The myelodysplastic syndromes: diagnosis, molecular biology and risk assessment

Myelodysplastic syndromes (MDS) are heterogeneous group of neoplastic clonal stem cell diseases characterized by dysplastic morphological features and clinical bone marrow failure. The FAB (French-American-British) system served as the gold standard for MDS classification for more than two decades. The WHO classification, built on the backbone of FAB classification, is an attempt to further improve the prognostic value of MDS classification as well as establish its clinical utility as a tool to select different treatments. In this article we review the epidemiology, pathogenesis, molecular biology, diagnosis and classification of MDS. We highlight the major differences between the FAB classification and the WHO MDS classification. We discuss in more detail the experience of using the new WHO classification since its publication and review the studies that tried to validate the prognostic value of the new classification or apply it to predict clinical responses to various treatments.     

Myelodysplastic syndromes according to FAB and WHO classification. Single center experience

The results of clinical and laboratory observations of 119 MDS patients divided acc. to FAB, and - after excluding RAEB-t and CMML groups -- of 95 patients divided accordingly to WHO classification are presented. The diagnosis of MDS was based on medical interview, physical examination, blood biochemistry, peripheral blood (PB) and bone marrow (BM) cytomorphology and cytochemistry, trephine biopsy and cytogenetic examination. All hematologic examinations were done according to routine methods. Cytogenetic analyses were carried out on BM cells from 24-48 h cultures in standard conditions. At least 15-20 GTG-banded metaphases were analyzed in every patient. The survival time (ST) of patients differed significantly between the FAB or WHO groups, with p=0.0004 for FAB and p=0.02 for WHO. The progression to AML was more common in less favorable groups, with p=0.0001 for FAB and p=0.00016 for WHO. The distribution of IPSS prognostic index among the groups showed statistically significant difference (p=0.0004 for FAB, and p=0.0001 for WHO), whereas the distribution of karyotypic abnormalities did not. However, in univariate analysis statistically significant influence on ST showed, beside the both classification systems: cytogenetics, the presence of blasts in PB, age and IPSS index. In multivariate analysis the sole independent prognostic factors were: PB blasts and cytogenetics. The authors conclude that the WHO classification offers a good prognostic tool for MDS patients. However, the karyotype and the presence of blasts in PB should always be taken into account.     

The myelodysplastic syndromes: predictive value of eight prognostic systems in 143 cases from a single institution

BACKGROUND AND OBJECTIVE: Despite the fact that several prognostic systems for myelodysplastic syndromes (MDS) have been proposed, few studies have been designed to test their effectiveness in independent patient populations. The aim of this study was to compare the prognostic value of 8 previously described prognostic systems in a series of consecutive MDS patients observed at a single institution over a 10-year period. DESIGN AND METHODS: One hundred and forty-three patients were diagnosed as having myelodysplastic syndrome (MDS) according to the French-American-British (FAB) criteria. They were studied retrospectively in order to assess the prognostic value of the FAB classification and 7 other prognostic systems. RESULTS: On the basis of data at diagnosis, all investigated systems effectively stratified patients into groups with different life expectancies and identified a subset of patients with poor clinical outcome. However, the systems had different outcomes concerning median survival of patients classified as low-risk, ranging from less than 3 years for the Mufti scoring system to more than 8 years for the FAB classification modified according to Rosati et al. Moreover, patient distribution into different risk categories was quite different with the different prognostic systems. INTERPRETATION AND CONCLUSIONS: When applied to our case series, some of the prognostic systems had a much lower prognostic value than in the patient population from which they derived. This evidence suggests that testing of prognostic systems in independent case series is necessary before using the systems in clinical practice.     

