Prolonged administration of erythropoietin increases erythroid response rate in myelodysplastic syndromes: a phase II trial in 281 patients

Treatment with recombinant human erythropoietin (rHuEpo) improves anaemia in approximately 20% of patients with myelodysplastic syndromes (MDS). We investigated the potential advantage of a prolonged administration of rHuEpo to achieve higher erythroid response rates (RR) in 281 MDS patients: 118 with refractory anaemia (RA), 77 with refractory anaemia and ringed sideroblasts (RARS), 59 with refractory anaemia with excess of blasts and blast count < 10% (RAEB-I), and 27 with RAEB and blast count between 11-20% (RAEB-II). rHuEpo was given subcutaneously at a dose of 150 U/kg thrice weekly, for a minimum of 26 weeks. Response to treatment was evaluated after 12 and 26 weeks of therapy. The overall RR was 45.1%; the RR for RA, RARS, RAEB-I and RAEB-II were 48.3%, 58.4%, 33.8% and 13% respectively. A significant increase in RR was observed at week 26 in RA, RARS and RAEB-I patients, as the response probability increased with treatment duration. The RR was higher in the good cytogenetic prognostic group and serum Epo level of > 150 U/l at baseline predicted for non-response. The median duration of response was 68 weeks and the overall risk of leukaemic transformation was 21.7%. These results suggest that prolonged administration of rHuEpo produces high and long-lasting erythroid RR in MDS patients with low blast counts, particularly in those with pretreatment serum Epo levels of < 150 U/l and good cytogenetic prognosis.     

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99例临床分析

目的探讨骨髓增生异常综合征(MDS)患者WHO亚型分布、细胞遗传学特点及其与MDS诊断分型、疾病进展和预后的关系。方法回顾性分析2001年1月至2007年12月安徽医科大学附属安徽省立医院血液科收治的99例成人原发MDS患者的染色体核型、WHO分型及预后情况,随访观察并进行相关性研究。结果99例MDS患者难治性贫血(RA)型26例(26.26%);难治性贫血伴环形铁幼粒细胞增多(RAS)型6例(6.06%);难治性贫血伴多系发育异常(RCMD)型23例(23.23%);难治性贫血伴原始细胞增多(RAEB)型44例(44.44%)。按IPSS预后分组,中危Ⅱ和高危组的染色体核型异常检出率明显高于低危和中危Ⅰ组(χ2=17.88,P<0.01);中危Ⅱ和高危组患者进展为急性白血病的发生率明显高于低危和中危Ⅰ组(χ2=40.22,P<0.01)。按IPSS染色体核型分组,预后好、中、差的患者中位存活期分别为45(95%CI:39~51)、37(95%CI:25~49)和23(95%CI:13~31)个月,Log-rank检验三组总体生存(OS)率差异有统计学意义(P=0.010)。结论中国有别于西方国家MDS患者的WHO亚型分布,染色体核型分析是MDS诊断分型及预后评估的重要指标。     

Identification of distinct prognostic subgroups in low- and intermediate-1-risk myelodysplastic syndromes by flow cytometry

The World Health Organization (WHO) classification contributes to refined classification and prognostication of myelodysplastic syndromes (MDSs). Flow cytometry might add significantly to diagnostic and prognostic criteria. Our analysis of bone marrow samples from 50 patients with MDS showed aberrant expression of differentiation antigens in the myelomonocytic lineage. This also accounted for refractory anemia (RA) with or without ringed sideroblasts (RS), indicating multilineage dysplasia. In 38% of patients, CD34(+) myeloid blasts expressed CD5, CD7, or CD56. Flow cytometry data were translated into a numerical MDS flow-score. Flow-scores increased significantly from RA with or without RS, refractory cytopenia with multilineage dysplasia (RCMD) with or without RS up to refractory anemia with excess of blasts-1 (RAEB-1) and RAEB-2. No significant differences were observed between WHO cytogenetic subgroups. Flow-scores were highly heterogeneous within International Prognostic Scoring System (IPSS) subgroups. Patients in progression to advanced MDS or acute myeloid leukemia had a significantly higher flow-score compared with non-transfusion-dependent patients. In 60% of patients with transfusion dependency or progressive disease, myeloid blasts expressed CD7 or CD56, in contrast to only 9% of non-transfusion-dependent patients. Moreover, all patients with pure RA with or without RS with aberrant myeloid blasts showed an adverse clinical course. In conclusion, flow cytometry in MDS identified aberrancies in the myelomonocytic lineage not otherwise determined by cytomorphology. In addition, flow cytometry identified patients at risk for transfusion dependency and/or progressive disease independent of known risk groups, which might have impact on treatment decisions and the prognostic scoring system in the near future.     

