE gene (C282Y, H62D, S65C) mutations, done inside or outside our institution. Survival estimates were calculated using Kaplan-Meier curves. Results: Out of the 168 RARS patients, only 17 (10%) were tested for HFE gene mutations. Out of the 17 tested, 11 (65%) were found to have mutations; 2 of which (18%) had homozygous H63D mutation, 1 patient (9%) had double heterozygous H63D and C282Y mutations, 5 (45%) had only one H36D heterozygous mutation vs 3 patients (27%) with only one C282Y heterozygous mutation. Only one patient was tested for the additional S65C mutation and it was not detected. H63D mutation was present in a total of 8 patients (73%) vs C282Y mutation which was present in 4 patients (36%). Bone marrow iron stores were increased in all 17 tested patients, except one who had decreased stores, this patient had one heterozygous C282Y mutation. Median overall survival (mOS) was 117 months in the HFE mutated patients vs 75 months in the non-mutated (p = 0.6). Conclusions: Our study found the HFE gene, when tested, to be mutated in higher frequencies among patients with RARS compared to that reported in the general population (65% vs 36%), with H63D mutation in almost three quarters of all mutated patients. Although it did not reach statistical significance, the longer survival observed among HFE mutated patients compared to the wild-type raises the question whether testing for HFE gene mutations among patients with MDS-RARS should be further explored.

Difference in clinical features between Japanese and German patients with refractory anemia in myelodysplastic syndromes

Blood ◽  
2005 ◽  
Vol 106 (8) ◽  
pp. 2633-2640 ◽  
Author(s):  
Akira Matsuda ◽  
Ulrich Germing ◽  
Itsuro Jinnai ◽  
Motohiro Misumi ◽  
Andrea Kuendgen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Clinical Features ◽  
Cumulative Risk ◽  
Japanese Patients ◽  
World Health ◽  
Refractory Anemia ◽  
Ringed Sideroblasts ◽  
Fab Classification ◽  
Health Organization ◽  
French American British

AbstractSeveral reports indicate that there might be differences in clinical features between Asian and Western myelodysplastic syndrome (MDS) cases. We analyzed refractory anemia (RA) in French-American-British (FAB) classification cases diagnosed in Japan and Germany to perform a more exact comparison between Asian and Western MDS types. In the first step, we analyzed agreement of morphologic diagnosis between Japanese and German hematologists. Blood and bone marrow slides of 129 patients diagnosed with FAB-RA, FAB-RA with ringed sideroblasts (RARS), or aplastic anemia were selected randomly and evaluated separately by each group. The agreements of diagnoses according to FAB and World Health Organization (WHO) classifications were 98.4% and 83.8%, respectively. Second, we compared clinical features between 131 Japanese and 597 German patients with FAB-RA. Japanese patients were significantly younger than German patients. Japanese patients had more severe cytopenias. However, prognosis of Japanese patients was significantly more favorable than that of German patients. Japanese patients had a significantly lower cumulative risk of acute leukemia evolution than did German patients. Frequency of WHO-RA in Japanese patients with FAB-RA was significantly higher than that in German patients. In conclusion, our results indicate that the clinical features of Japanese patients with FAB-RA differ from those of German patients.

Refractory Anemia with Ringed Sideroblasts Associated with Marked Thrombocytosis (RARS-t): A Clinicopathological Entity with Questionable Pathogenesis

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5252-5252
Author(s):  
Anupma Nayak ◽  
Abha Goyal ◽  
Judith Brody ◽  
Peihong Hsu ◽  
Steven Savona ◽  
...  
Keyword(s):  
Expression Profiles ◽  
Normal Karyotype ◽  
Jak2 V617f ◽  
Clinicopathological Features ◽  
Jak2 V617f Mutation ◽  
Refractory Anemia ◽  
Simultaneous Occurrence ◽  
Jak2 Mutation ◽  
Ringed Sideroblasts ◽  
V617f Mutation

