Application of different prognostic scoring systems and comparison of the FAB and WHO classifications in Korean patients with myelodysplastic syndrome.

We retrospectively studied 227 patients with MDS (1) to identify the prognostic factors of survival and acute leukemia evolution in Korean patients with MDS, (2) to apply different prognostic scoring systems to the same group of patients, and (3) to compare the FAB with the WHO classification. Six scoring systems were applied to the patients, and the FAB and WHO classifications were compared. The patients' median age was 57 years. The median survival time was 21 months, and age, dysgranulopoiesis and the IPSS cytogenetic groups were independent prognostic factors for survival. Acute leukemia occurred in 34 patients, and the cumulative incidence was 27.1% at 3 years. Marrow blast percentage was the only independent prognostic factor for acute leukemia evolution. Most scoring systems successfully discriminated risk groups for survival and acute leukemia evolution, but patient distribution into risk groups varied according to the scoring systems. Refractory cytopenia with multilineage dysplasia and RAEB II seemed to have different prognoses from RA or RARS and RAEB I, respectively. In summary, our MDS patients had different disease natures from those of Western countries regarding clinical features, prognostic factors and cytogenetic profiles. Although the WHO classification seems to improve the FAB classification, further studies are warranted to validate the utility of the WHO classification before it is accepted for routine clinical use. Our study has the limitations of retrospective analysis, and our results should be verified in future prospective studies.     

Usefulness and prognostic impact on survival of WHO reclassification in FAB low risk myelodyplastic syndromes

In 1999, WHO proposed a revised classification for myelodysplastic syndromes (MDS). According to this system, FAB low risk MDS (RA and RARS) were defined as such when the presence of dysplastic features was only restricted to the erythroid lineage, and new categories, refractory cytopenia with multilineage dysplasia (RCMD) and refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS), were added. In a retrospective analysis of 240 consecutive patients diagnosed at our institution as having FAB RA and RARS, we reclassified the disease following the WHO criteria and we found that 179/214 patients (84%) still remained in the RA category, while 35/214 (16%) moved to RCMD. Moreover, 17/26 patients (65%) maintained the RARS diagnosis, whereas 9/26 (35%) were re-classified as RCMD-RS. We detected differences among the WHO subgroups as to age and sex distribution as well as to median survival observed by stratifying patients according to different prognostic scoring systems. Furthermore we confirmed the usefulness of WHO segregation with regard to its predictive value for evolution into acute leukaemia. Our study provides evidence that WHO classification may have prognostic impact on MDS subgroups which are usually categorized by FAB as having a favourable outcome.     

由FAB至WHO分类的骨髓增生异常综合征的演变

骨髓增生异常综合征（myelodysplastic syndrome，MDS）是一组获得性造血干／祖细胞克隆增殖性疾病，是良性多克隆造血由于多次基因损伤而逐步被恶性单克隆造血替代的过程。当其尚未发展为急性白血病之前，MDS的基本病理特征是骨髓的无效造血。造血组织处于高增殖、高凋亡状态，而反映在细胞形态学上的变化提示着DNA复制紊乱的病态造血以及后期不同程度的原始细胞增多。     

Prognosis in myelodysplastic syndromes: Are the new classifications useful?

Increased understanding of the biologic and clinical parameters that define subgroups of myelodysplastic syndromes has led to continuing refinement of classification strategies for diagnostic and prognostic use. The French-American-British classification, based primarily on morphology, was modified by the World Health Organization system to include the negative impact of multilineage dysplasias and higher blast counts. In addition, this system identifies a distinct clinical subgroup characterized by an isolated chromosome 5 deletion. The International Prognostic Scoring System was created to calculate prognosis, risk of transformation to acute myeloid leukemia, and median survival times. However, therapeutic decisions cannot be solely guided by these systems, and the clinician must decide whether the intent is curative or palliative. Clinical symptoms and degree of transfusion dependency will dictate the degree of therapeutic intervention.     

The WHO classification of the myelodysplastic syndromes

For more than two decades the French-American-British (FAB) classification has provided a framework for the diagnosis and classification of the myelodysplastic syndromes. However, with widespread use of this classification, it became clear that prognostic differences existed within single categories. The FAB classification has therefore been modified by a World Health Organization (WHO) expert group to take account of these prognostic differences. In addition, therapy-related myelodysplasia and the 5q- syndrome have been recognized as distinct types of disorder and the existence of mixed myelodysplastic/myeloproliferative disorders has been recognized; chronic myelomonocytic leukaemia, previously regarded as one of the myelodysplastic syndromes, was re-assigned to this latter group of disorders.     