World Health Organization classification in combination with cytogenetic markers improves the prognostic stratification of patients with de novo primary myelodysplastic syndromes

This study correlated chromosomal defects with French-American-British (FAB)/World Health Organization (WHO) classification subtypes, proposed a revised International Prognostic Scoring System (IPSS) cytogenetic grouping; and established which classification, when used with the IPSS cytogenetic categories, best predicted clinical outcome in the myelodysplastic syndromes (MDS). A higher prevalence of chromosomal defects and distinct defects were observed in patients with multi-lineage dysplasia and a blast cell percentage >10%. Abnormalities of the long arm of chromosome 3, del(7)(q31q35), trisomy 8, del(11)(q14q23), del(12p) and 20q- could be segregated from their respective IPSS cytogenetic categories and used to develop new cytogenetic subgroups. Clinical parameters, FAB/WHO classification, IPSS score and standard or revised cytogenetic categories were statistically relevant for overall survival (OS) and progression-free intervals (PFI) and were included within five distinct multivariate models compared by the Akaike Information Criterion. To predict OS, the best models included age, WHO classification and standard or revised IPSS cytogenetic categories; to predict PFI, the best model included the same variables and revised cytogenetic categories. In conclusion, (i) the WHO classification was associated with a more homogeneous cytogenetic pattern than the FAB classification, (ii) WHO classification and standard/revised IPSS cytogenetic categories were much more effective than IPSS for predicting MDS clinical outcome, (iii) revised cytogenetic subgroups predicted PFI more effectively than standard categories.     

Detection of risk groups in myelodysplastic syndromes. A multicenter study.

BACKGROUND AND OBJECTIVES: Myelodysplastic syndromes (MDS) comprise a group of heterogeneous hematologic disorders with risk of leukemic evolution (LE). The French-American-British (FAB) co-operative group classifies them into five morphologic entities and the International Prognostic Scoring System (IPSS) proposes four groups of risk on the basis of clinical and cytogenetic variables. The aim of this study was to evaluate the application of the IPSS in our Argentine population, to test the prognostic value of its variables and to determine whether this score helps to associate prognostic subgroups of risk into FAB subtypes. DESIGN AND METHODS: Two hundred and thirty-four patients with primary MDS and a median follow-up of 28 months were evaluated using univariate analyses to determine median survival (SV) and the time to LE. The variables analyzed were FAB classification, IPSS, percentage of myeloblasts, cytogenetic groups of risk and number of cytopenias. RESULTS: Univariate analyses showed that all variables analyzed were predictive for SV and for LE in our MDS population. Application of the IPSS allowed discrimination into the 4 groups of risk and helped to identify prognostic subclasses among the FAB classification, associating 5%, 15% and 19% of cases with worse prognosis within the FAB classification of refractory anemia (RA), RA with ringed sideroblasts and RA with excess of blasts (RAEB), respectively. The IPSS was not informative for RAEB in transformation cases and would not be applied to patients with chronic myelomonocytic leukemia. INTERPRETATION AND CONCLUSIONS: This score could be applied to our MDS population, showing no geographic differences. Stratification of FAB patients according to IPSS would be helpful to develop risk-adapted therapeutic strategies.     

原发骨髓增生异常综合征患者IPSS及染色体核型的临床分析

目的:比较原发性骨髓增生异常综合征(MDS)患者WHO(2001)分型与FAB分型的IPSS染色体核型分析及预后的相关性分析。方法:经FAB标准确诊的原发MDS的患者重新按WHO标准分型,对2种结果的IPSS及染色体异常与各亚型的关系进行分析。结果:按FAB分型各亚型的IPSS及染色体异常无显著性差异,按WHO分型的难治性细胞减少伴多系增生异常(RCMD)与难治性贫血(RA)患者染色体异常率有统计学意义(66.6%,41.7%,P<0.01),RAEB-2高危组比例明显高于RAEB-1组(25%,0%,P<0.01)。结论:原发MDS的WHO分型与FAB分型相比,前者与预后的相关性更好。     

Prognostic factors in chronic myelodysplastic syndromes: a multivariate analysis in 107 cases

A retrospective multivariate analysis of 37 clinical, biochemical, and hematological data was performed in 107 cases of primary myelodysplastic syndromes (MDS) in order to recognize their prognostic significance. The most important individual variables, isolated in a previous univariate analysis, were placed in a multiple regression modeling procedure to identify major significant prognostic factors. Multivariate analysis tends to identify prognostic variables containing significant independent predictive information. Characteristics were examined on both continuous and binary bases. The FAB classification was the first parameter entered in regression equations on both models, followed by platelet count, hemoglobin level, and circulating erythroblasts in the binary model, and by hemoglobin level, systemic symptoms, platelet count, age, and dyserythropoiesis in the continuous model. Our analysis confirms FAB classification as the main prognostic factor in MDS, supports the previously noted predictive value of platelet count, hemoglobin level, and age, and recognises the importance of circulating erythroblasts, systemic symptoms, and dyserythropoiesis as prognostic characteristics in MDS.     