Abstract Refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-t) is a clinicopathological entity with features of both myelodysplastic syndrome and myeloproliferative disorder. The cases of RARS-t reported in literature are few and do not confirm whether this disease represents a variant of Refractory anemia with ringed sideroblasts (RARS), a variant of Essential Thrombocythemia (ET), or the simultaneous occurrence of two separate disorders (RARS and ET). Because of this ambiguity, RARS-t has been assigned to MDS/MPD- Unclassifiable subcategory as a provisional entity in the WHO (2001) classification. Recent studies have demonstrated association of RARS-t with JAK2 V617F mutation in up to 67% of cases, suggesting its proximity to MPD. In a few studies, presence of JAK2 mutation was related with better prognosis. Based on this evidence, there are chances that this provisional entity may be clubbed with the group of MPD disorders in the revised WHO classification. We present here 4 cases of RARS-t diagnosed within a period of 1 year (2007–2008) at our institution. Clinicopathological features of these cases are mentioned in the attached table (Table-1). Two of these cases were not associated with anemia at the time of presentation, however could be diagnosed as RARS-t based on the presence of dyserythropoetic features and &gt;15% ringed sideroblasts in marrow on iron stains. Other causes of reactive ring sideroblasts and thrombocytosis were ruled out in these cases. 2/4 cases were positive for JAK2 V617F mutation, however no correlation was found between the JAK2 positivity and the clinicopathological features including prognosis. All the 4 patients were given hydroxyurea and pyridoxine therapy. In contrast to other studies, one of our JAK2 positive cases had to be maintained on the transfusion support alone due to the multiple treatment failures. Our data adds to the literature supporting the association of RARS-t with JAK2 mutation. However, we do not agree with the notion that JAK2 positivity renders a better prognosis. Also, lack of any correlation of clinicopathological features in our cases with the JAK2 mutation drives us to think that it might be only a secondary association rather a primary pathogenesis event. Review of the literature reminds us that the pathogenetic events resulting in myelodysplastic component of this overlap syndrome have only been rarely addressed. In future, more studies focusing on the mutations responsible for genesis of ringed sideroblasts such as ALAS2, ABCB7, FECH and gene expression profiles of bone marrow progenitor cells are required for better understanding of this common but under reported entity. Table 1 Case Age Sex Hb. (g/dL) Hct. MCV (fL) RS% Platelet (× 109/L) WBC (× 109/L) JAK2mutation Other cytogenetics Fibrosis Organomegaly Case#1 84 F 12.9 38.9 94.6 &gt;15% 709 8.3 Negative normal karyotype 1+ reticulin Absent Case#2 85 M 10.3 28.3 131 &gt;15% 1072 7.2 Negative normal karyotype 1+ reticulin Absent Case#3 68 M 6.9 25 101.3 &gt;15% 634 5.4 Positive normal karyotype 1+ reticulin Absent Case#4 63 M 13.7 41.5 78.7 &gt;15% 1272 17.7 Positive normal karyotype 1+reticulin Absent

Myelodysplastic Syndromes in Adults - Preliminary Results From the First, Retrospective, Multicenter Brazilian Registry.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4841-4841
Author(s):  
Silvia M.M. Magalhães ◽  
Rosane Bittencourt ◽  
Elvira Velloso ◽  
Maria de Lourdes Chauffaille ◽  
Alita Andrade Azevedo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Clinical Features ◽  
Myelodysplastic Syndromes ◽  
Tertiary Care ◽  
Incidence Rates ◽  
Low Risk ◽  
Refractory Anemia ◽  
Survival Curves ◽  
Fab Classification

Abstract Abstract 4841 Myelodysplastic syndromes (MDS) are a group of acquired clonal stem cell disorders that mainly affect the elderly population, characterized by ineffective hematopoiesis and high risk of leukemic transformation. MDS are heterogeneous in terms of morphology, clinical features and survival. An increasing body of work reveals that there might be differences in clinical features between Asian and Western cases. Japanese patients seem to be younger, have a lower frequency of refractory anemia (RA) with ringed sideroblast (RARS) and a higher frequency of RA, according to FAB classification, as well as different prognostic factors such as the frequency of cytogenetic abnormalities. Incidence rates for MDS in Brazil are unavailable. The purpose of the study was to obtain epidemiological data of MDS adult patients who presented from January 2003 to December 2007 in 10 Brazilian tertiary-care hematology centers from different regions of the country. Patient data collected by participating physicians were entered and stored with the use of an internet-based, data collection tool. Blood counts, bone marrow aspiration, trephine biopsy and chromosomal study were recorded. Survival was estimated through Kaplan-Meier method and the difference between survival curves was assessed by means of Log-Rank Test. Death incidence rates were estimated and compared. Statistical analyses of relevant variables were performed. Three hundred and forty three patients with diagnosis of MDS according to FAB/WHO classification were included in this retrospective analysis. The mean age at presentation was 68 years (range 17 to 98). Fifty percent of cases were male. Cigarette smoking, alcohol abuse and pesticide/herbicide exposure were reported in 33.5%, 13.4% and 14.3% respectively. Median hemoglobin was 8.7 g/dL, median neutrophils count was 1,575/mm3 and median platelets count was 97,000/mm3. There was no excess of blasts in 68.4% of cases. Bone marrow biopsy was performed in 78.5% of patients. Lymphoid nodules were seen in 11.3% and any degree of fibrosis in 28.6%. Cytogenetic analysis was performed in 67.8% of cases and showed chromosomal abnormalities in 50.5%. The del(5q) isolated or combined with other alterations were observed in 6.0%. Flow cytometry analysis for CD55 and CD59 was performed in 11,3% and was normal in 97,4%. Near 8% of cases were classified as secondary MDS. The distribution of disease subtypes according to FAB classification was: RA 42,3%, RARS 9,0%, RA with excess of blasts (RAEB) 20,7%, RAEB-t 4,2% and chronic myelomonocytic leukemia (CMML) 3,9%. According to IPSS patients were stratified as low-risk (low risk plus intermediate I) 55,9% and high risk (intermediate II and high risk) 13,1%. In 30,1% no stratification was possible. In 26,5% of cases iron overload was diagnosed although only 28,3% of cases had performed serum ferritin. The follow-up time ranged from 1 to 78 months (mean: 28 months). Thirty-six percent of patients died and the death was MDS-related in 68.3% of cases. The high and low risk survival curves were significantly different (p<0,001), and, the death incidence rate (per 1000 person.month) was 8,7 (95% CI: 6,6-11,4) and 29,1 (95% CI: 19,5-43,4) for the low and high-risk group respectively. This clinical registry of adult Brazilian MDS patients represents a unique opportunity to gain insight about these disorders and its demographic and clinical features and provide an important baseline for future studies. Disclosures No relevant conflicts of interest to declare.

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.

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