Erythroleukemia: a comparison between the previous FAB approach and the WHO classification

Erythroleukemia is, within FAB classification, a proliferation of erythroblasts superior to 50% and of myeloblasts superior to 30%. The new WHO classification abolishes the frontier between RAEB-t with 20% and leukemia with 30% of blasts. AML6 variant is a new entity characterized by the proliferation of immature erythroblasts and the absence of non-erythroid blast cells. We analyzed 16 erythroleukemia, 5 RAEB-t and 2 AML6 variants to clarify their relationship.We suggest on survival, karyotype and cytologic characteristics that secondary erythroleukemia are the same entity as RAEB-t, confirming the WHO classification and that amongst de novo erythroleukemia, there is 'AML6 variant' with pure erythroid lineage proliferation.     

Who is WHO in myelodysplastic syndromes? Clinical implications of the WHO classification

Myelodysplastic syndromes (MDS) are a heterogeneous group of neoplastic clonal stem cell diseases characterized by dysplastic morphologic features with a varying percentage of leukemic blasts and clinical bone marrow failure. The French-American-British (FAB) system served as the gold standard of MDS classification for more than two decades. The World Health Organization (WHO) classification, built on the backbone of the FAB classification, is an attempt to further improve the prognostic value of MDS classification as well as to establish its clinical utility as a tool to select different treatments. In this article 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 have tried to validate the prognostic value of the new classification or apply it to predict clinical responses to various treatments.     

Fas ligand expression in the bone marrow in myelodysplastic syndromes correlates with FAB subtype and anemia, and predicts survival.

Increased apoptosis in the bone marrow (BM) may contribute to the cytopenias that occur in myelodysplastic syndromes (MDS). The Fas receptor, Fas ligand (FasL) pathway is a major mechanism of apoptosis. Since hematopoietic progenitors can express the Fas receptor, they may be susceptible to apoptosis induced by FasL-expressing cells. We examined FasL expression in the BM of patients with MDS (n = 50), de novo acute myeloid leukemia (AML; n = 10), AML following prior MDS (n = 6), and normal controls (n = 6). Compared to controls, FasL expression was increased in MDS, and was highest in AML. In MDS, FasL expression was seen in myeloid blasts, erythroblasts, maturing myeloid cells, megakaryocytes and dysplastic cells, whereas in AML, intense expression was seen in the blasts. FasL expression correlated with the FAB subtype groups of MDS, and also correlated directly with the percentage of abnormal metaphases on cytogenetic analysis. The FasL expressed in MDS BM inhibited the growth of clonogenic hematopoietic progenitors. This inhibition could be blocked by a soluble recombinant FasFc protein. In MDS, FasL expression in the initial diagnostic BM was higher in patients who were more anemic, correlated directly with red cell transfusion requirements over the subsequent course of the disease, and was predictive of survival. These studies indicate that FasL expression in MDS is of prognostic significance, and suggest that pharmacological blockade of the Fas-FasL pathway may be of clinical benefit.     

Comorbidities and survival in a large cohort of patients with newly diagnosed myelodysplastic syndromes

Comorbid conditions have rarely been systematically studied among patients with myelodysplastic syndromes (MDS). We conducted a large population-based study to assess the role of comorbidity in the survival of newly diagnosed MDS patients. This study included 1708 MDS patients (age ≥ 66 years) diagnosed in the US during 2001–2002, with follow-up through the end of 2004. Hazard ratios (HRs) were estimated using multivariate Cox proportional hazard models. The median survival time was approximately 18 months. Fifty one percent of MDS patients had comorbid conditions. Patients with comorbid conditions had significantly greater risk of death than those without comorbidities. The HR was 1.19 (95% confidence interval (CI): 1.05–1.36) and 1.77 (95% CI: 1.50–2.08) for those with a Charlson index of 1–2 and ≥ 3, respectively. The risk of death increases with Charlson index. MDS patients who have congestive heart failure or chronic obstructive pulmonary disease had significantly shorter survival than patients without those conditions, whereas diabetes did not appear to have an impact on survival. This study confirms comorbidity as a significant and independent determinant of MDS survival, and the findings underscore the importance to take comorbid conditions into account when assessing the prognosis of MDS.     

Factors influencing survival in carcinoma of the ovary. Study from a well-defined Swedish population

Prognostic factors were studied in 770 cases of carcinoma of the ovary treated at Radiumhemmet during 1974 to 1979. Centralization of the treatment in a well-defined population with complete follow-up permits a nonselective study of the disease. The analysis was made separately for early and late stages. For the early cases, histology and grading were the most dominant prognostic factors. For the most advanced cases successful surgical treatment, either primary or secondary, showed significant relation to survival. Successful secondary surgery could be achieved in twice as many cases where radiotherapy was included in the treatment. Even for the advanced cases, the stage but not the histology was of prognostic significance. The major difficulties in evaluating treatment of ovarian cancer, especially in advanced cases, are associated with the multiplicity of sites of the disease and the prognostic factors that may contribute independently to the outcome.     