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.     

Myelodysplastic syndromes: analysis of 131 cases according to the FAB classification

The clinical and haematological findings in 131 patients with myelodysplastic syndromes (MDS), none of which had previously received chemotherapy or radiotherapy, classified according to the FAB criteria, were analysed. The distribution among the 5 subgroups was: RA 31 patients, RAS 19, RAEB 23, CMML 29 and RAEBT 29 patients. There were difficulties in the classification of 24 patients. These included, first, 8 cases with myeloid hyperplasia of the bone marrow (BM) but without monocytosis or excess of blasts of the BM. They were classified as RA. Second, 8 cases with sideroblastosis but with monocytosis or excess of blasts of the BM were classified 3 as RAEB, 2 as CMML and 3 as RAEBT. Finally, 8 cases with absolute monocytosis and BM blasts 15-30% were classified as CMML. 37 of 82 dead patients (45.1%) had transformed to acute non-lymphoblastic leukaemia (ANLL). The incidence of evolution to ANLL was low for RA and RAS (6.30% and 12.5% respectively), while it was 37.5% for RAEB, 57.1% for CMML and 77.2% for RAEBT. The median survival for each subgroup was: RA 18 months; RAS 25; RAEB 13; CMML 14 and RAEBT 10 months. It is concluded that the FAB classification with some modifications recognises group of MDS with different prognosis.     

Correlations between cytogenetics and morphology in myelodysplastic syndromes

Summary In order to detect possible relationships between cytogenetic abnormalities and morphologic features in myelodysplastic syndromes (MDS), 48 patients with MDS were investigated. Clonal cytogenetic abnormalities were present in bone marrow cells from 27 patients (56%). The most frequent single anomaly was del (5 q) (10 cases), followed by monosomy 7 (3 cases), trisomy 8 (3 cases) and del (20 q) (2 cases). Complex anomalies were present in 6 patients. Morphologically, according to the French-American-British (FAB) classification: 17 cases were considered as refractory anemia (RA), 17 as RA with excess of blasts (RAEB), 2 as RAEB in transformation, 2 as acquired idiopathic sideroblastic anemia and 10 as chronic myelomonocytic leukemia. With regard to the FAB classification, del (5 q) was often associated with RA and complex cytogenetic anomalies with RAEB. When myelodysplasia was studied in individual myeloid lineages, del (5 q) was associated with hypolobulated megakaryocytes, monosomy 7 with micromegakaryocytes and complex chromosomal anomalies with the association of two or more features of dysmegakaryocytopoiesis. Del (11 q) was associated with increased iron storage and del (20 q) with marked dyserythropoiesis. No correlation was observed between cytogenetic anomalies and features of dysgranulocytopoiesis.     

Allogeneic bone marrow transplantation in children with myelodysplastic syndrome or juvenile myelomonocytic leukemia: the Seattle experience

The purpose of this study was to evaluate the role of allogeneic bone marrow transplantation (BMT) in children with myelodysplastic syndrome (MDS). In total, 94 consecutive pediatric patients with MDS received an allogeneic BMT from 1976 to 2001 for refractory anemia (RA) (n=25), RA with ringed sideroblasts (RARS) (n=2), RA with excess blasts (RAEB) (n=20), RAEB in transformation (RAEB-T) (n=14), juvenile myelomonocytic leukemia (JMML) (n=32) or chronic myelomonocytic leukemia (CMML) (n=1). The estimated 3-year probabilities of survival, event-free survival (EFS), nonrelapse mortality and relapse were 50, 41, 28 and 29%, respectively. Patients with RA/RARS had an estimated 3-year survival of 74% compared to 68% in those with RAEB and 33% in patients with JMML/CMML. In multivariable analysis, patients with RAEB-T or JMML were 3.9 and 3.7 times more likely to die compared to those with RA/RARS and RAEB (P=0.005 and 0.004, respectively). Patients with RAEB-T were 5.5 times more likely to relapse (P=0.01). The median follow-up among the 43 surviving patients is 10 years (range 1-25). We conclude that allogeneic BMT for children with MDS is well tolerated and can be curative.     

