骨髓增生异常综合征.ppt

Myelodysplastic syndromes (MDS)骨髓增生异常综合征骨髓增生异常综合征Chen Yun, MD, PhD陈昀陈昀Professor of Shandong UniversityJinan Central HospitalE-mail: Content•Definition（定义）•History（历史）•Etiology（流行病学）•Classifications（分类）•Pathogenesis（发病机理）•Diagnosis and differential diagnosis（诊断）•Treatment（治疗）Definition•Myelodysplastic syndrome (MDS) is a clonal disorder characterized by ineffective hematopoiesis, which led to either fatal cytopebias or acute myelogenous leukemias (AML) 克隆性疾病、无效造血、致命性血细胞减少症或急性髓细胞白血病演变•Pathogenetically related to about half of AML cases, especially in older patients 常见于老年人•Clinical features of MDS, are usually presented by bone marrow failure通常表现为骨髓衰竭•Peripheral blood cytopenias in combination with a hypercellular bone marrow exhibiting dysplastic changes are the hallmarks of MDS. History•1941, Bomford and Rhoads—Refractory anemia (RA)•1953, Block—Progression to leukemia (PL)•1956, Björkman—Refractory anemia with ringed sideroblats (RARS)•1970, Dreyfus—Refractory anemia with excess blats (RAEB)•1974, Miescher– Chronic myelomonocytic leukemia (CMML)•1976, FAB cooperative group-the definition of Myelodysplatic syndrome (MDS)•1982, FAB cooperative group-the diagnosis and classification of MDS•1987, Benner—Morphological, Immunogical, and Cytogenetic classification of MDS•2000, World Health Organization (WHO)—MDS is categorized to myeloid malignances Etiology•The incidence curves for populations at risk for AML and MDS are similar in shape, with MDS exceeding AML and with a potential increase for both with advancing age.•Similar to AML, the sex distribution of MDS is approximately equal until age 60, after which a substantial male predominance develops. •MDS-related AML, a subtype of AML, mirrors the incidence of AML, including the progressive male predominance that develops with advancing age beyond 60 years. Classification-FAB•In 1982, the French-American-British (FAB) Cooperative Group classified five subtitles of MDS–Refractory anemia (RA)–Refractory anemia with excess of blasts (RAEB)–Refractory anemia with excess of blasts in transformation (RAEB-T)–Refractory anemia with ringed sideroblasts (RARS)–Chronic myelomonocytic leukemia (CMML)Classification-WHO•The classification based on morphologic criteria was revised resulting in WHO classification, which provides more homogenous MDS categories but eliminates the “RAEB-T” category.•The better prognosis of patients with an isolated cytogenetic aberration at 5q was identified as 5q-•Patients with >10% BM blasts have a shorter median survival and a higher transformation rate to AML as compared to those with ≤10% blasts, RAEB is divided into two subgroups, RAEB-1 and RAEB-2, depending on the number of blasts in BM and PB. •In addition to the number of blast cells, the presence of Auer robs can be predictive for RAEB-2. Classification-WHOComparison of FAB and WHO classifications of MDSInternational Prognostic Scoring System (IPSS)•The initial chromosomal aberration, the age of patients, and the number and severity of the cytopenia are important to evaluate the prognosis of MDS as summarized in IPSS.•The median survival of MDS patients according to this classification ranges from 6 years for low-risk to 6 months for high-risk patients. •Therefore, the implication of this scoring system in any clinical trial evaluating treatment options in MDS is now a standard requirement. International Prognostic Scoring System for Risk Assessment in Primary MDSIPSS Groups and OutcomesMorphologic features of MDS•A variety of morphologic abnormalities of all three hematoloietic lines are found in blood and marrow in MDS. •In peripheral blood, common findings in red cells are macrocytic or dimorphic (macrocytic and normocytic) populations, basophilic stippling, and nucleated red blood cells. Granulocytes may have Pelger-Huet morphology, hepersegmentation, hypogranulation, and immature forms. Platelets may be large, agranular, or vacuolated. •In marrow, additional erythroid changes are megaloblastoid changes (nucleocytoplasmic asynchrony), irregular nuclear shapes, bi- or multinucleation, ringed and abnormal siderob;asts, PAS positivity, and internuclear bridging (INB). Additional granulocytic changes include megaloblastoid or blocked maturation and loss of MPO reactivity. •Megakaryocytes may be small woth single or multiple small nuclei, larger and monolobate, or large with large, hyperchromatic, irregular nuclei. Immature cells in peripheral blood may show most of the same features as marrow cells. DysplasiaHypogranulationMultinuclearityNegative for neutrophil myeloperoxidase Morphologic features of MDSRefractory anemia(marrow clot section)HyperproliferationRefractory anemia(marrow smear)Ineffective erythropoiesisRefractory anemiaWith ringed sideroblasts(iron staining)Morphologic features of MDSRefractory anemiaWith excess blasts(RAEB-1)Marrow blasts 5~9%Refractory anemia with excess blasts(RAEB-2)Marrow blasts 10~19%Transformation (Progression) to leukemiaMarrow blasts≥20%Application of immunophenotyping to MDS•In additional to acquired morphologic functional, cytogenetic, and production abnormalities, marrow cells in MDS frequently demonstrate aberrant patterns of differentiation antigen expression and lineage-aberrant antigen expression. •Flowcytometry (FCM) in MDS using a panel of antibodies similar to those for AL has demonstrated aberrant differentiation patterns in both myeloid and erythroid precursors and lineage-aberrant antigen expression in myeloid precursors in a large percentage of cases.