Myelodysplastic syndromes, from French-American-British to World Health Organization: comparison of classifications on 431 unselected patients from a single institution.

In 1999 a working group of the World Health Organization (WHO) published a revised classification for myelodysplastic syndromes (MDS): RA, RARS, refractory cytopenia with multilineage dysplasia (RC+Dys), RAEB I and II, del (5q) syndrome, and MDS unclassifiable. Chronic myelomonocytic leukemia (CMML) and RAEB-t were excluded. Standard French-American-British (FAB) and new WHO classifications have been compared in a series of patients (n = 431) from a single center, analyzing morphologic, clinical, and cytogenetic data. According to the WHO findings, dysgranulocytopoiesis or dysmegakaryocytopoiesis only were found in 26% of patients with less than 5% medullary blasts. These patients are thus unclassified and should remain in the subgroups RA and RARS. Splitting of heterogeneous RAEB into 2 subgroups according to blast count was supported by a trend to a statistically significant difference in the single-center study population. Patients with CMML whose white blood cell counts are above 13 000/microL may be excluded from the MDS classification, as warranted by WHO, but a redistribution of patients with dysplastic CMML according to medullary blast count leads to more heterogeneity in other WHO subgroups. Although the natural courses of RAEB-T and acute myeloid leukemia (AML) with dysplasia are different, comparable median survival durations after treatment in patients with RAEB-T and AML were in favor of the proposed 20% medullary blast threshold for AML. The homogeneity of subgroups was studied by evaluating prognostic scores. A significant shift into lower IPSS risk groups was evident in the new classification. These data cannot provide evidence for the new WHO proposal, which should not be adopted for routine clinical use at present. Some of its aspects can provide a starting point for further studies involving refined cytogenetics and clinical results.     

骨髓增生异常综合征WHO分型标准的临床应用

目的:分析世界卫生组织(WHO)与法-美-英协作组(FAB)2种标准分型结果的不同点,探讨WHO分型标准临床应用价值.方法:选择179例骨髓增生异常综合征(MDS)患者,其中168例是2003年～2006年确诊的原发性MDS,11例有血细胞减少伴有病态造血的病例.对179例患者按FAB与WHO 2种分型方案重新进行评价.结果:按FAB分型标准:RA 50例,RAS 9例,RAEB 62例,RAEB-T 23例,CMML 24例,11例未明确诊断,只描述了形态学特点.按WHO分型标准:RA 14例,RAS 5例,RCMD 36例,RCMD-RS 4例,MDS-U 5例,6例不能确诊.结论:2种分型方案有较大差异,由于WHO分型中RA只限于贫血, 单纯红系病态造血; 将2系以上血细胞减少,2系以上病态造血,原始细胞<5%的病例归入了WHO新的亚型RCMD.通过本组病例分析:RCMD介于RA与RAEB中间,原始细胞不增多与RA相似,临床症状、实验室检查、血细胞形态学特点与RAEB相似.WHO将RAEB根据原始细胞数量分为两型,RAEB-T归入急性白血病,CMML归入骨髓增殖性疾病中,更符合临床的实际需要,有利于临床医师对治疗方案的选择.WHO分型方案仍需补充、修正、给血液学工作者提供更为完善的诊断标准.     