Gamma-interferon in myelodysplastic syndromes: a pilot study

Eight patients with myelodysplastic syndrome (MDS; RA = 1, RAEB = 2, RAEB-t = 4, CMML = 1) received three cycles of recombinant gamma-IFN administered in 2-week intervals, each consisting of a 14-day period of subcutaneous injections at a daily dose of 0.1 mg/m2. Neither a complete nor a partial remission could be obtained. There was only one definite improvement consisting in a rise of hemoglobin level from 7 to more than 12 g/dl. Two minor improvements were due to a slight rise of platelet counts. Three patients developed acute leukemia under treatment with gamma-IFN. Our data suggest that gamma-IFN administered according to the treatment schedule as used in our trial has only a minimal beneficial effect in patients with MDS.     

Correlation of bone marrow colony growth in the myelodysplastic syndromes with the FAB classification and the Bournemouth score

Erythroid and myeloid colonies were grown from the bone marrow of 81 patients with myelodysplasia and the median number of colonies correlated with the FAB classification and Bournemouth score. CFU-GM were increased in CMML compared to RAEB and RAEBt. BFU-E were higher in RA than in the other FAB subgroups. Patients with a high Bournemouth score had poorer CFU-GM and BFU-E growth than those with a low score.     

Validation of the WHO proposals for a new classification of primary myelodysplastic syndromes: a retrospective analysis of 1600 patients

In 1982, the French–American–British (FAB) cooperative group proposed a classification of myelodysplastic syndromes (MDS) based on morphological features in blood and bone marrow, namely on medullary and peripheral blast count, Auer rods, ring sideroblasts and the number of monocytes in the peripheral blood. This classification has been used for numerous studies regarding morphology, prognosis and treatment of MDS. Some details of this morphological classification remained unclear, and some patients were unclassifiable. A working group of the World Health Organization (WHO) recently proposed a new classification of MDS, based on a significant modification of the original FAB proposals. CMML and RAEB-T were removed from the MDS classification and RAEB was split into two groups with medullary blast counts below and above 10%. In addition, a group of patients with less than 5% medullary blasts but evidence of multilineage dysplasia was defined. MDS patients with 5q− as the sole chromosomal anomaly were also considered a separate group. The aim of the present study was to validate the new classification with respect to prognostic importance, and to correlate it with cytogenetic and hematological features in a large series of patients (n=1600) with a long-term follow up. We were able to confirm a significant difference in prognosis between RAEB I and RAEB II, as well as a difference between refractory anemia and multilineage dysplasia. Furthermore, patients with 5q− anomaly had a much better prognosis than other WHO subtypes, but this was only true for patients with a medullary blast count below 5%. In summary, the WHO classification appears to define morphological subgroups that are more homogeneous with respect to prognosis than the FAB subtypes.     

Treatment of pediatric myelodysplastic syndromes and juvenile myelomonocytic leukemia: the Brazilian experience in the past decade

BACKGROUND: Therapy strategies for myelodysplastic syndromes (MDS) and juvenile myelomonocytic leukemia (JMML) vary considerably. OBJECTIVE: To review the treatment of Brazilian children who were diagnosed with MDS or JMML in the past decade and reported to the Brazilian Cooperative Group on Pediatric Myelodysplastic Syndromes (BCG-MDS-PED). RESULTS: Of 173 children reported to the BCG-MDS-PED from January 1997 to January 2003 with a suspected diagnosis of MDS or JMML, 91 had the diagnosis confirmed after central review of the bone marrow aspirate and biopsy. Information on previous treatments was available for 78 MDS/JMML patients. Treatment varied from different schedules of low-dose (14%) and standard-dose chemotherapy (50%), granulocyte-colony-stimulating factor (G-CSF 7%), interferon (5%), steroids (2%) and erythropoietin (2%) to allogeneic stem-cell transplantation (SCT) (14%). No survival advantage could be demonstrated based on Hasle's classification or based on treatment. CONCLUSION: This report reflects the current practice in treating Brazilian children with MDS/JMML without specific Cooperative Group guidelines. Treatment modalities were very heterogeneous. The strategies for implementing a national protocol should consider international guidelines and focus on local experience and available resources.     

A retrospective analysis of myelodysplastic syndromes with thrombocytosis: reclassification of the cases by WHO proposals

Myelodysplastic syndromes (MDS) show occasionally thrombocytosis, common feature of myeloproliferative diseases (MPD), with the overlapping of both disorders. Classically, thrombocytosis has been associated with some MDS subtypes: refractory anaemia with ringed sideroblasts (RARS), 5q- syndrome and those MDS with 3q chromosome rearrangements. The recent WHO classification recognises an unclassifiable MDS/MPD category including some of these disorders. Our aim is to determine the frequency of presentation, subtype classification and chromosome abnormalities of MDS with thrombocytosis diagnosed in our institution. Between 1990 and 2003 we studied 317 SMD patients according to FAB and WHO revised classifications and identified 22 cases presenting thrombocytosis associated with dysplasia, that are analysed in this article.