•This approach may provide additional information to confirm diagnosis of MDS in difficult cases and may possibly contribute to subclassification of MDS. •However, evaluation of both myeloid and erythroid lineages for this purpose requires use of a large panel of antigens, and this approach has not yet gained widespread clinical use. •If validate and simplified with improvements in flow technology, it may become a valuable adjunct for diagnosis and subclassification of MDS. Cytogenetic and molecular alterations in MDS •The cytogenetic changes found in MDS are not unique. Both structural and numerical cytogenetic changes may occur. •The most frequent chromosomal abnormalities in MDS involved deletions of chromosomes 5, 7, 11, 12, and 20 and/or trisomy 8. •The incidence of chromosomal abnormalities is about 30%~50% in primary MDS and 80% in mutagen-related MDS. •The latter often has complex changes that frequently involve deletions of chromosomes 5 and/or 7 or the long arms of these chromosomes. •Relative percentage of various cytogenetic abnormalities in de novo myelodysplastic syndrome (MDS).Cytogenetic and molecular alterations in MDS•Translocations are rare in MDS. •MDS-related chromosomal deletions suggest that tumor suppressor genes or DNA repair genes are altered in this group of disease. •Usually these changes require two hits: mutation of the target gene and loss of the second allele through one of several genetic events including deletion, duplication, or recombination. FISH for 5q deletion位于5q31上的红色信号只有一个，表示5q31缺失。

探针：1、EGR1（红色），定位：5q31； 2、D5S23，D5S721（绿色），定位：5p15位于5q33上的红色信号只有1个，表示5q33缺失探针：1、CSF1R（红色），定位：5q33； 2、D5S23，D5S721（绿色），定位：5p15Pathogenesis•The underlying causes of primary MDS are still being defined. •A proposal for multistep pathogenesis of MDS is shown. •After initial damage of the progenitor cell by a toxin or spontaneous mutation, several additional laterations may affect these cells providing them with a growth advantage. •These alterations can influence expression of cell cycle-related genes, transceiption factors as well as tumor suppressor genes. Pathogenesis•Enhanced intramedullary apoptosis may contribute to the ineffective hematopoiesis in MDS. •The activity of the caspases 1 and 3 was found to be increases in bone marrow cells from patients with low-risk MDS. •Early MDS was described to be associated with an elevated ration of apoptosis to proliferation, but the mechanisms for this finding are not yet established. •Recently, microarray analyses can provide sufficient data to detect genes or gene patterns that associated with MDS, for example, hypermethylation. The approach may have a strong impact on the further classification and risk definition of MDS. Multistep pathogenesis in MDSOutcome and prognostic factors•The evaluation of disease risk and outcome of patients with MDS is one of the most critical points. •The introduction of IPSS could demonstrate for the first time that multiple parameters including chromosomal changes, bone marrow blast cells, and the number of cytopenias are required to predict for the survival and transformation rate to AML. •In patients with IPSS low or intermediate-1 risk, the disorder can be stable for years without worsening of anemia or symptoms. The median survival is about 6 years. •In such patients, iron overloaded is a common problem in polytransfused patients leading to secondary hemosiderosis and sometimes to hemochromatosis. •The survival time is considerably shorter for patients with increased blasts in the bone marrow.Outcome and prognostic factors•Besides the application of classical morphological and cytogenetical techniques, the introduction of mutational and epigenetic (DNA-methylation) analysis of key genes (eg FILT3, CHK2, p14ARF, p15INK4b, p16INK4a) involved into the cell cycle provided evidence for the risk evaluation in MDS. •Furthermore, it has been recently shown that gene expression profiling of hematopoietic stem cells od patients with MDS can distinguish between low- and high-risk patients with high accuracy. •The knowledge about the risk classification of MDS at time of initial diagnosis could result in more individule treatment strategies in patients with MDS. Differential Diagnosis•The clinical diagnosis of typical MDS according to FAB criteria is often straightfoward and presents no difficulty. While the diagnosis may be suspected on the basis of the history and the peripheral blood findings, morphological examination of BM is essential to establish the diagnosis. •Exclusion of hypoplastic/aplastic anemia may be difficult in hypocellular MDS. •Rarely, disorders with hypoplastic hematopoiesis, for example, amegakaryocytic thrombocytopenia, chronic neutropenia, and aplastic anemia can evolve into acute leukemia and must be distinguished