Clinical, haematological and histomorphological profile of adult myelodysplastic syndrome. Study of 96 cases in a single institute

Myelodysplastic syndromes (MDS) are clonal haematopoietic stem cell disorders characterised by ineffective and dyspoietic haematopoiesis. The natural history of these disorders is variable and ranges from a chronic to a rapid course towards leukaemic progression. Certain shortcomings have been encountered in the French-American-British (FAB) classification over the years, and therefore there is a need for an alternative method of classification. In 1999, the WHO published a revised classification of MDS. In the present study, we have analysed the clinical, haematological and histomorphological features in 96 cases of primary MDS seen in the department of haematology at the All India Institute of Medical Sciences (AIIMS) over a 6-yr period (1996-2001). Both FAB and WHO classifications have been incorporated and the Bournemouth scoring system applied in each case at presentation. The Bournemouth scoring system, in the absence of a cytogenetic study, offers a good prognostication and long-term survival estimate.     

Can t(8;21) oligoblastic leukemia be called a myelodysplastic syndrome?

The new World Health Organization (WHO) classification of hematologic malignancies has incorporated t(8;21) myelodysplastic syndromes (MDS) according to the French-American-British classification into the category of acute myeloid leukemia (AML) with t(8;21)(q22;q22), while our knowledge about clinicopathological features of t(8;21) oligoblastic leukemia is still limited. We present our experience with 12 patients meeting the FAB diagnostic criteria of MDS and having t(8;21), who were compared to 43 t(8;21) AML patients. The MDS and AML patients shared most hematomorphologic, immunophenotypic, and clinical features, whereas the differences lay along myeloid maturation. The MDS patients had higher percentages of circulating neutrophils and marrow myeloid cells beyond promyelocytes than the AML patients. The incidence of Auer rods in mature neutrophils in MDS was significantly higher than that in AML, and furthermore, the neutrophils in MDS more commonly contain t(8;21) than in AML. Our findings support the rationale for the WHO classification, and future studies on large patient populations should help clarify whether the spontaneous differentiation potential could be actively associated with a hematological manifestation of t(8;21) leukemias.     

Evaluating the prognosis of patients with myelodysplastic syndromes

One of the hallmarks of myelodysplastic syndromes (MDS) is their prognostic heterogeneity which complicates decision making regarding treatment for individual patients. The French-American-British (FAB) classification provides significant prognostic information, but carries the disadvantage of arbitrary demarcation of subgroups and overemphasis of morphological findings. In addition, there is considerable variation in survival and risk of acute myeloblastic leukemia (AML) development even within defined FAB subgroups, particularly in patients with refractory anemia with ring sideroblasts (RARS) and chronic myelomonocytic leukemia (CMML). Over the last 2 decades, several research groups have tried to identify additional clinical, hematological, and cell biological parameters in order to more accurately predict the natural course of MDS. These investigations have clarified that the number and extent of peripheral blood cytopenias, the bone marrow blast count, and the cytogenetic pattern are the most powerful prognostic indicators in MDS. Recent efforts have been directed at constructing prognostic scoring systems. These scoring systems try to enhance the predictive power by combining several features of the disease, which have proved their independent prognostic weight on multivariate analysis. The International MDS Risk Analysis Workshop substantially advanced the prognostic categorization of MDS patients by proposing a new scoring system (International Prognosis Scoring System, IPSS) that can be successfully applied to risk assessment of newly diagnosed patients and will likely prove useful for the design and analysis of therapeutic trials in MDS.     

Refined chromosome study helps define prognostic subgroups in most patients with primary myelodysplastic syndrome and acute myelogenous leukaemia

Based on a 6 1/2-year study of 284 consecutive adult patients with primary myelodysplastic syndrome (MDS) and and acute myelogenous leukaemia (AML), we have found that refined chromosome analysis can be used as an independent prognostic indicator in the great majority of patients with MDS and AML. In MDS, the FAB subtype was also found to have prognostic value and this was enhanced when the chromosomal findings were taken into consideration. In AML, the age of the patient correlated more closely with the chromosomal changes in predicting prognosis in most patients than did the FAB classification. Previously we reported that refined chromosome analysis of bone marrow specimens from 161 adult patients with primary or non-therapy related MDS and AML identified three prognostic chromosomal categories in each disease, representing 40% of all patients (Yunis et al, 1984, 1986). By extending our study to 284 patients, as well as a longer follow-up, it was possible to determine the prognostic implications of two additional chromosomal categories in MDS and five in AML. Since 73% of all patients are now represented in well-defined chromosomal subgroups with prognostic significance, refined chromosome analysis emerges as a tool that could have considerable impact in protocols.     