骨髓增生异常综合征435例WHO分型和细胞遗传学分析

目的 探讨我国骨髓增生异常综合征(MDS)WHO亚型分布和细胞遗传学异常特点,并与西方国家进行比较.方法 采用前瞻性方法收集了协作组435例MDS患者,进行WHO分型,采用染色体G显带和荧光原位杂交(FISH)技术进行细胞遗传学分析.结果 MDS中位发病年龄为58(18～90)岁.难治性血细胞减少伴多系发育异常(RCMD)病例比例最高,约占69.6%(303/435),其他亚型依次为难治性贫血伴原始细胞增多(RAEB)24.1%(105/435)、难治性贫血(RA)2.3%(10/435)、不能分类MDS(MDS-U)2.3%(10/435)、难治性贫血伴环状铁粒幼细胞增多(RAS)1.2%(5/435)和5q-综合征0.5%(2/435),而西方国家RA、RAS、5q-综合征比例较高,RCMD亚型比例低于中国.11例染色体检查失败,424例染色体检查成功的染色体克隆性异常率为38.7%(164/424),其中RAEB-Ⅰ异常率最高62.5%(25/40),其次RAEB-Ⅱ 48.4%(30/62)、RCMD 34.5%(102/296).常见的染色体异常依次为:+8为12.7%(54/424)、复杂核型为9.O%(38/424)、染色体易位为7.8%(33/424)、-20q为6.6%(28/424)、-7/-7q为5.2%(22/424)、-5/-5q为4.2%(18/424),而国外最常见的是-5/-5q、-7/-7q、+8、11q及12p/12q异常.以国际预后积分系统染色体预后分组,染色体预后良好组68.2%(289/424),预后中等组19.1%(81/424),预后不良组12.7%(54/424).有17例患者因为异常细胞的比例偏低,染色体检查正常,但FISH检测到低水平的异常.结论 我国MDS的WHO亚型分布与染色体异常分布与西方国家不同.FISH和常规染色体检查相结合,可以提高检测的灵敏度.     

The WHO classification of MDS does make a difference

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 <.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).     

Prognostic implications of morphology and karyotype in primary myelodysplastic syndromes

Forty-nine patients with primary myelodysplastic syndromes (MDS) were subclassified according to French-American-British (FAB) Cooperative Group criteria. Eight patients had acquired idiopathic sideroblastic anemia (AISA), ten had chronic myelomonocytic leukemia (CMMoL), 14 had refractory anemia (RA), nine had refractory anemia with excess blasts (RAEB), and five had refractory anemia with excess blasts in transformation (RAEB-T); three patients could not be subclassified. The actuarial median survival for patients with AISA or with RA had not been reached at 60 months of follow-up. The median survival times for patients with CMMoL, RAEB, and RAEB-T were 25, 21, and 16 months, respectively. The percentages of patients with each subtype who developed ANLL were none in AISA, 20% in CMMoL, 7% in RA, 56% in RAEB, and 40% in RAEB-T. Patients with CMMoL had a poor prognosis independent of transformation to acute nonlymphocytic leukemia (ANLL), whereas patients with RAEB and RAEB-T had a high incidence of transformation and short survival times. Clonal chromosomal abnormalities were present in bone marrow cells from 19 patients at the time of diagnosis, and two others developed an abnormal karyotype at the time of leukemic transformation. The most frequent abnormalities, including initial and evolutionary changes, were trisomy 8 (9 patients), deletion of 5q (4 patients), and deletion of 20q (4 patients). The median survival times were 32 months for patients with an abnormal karyotype, and 48 months for those with a normal karyotype (P = 0.2). Specific chromosomal abnormalities were not associated with particular histologic subtypes; however, a high percentage of patients with RAEB and RAEB-T had an abnormal clone (89% and 80%, respectively). The percentages of patients with clonal abnormalities were 13% for AISA, 20% for CMMoL, and 29% for RA. The MDS transformed to ANLL in 42% of patients with an abnormal karyotype, compared to 10% of those with an initially normal karyotype (P less than .01). Among patients with RA, RAEB, and RAEB-T, the risk of leukemic transformation was confined to those with an abnormal karyotype (P less than .01). Thus, in the present study, morphology and karyotype combined were the best indicators of outcome in patients with MDS.     