Validation of the new comprehensive cytogenetic scoring system (NCCSS) on 630 consecutive de novo MDS patients from a single institution

This study evaluated whether the NCCSS truly improves the prognostic stratification of 630 consecutive de novo MDS patients and established which cytogenetic grouping [NCCSS or International Prognostic Scoring System (IPSS)], when combined with the WHO classification, best predicted the clinical outcome of myelodysplastic syndromes (MDS). The frequency of chromosomal defects was 53.8%. Clinical parameters, including number of cytopenias, WHO classification, IPSS cytogenetic categories and scores, NCCSS were all relevant for overall survival (OS) and leukemia‐free survival (LFS) and were included in six distinct multivariate models compared by the Akaike Information Criterion (AIC). The most effective model to predict OS included the number of cytopenias, the WHO classification and the NCCSS, whereas the model including the number of cytopenias, blast cell percentage and the NCCSS and the model including the number of cytopenias the WHO classification and the NCCSS were almost equally effective to predict LFS. In conclusion, the NCCS (i) improves the prognostic stratification of the good and poor IPSS cytogenetic categories by introducing the very good and the very poor categories; (ii) is still incomplete in establishing the prognostic relevance of rare/double defects, (ii) applied to patients who receive supportive treatment only identifies five different prognostic subgroups, but applied to patients treated with specific therapies reveals only a trend toward a significantly different OS and LFS when patients of the poor and intermediate cytogenetic categories are compared, (iii) combined with the WHO classification is much more effective than the IPSS in predicting MDS clinical outcome. Am. J. Hematol. 88:120–129, 2013. © 2012 Wiley Periodicals, Inc.     

Comparison of five prognostic scoring systems, the French–American–British (FAB) and World Health Organization (WHO) classifications in patients with myelodysplastic syndromes: results of a single-center analysis

We retrospectively studied 89 consecutive patients diagnosed with primary myelodysplastic syndrome (MDS) over a period of 10 years to (1) identify prognostic factors for overall survival (OS) and leukemia-free survival (LFS); (2) to assess and compare the Bournemouth-, Spanish-, Düsseldorf-, Lille-, and the International prognostic scoring systems (IPSS); and to (3) compare the French–American–British (FAB) and World Health Organization (WHO) classifications. The median age of patients was 63 years (range, 26–85). Karyotype analyses were done in 85 patients (96%). Median OS was 3 years; 67 patients (75%) have died, and 28 (31%) had progression to acute myeloid leukemia (AML). Major independent prognostic variables for both OS and LFS (multivariate analysis) were percentage of bone marrow (BM) blasts (P<0.0001), and in patients with cytogenetic data available, cytogenetic risk groups by Lille-score (OS, P=0.031/LFS, P=0.002) and IPSS (OS, P=0.024). All five prognostic scoring systems successfully discriminated risk groups as regards OS and LFS, but in patients with cytogenetic data available, the major independent prognostic score for OS (P<0.0001) and LFS (P=0.006) was the IPSS. The FAB and WHO classifications also successfully discriminated between risk groups. The new WHO subgroups [refractory cytopenia with multilineage dysplasia (RCMD), with (RCMD-RS) or without ringed sideroblasts] showed a significantly (P=0.0454) different prognosis for OS, but not for LFS (P=0.0839), in comparison to the subgroups having erythroid dysplasia only (RA/RARS). Risk stratification into refractory anemia with excess blast-I (RAEB-I) and RAEB-II tended to yield different prognoses for OS and LFS. The 5q-minus syndrome strongly predicted for a good prognosis. In patients treated with the demethylating agent decitabine (n=24), IPSS “poor risk” cytogenetics were unable to predict for the expected worse prognosis when compared to “intermediate-risk” cytogenetics. In conclusion, we confirm in a single-center patient cohort that the use of the WHO classification improves the predictive value of the FAB classification and that, in patients with cytogenetic data available, the IPSS can be used for clinical decision-making.     

Epidemiology, classification and prognosis of adults and children with myelodysplastic syndromes

Myelodysplastic syndromes (MDS) belong to the most frequent bone marrow diseases with a crude incidence of about 4 in 100,000 per year. The diagnosis of MDS still is mainly based on morphologic findings in blood and marrow. The new WHO classification system takes into account the medullary and peripheral blast count as well as the degree of dysplasia in the different cell lines. To correctly identify MDS types, cytogenetic evaluation is of importance, as the WHO classification introduced the entity MDS with del(5q), which is characterized by special morphologic and hematologic features. The separation of MDS from acute leukemias has been redefined using a cutoff value of 20% peripheral and/or medullary blasts. The International Prognostic Scoring System still is the gold standard in prognostication, but new items like transfusion need will be used more and more and have been incorporated into the WHO adapted Prognostic Scoring System. In childhood, MDS is uncommon, accounting for less than 5% of all hematopoietic neoplasms in patients less than 14 years of age. To accommodate for the characteristics of pediatric MDS, a simple classification scheme based on morphological features and conforming with the WHO suggestions was proposed. The dysplastic prodrome of acute myeloid leukemia in Down syndrome is classified within myeloid leukemia in Down syndrome and excluded from the population-based studies of MDS.     

Refractory anaemia with excess of blasts in transformation re-evaluated with the WHO criteria: identification of subgroups with different survival

One of the major changes suggested by the World Health Organization (WHO) classification with respect to the French-American-British (FAB) proposal for myelodysplastic syndromes (MDS) was to lower the bone marrow (BM) blast count from 30 to 20%, thus eliminating the refractory anaemia with excess of blasts in transformation (RAEB-t) category. However, a general consensus has not been reached, and several authors still retain RAEB-t as an MDS sub-entity. We re-evaluated our series of 74 patients classified as RAEB-t according to the FAB criteria by stratifying them into two subsets: patients with at least 5% peripheral blast (PB) cells but with BM blasts <20% (group I) and patients with BM blastosis between 20 and 30% and PBs <5% (group II). We found differences among the two groups regarding sex, haematological parameters at presentation (white blood cell and neutrophil counts, haemoglobin level) and frequency of infectious episodes during the course of disease. We did not find differences as to the frequency of acute myeloid leukaemia transformation, but a significant difference was evidenced as to survival (9.3 vs. 16 months in group I vs. group II, respectively; p = 0.02). Furthermore, at our institution, we compared the RAEB-t group I patients who, based on >5% PBs, should be included in the RAEB-II category according to the WHO criteria, with a group of 98 patients who were diagnosed as RAEB-II according to the WHO criteria. The findings showed that the aggregation of these two subsets appeared inappropriate, because patients of the two groups showed different clinical features and rates of acute transformation. In conclusion, the RAEB-t entity according to the FAB criteria, although including heterogeneous clinical patient subsets, should more likely be considered as an advanced stage of MDS, rather than a true acute myeloid leukaemia.     

Inter-observer variance with the diagnosis of myelodysplastic syndromes (MDS) following the 2008 WHO classification