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。     

Primary myelodysplastic syndrome in children--clinical, hematological and histomorphological profile from a tertiary care centre in India

We describe the clinical, hematological and histomorphological features in children of primary myelodysplastic syndrome (MDS) seen at the All India Institute of Medical Sciences over three years (Jan 2001-Jan 2004). Twenty-one patients of primary MDS aged 17 year or less were classified using the latest proposed WHO classification for Pediatric MDS. The median age was 9 years with male predominance (80%). Pallor was present in all the cases while fever and bleeding diathesis was present in more than 50% of the cases. Morphological assessment of the peripheral blood showed macrocytosis in 50%, pancytopenia in 15% and blast cells in 45% of cases. A complete analysis of clinical features in conjunction with the bone marrow profile revealed 8 cases of refractory cytopenia (RC), 3 cases of refractory anemia with excess blasts (RAEB), 5 cases of refractory anemia with excess blasts in transformation (RAEB-T), 4 cases of Juvenile myelomonocytic leukemia (JMML) and a solitary cases of acute myeloid leukemia (AML) in Downs syndrome.These children were followed up from 1-36 months (mean 15 months). Three patients of RAEB-T progressed to AML within 3-4 months. RC had the best prognosis and all are alive and under regular follow up. The solitary case of AML of Downs syndrome died 1.5 months after initial diagnosis. All 3 cases of RAEB are under regular follow-up and doing well. Three cases of RAEB-T died (all had progressed to AML); the remaining 2 cases were lost to follow up. Of the 4 cases of JMML 1 died within 6 months of diagnosis; the other 3 cases are under regular follow up of whom 1 has a progressively increasing blast count.We conclude that the latest proposed WHO classification for Pediatric MDS can be successfully applied to all cases of primary MDS.     

Prospective analysis of clinical and cytogenetic features of 435 cases of MDS diagnosed using the WHO (2001) classification: a prognostic scoring system for predicting survival in RCMD

We characterized the prevalence, clinical and cytogenetic characteristics and survival of 435 patients diagnosed with de novo MDS in a single laboratory according to WHO criteria, and compared the utility of different scoring systems to predict survival for individual subtypes of MDS. The mean follow-up period was 25.1 (5.5–53.2) months. Our results confirm major differences in the age-distribution and prevalence of individual subtypes of MDS between Asian and Western patients with a median age of 58 years and a predominance of RCMD (69.9%). Survival rates were similar to those reported in the West: the 3-year survival rate for MDS was 46.7% with a median survival time for RCMD of 38 months and RAEB, 10 months. We found that the IPSS and WPSS scoring systems, which are weighted heavily by blast cell count and karyotype, were not independent predictors for survival in RCMD patients. Multivariate analysis demonstrated that a scoring system based on age (≥60 years), ANC (<1.0 × 10⁹/L), Hb (<90 g/L), number of cytopenias and complex karyotype is a more useful predictor of survival in RCMD.     

Cytogenetics and clinical features of pediatric myelodysplastic syndrome in Japan

We analyzed the cytogenetics and clinical features of pediatric myelodysplastic syndrome (MDS) in Japan. Data on patients (<16 years) diagnosed with MDS from 1990 to 2000 were retrospectively collected from pediatric hematologists in 234 institutions. Chromosome analysis was successfully performed in 255 of 277 MDS patients. The numbers of patients with refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess of blasts (RAEB), refractory anemia with excess of blasts in transformation (RAEBt), chronic myelomonocytic leukemia, and juvenile myelomonocytic leukemia were 67 (24 %), 51 (18 %), 51 (18 %), 20 (7 %), and 65 (23 %), respectively. The other 23 patients (8 %) could not be classified specifically. The distribution of childhood MDS in Japan according to the French–American–British subclassification was similar to that in other countries. However, we identified a higher incidence of therapy-related cases. As for relationship between cytogenetics and prognoses, abnormal karyotypes were related to poorer prognoses than normal karyotype (P < 0.01). However, patients with trisomy 8 had prognoses comparable to those with normal karyotypes. Complex karyotypes were associated with poorer prognoses among RAEB and RAEBt patients. In conclusion, prognosis of pediatric MDS is related to cytogenetics. A more precise diagnosis and classification system is needed for childhood MDS.     

Quick measurement of hematocrit and erythrocyte sedimentation-rate by means of a density tracking method