Morphology is the basis of the diagnosis of myelodysplastic syndromes (MDS). The WHO classification offers prognostic information and helps with the treatment decisions. However, morphological changes are subject to potential inter-observer variance. The aim of our study was to explore the reliability of the 2008 WHO classification of MDS, reviewing 100 samples previously diagnosed with MDS using the 2001 WHO criteria. Specimens were collected from 10 hospitals and were evaluated by 10 morphologists, working in five pairs. Each observer evaluated 20 samples, and each sample was analyzed independently by two morphologists. The second observer was blinded to the clinical and laboratory data, except for the peripheral blood (PB) counts. Nineteen cases were considered as unclassified MDS (MDS-U) by the 2001 WHO classification, but only three remained as MDS-U by the 2008 WHO proposal. Discordance was observed in 26 of the 95 samples considered suitable (27 %). Although there were a high number of observers taking part, the rate of discordance was quite similar among the five pairs. The inter-observer concordance was very good regarding refractory anemia with excess blasts type 1 (RAEB-1) (10 of 12 cases, 84 %), RAEB-2 (nine of 10 cases, 90 %), and also good regarding refractory cytopenia with multilineage dysplasia (37 of 50 cases, 74 %). However, the categories with unilineage dysplasia were not reproducible in most of the cases. The rate of concordance with refractory cytopenia with unilineage dysplasia was 40 % (two of five cases) and 25 % with RA with ring sideroblasts (two of eight). Our results show that the 2008 WHO classification gives a more accurate stratification of MDS but also illustrates the difficulty in diagnosing MDS with unilineage dysplasia.     

Clinical implications of the SETBP1 mutation in patients with primary myelodysplastic syndrome and its stability during disease progression

Mutations of the SET binding protein 1 (SETBP1) gene have been identified in patients with myeloid neoplasms, but the clinical relevance of this mutation and its association with other gene mutations in myelodysplastic syndrome (MDS) and the stability during disease progression remains unclear. Mutations in SETBP1 gene at exon 4 were analyzed by polymerase chain reaction and direct sequencing in 430 MDS patients. The results were correlated with clinical features, cytogenetics, gene mutations and treatment outcomes. SETBP1 mutations were identified in 14 (3.3%) of the 430 patients with primary MDS based on the FAB classification and 8 (2.4%) of the 333 patients based on the WHO classification. The SETBP1 mutation was closely associated with higher white blood cell counts, isochromosome of 17q, monosomy 7, and mutations of ASXL1, EZH2 and SRSF2. With a median follow‐up of 43.9 months, MDS patients, based on either the FAB or WHO classification, had a significantly poorer overall survival (OS) if they harbored SETBP1 mutation. Further, SETBP1 mutation was an independent poor prognostic factor for OS (HR = 1.842, CI 95%, 1.1018–3.332, P = 0.043) irrespective of age, sex, and the International Prognostic Scoring System. Sequential analysis showed that the original SETBP1 mutations in the eight SETBP1‐mutated patients studied were retained while two of the 101 SETBP1‐wild patients acquired novel SETBP1 mutations during follow‐ups. The SETBP1 mutation is associated with poor prognosis in MDS. The mutation can be acquired during the clinical course suggesting it may play a role in disease progression. Am. J. Hematol. 89:181–186, 2014. © 2013 Wiley Periodicals, Inc.     

IDH mutations are closely associated with mutations of DNMT3A,ASXL1 and SRSF2 in patients with myelodysplastic syndromes and are stable during disease evolution

Current information about clinical significance of IDH mutations in myelodysplastic syndromes (MDS), their association with other genetic alterations and the stability during disease progression is limited. In this study, IDH mutations were identified in 4.6% of 477 patients with MDS based on the FAB classification and in 2.2 % of 368 patients based on the 2008 WHO classification. IDH mutations were closely associated with older age, higher platelet counts, and mutations of DNMT3A (36.4% vs. 8.7%, P < 0.001), ASXL1 (47.6% vs. 22.0%, P = 0.007), and SRSF2 (45.5% vs. 11.8%, P < 0.001). IDH2 mutation was a poor prognostic factor for overall survival in patients with lower‐risk MDS, based on international prognosis scoring system (IPSS), FAB classification, WHO classification, or revised IPSS (all P ≦ 0.001), but not in higher‐risk groups. Sequential studies in 151 patients demonstrated that all IDH‐mutated patients retained the same mutation during disease evolution while none of the IDH‐wild patients acquired a novel mutation during follow‐ups. In conclusion, IDH mutation is a useful biomarker for risk stratification of patients with lower‐risk MDS. IDH mutations are stable during the clinical course. The mutation, in association with other genetic alterations, may play a role in the development, but not progression of MDS.Am. J. Hematol. 89:137–144, 2014. © 2013 Wiley Periodicals, Inc.