Summary One hundred and one patients with refractory cytopenia were reviewed for morphological classification (using bone marrow, BM, imprints for cytology and Jamshidi biopsies for BM cellularity) and clinical course. Final diagnoses were: moderate aplastic anemia (MAA), myelodysplastic syndromes (MDS) and hypoplastic acute leukemia (HAL). Ninety-two patients received high dose testosterone enanthate (TE) as first treatment (starting dose=7–10 mg/week i.m. for at least three months). Median survival was significantly longer in MAA than in MDS and in HAL. Among MDS patients, those with primary acquired sideroblastic (AISA) and refractory (RA) anemia had median survival similar to those with MAA, but distinctly longer (p=0.01) than patients with RA with an excess of blasts (RAEB), RAEB in transformation (RAEBtr) and chronic myelomonocytic leukemia (CMMoL). Acute leukemia (AL) developed more rarely (p<0.02) in MAA, AISA and RA than in RAEB, RAEBtr and CMMoL. Response to TE was seen in about two thirds of MAA and in a half of MDS and HAL patients. Among MDS patients, those with hypocellular BM developed leukemia less frequently, responded to androgens more often and survived longer than those with normocellular and, especially, with hypercellular BM. These data indicate that the cytohistological classification of refractory cytopenias identifies essentially two groups with different clinical behaviour, one (MAA, AISA and RA) having long life expectancy and a low probability of developing AL and the other (RAEB, RAEBtr, CMMoL) with a short survival and relatively frequent leukemic complication. Bone marrow hypocellularity seems to be a favourable prognostic factor in MDS. Patients with refractory cytopenias, especially those with a hypocellular BM, can be advantageously treated with androgens.Research supported by C. N. R. (Consiglio Nazionale delle Ricerche, Roma, Progetto Finalizzato Oncologia, grants no. 85.02329.44 and no. 85.02084.44) and A. I. R. C. (Associazione Italiana per la Ricerca sul Cancro)     

CD34/QBEND10 immunostaining in bone marrow biopsies: an additional parameter for the diagnosis and classification of myelodysplastic syndromes

CD34/QBEND10 immunostaining has been assessed in 150 bone marrow biopsies (BMB) including 91 myelodysplastic syndromes (MDS), 16 MDS-related AML, 25 reactive BMB, and 18 cases where RA could neither be established nor ruled out. All cases were reviewed and classified according to the clinical and morphological FAB criteria. The percentage of CD34-positive (CD34 +) hematopoietic cells and the number of clusters of CD34+ cells in 10 HPF were determined. In most cases the CD34+ cell count was similar to the blast percentage determined morphologically. In RA, however, not only typical blasts but also less immature hemopoietic cells lying morphologically between blasts and promyelocytes were stained with CD34. The CD34+ cell count and cluster values were significantly higher in RA than in BMB with reactive changes (p<0.0001 for both), in RAEB than in RA (p=0.0006 and p=0.0189, respectively), in RAEBt than in RAEB (p=0.0001 and p=0.0038), and in MDS-AML than in RAEBt (p<0.0001 and p=0.0007). Presence of CD34+ cell clusters in RA correlated with increased risk of progression of the disease. We conclude that CD34 immunostaining in BMB is a useful tool for distinguishing RA from other anemias, assessing blast percentage in MDS cases, classifying them according to FAB, and following their evolution.     

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

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.     

Prognostic value of clonal chromosomal abnormalities in patients with primary myelodysplastic syndromes

Chromosome analyses were carried out on bone marrow cells from 43 consecutive patients with primary myelodysplastic syndromes (MDS), classified according to the French-American-British (FAB) cooperative group criteria. The objective was to evaluate the prognostic value of clonal chromosomal abnormalities and of an excess of blasts for early death from acute nonlymphocytic leukemia (ANLL) and/or bone marrow failure (BMF). Patients were subdivided into two main groups: (1) refractory anemia without an excess of blasts (RAWEB), grouping patients with refractory anemia (RA) and refractory anemia with ringed sideroblasts (RARS), and (2) refractory anemia with an excess of blasts (RAEB), grouping patients with refractory anemia with an excess of blasts (RAEB) and refractory anemia with an excess of blasts in transformation (RAEBt). There were 29 patients with RAWEB and 14 with RAEB. The median time of observation was 26 months for RAWEB and 12 months for RAEB. Ten RAWEB patients (34%) and 11 RAEB patients (78%) had clonal chromosomal abnormalities. Among the ten RAWEB patients with clonal abnormalities, one (10%) died from ANLL, while of 19 RAWEB patients with a normal karyotype, two (10%) died from ANLL or BMF. The median survival for patients with RAWEB and an abnormal karyotype was not reached. In contrast, eight of the 11 RAEB patients with clonal chromosomal abnormalities (74%) died from ANLL or BMF. The median survival in this sub-group was 7 months. By using a Cox proportional hazard regression analysis, it was determined that a karyotype abnormality was not a significant predictory of survival once the contribution of the RAWEB/RAEB variable was taken into account. Being in the RAEB group was associated with a relative risk of 10.6 of dying from ANLL or BMF (beta = 2.36, standard error (SE) = 0.68, P = .0001). We conclude that classifying patients according to an excess of blasts will lead to a better prediction of survival than determining karyotype abnormality.