from MDS. In these cases, chromosomal abnormalities may be helpful to verify MDS. Differential Diagnosis•Serum vitamin B12 and folate levels are often measured to exclude these vitamin deficiencies. •In younger patients, congenital dyserythropoietic anemias and pure red cell anemia must be considered, the latter can be associated with MDS. •Sideroblastic changes may also be caused by drugs (chloramphenicol, tuberculostatic agents, penicillamine), or alcohol, and occupational toxins (lead, benzene), or be associated with nonmalignant disorders (renal or hepatic failure, connective tissue disease).Differential Diagnosis•Individuals infected with human immunodeficiency virus can have morphological features of MDS in their bone morrow and they have to be distinguished from primary MDS. •Disorders that result in peripheral destruction of the mature cells (immune phenomena, infectious agents, mechanical hemolysis, hypersplenism) must be excluded. •The distinction between CMML and chronic myelogenous leukemia (CML) can sometimes present diagnostic difficulties. Cytogenetic (Philadelphia chromosome) and molecular (bcr-abl-translocation) studies will help in such cases. •On the other hand, the distinction between osteomyelofibrosis and MDS with accompanying myelofibrosis can be difficult. Treatment Strategies•Patients with MDS are mainly older patients suffering from accompanying diseases. Therefore, various strategies have been used to treat patients with MDS. •Rather than offer a curative therapeutic option (which is allogeneic hematopoietic cell transplantation), the main therapeutic goal in patients with MDS is to improve the hematopoiesis and ensure the age-related quality of life. Treatment Strategies for Low-risk MDS•Low-intensity therapies, defined as treatments capable of permitting an outpatient management, are often directed at patients with low-risk MDS (IPSS low and intermediate-1). •Using such strategies, the goal is to improve hematopoiesis and to minimize the number of red blood cell transfusions. •Such strategies are not necessarily associated with improved overall survival or progression-free survival. Treatment Strategies for High-risk MDS•Patients with high-risk MDS (IPSS intermediate-2 and high) have a need to receive high-intensity therapies (aggressive antileukemic chemotherapy and/or hematopoietic cell transplantation) to eliminate the expanded clonal cells and to induce hematological responses. •As a result of the high median age of patients with MDS, only about one-third of high-risk MDS patients can enter intensive cytotoxic treatment. •For patients not qualifying for intensive therapy, the application of experimental treatment to suppress, differentiate, or eradicate the malignant clone are under investigation. New aspects in treatment of MDS•Demethylating agents•Immunosuppressive agents•Differentiation-inducing therapy•Antiangiogenic agents•Future experimental approachesDemethylating agents•Many genes have regions in their promoter (CpG islands) that can be methylated at the 5’ position of cytosine, which silences expression of these genes. •Theoretically, demethylation of methylated genes that are important in differentiation and/or apoptosis could have clinical applications. Demethylating agents•Initial pilot trials with low-dose Azacitidine and low-dose Decitabine provided encouraging results that were confirmed in multicenter studies. •The results of a multicenter phase II trial with low-dose intravenous Decitabine (45 mg/m2 for 3 days every 6 weeks) were reported for 66 mostly elderly patients with advanced (24% Int-1, 38% Int-2, 38% high-risk) MDS. The overall hematologic response rate was 49%, which included a response of 64% for high-risk individuals. •Cytogenetic remission following treatment with Decitabine have been noted in 31% of patients with an abnormal karyotype, and 38% with complex karyotype and/or chromosome 7 abnormalities. Immunosuppressive agents•Antithymocyte globulin (ATG)–ATG has been successfully in the treatment of severe aplastic anemia. In a large study, 42 transfusion-dependent MDS patients received ATG (40mg/kg/day for 4 days). RBC transfusion independence occurred in 16 individuals, and platelets increased in 14 of them. Three individuals with RA had a complete remission. The response rate was 64% in the low-risk individuals and 33% in those with high-risk MDS. •Cyclosporin A (CSA)–CSA can be effective in improving anemia in autoimmune disorders. Several small studies used CSA for MDS patients with variable results. A predictive marker for a good response may be the expression of the JLA-DRB1*1501 allele. Differentiation-inducing therapy•Arsenic trioxide (As2O3)–Arsenic trioxide has been used therapeutically for at least a millennium in China. It was employed in the middle of the last century in the Western countries for treatment of chronic myelogenous leukemia (CML). Most recently, it has produced very good response in acute promyelocytic leukemia (APL). Clinical studies to evaluate Arsenic trioxide in MDS are underway. Antiangiogenic agents•The bone marrow of individuals with MDS contains an abnormally high number of blood vessels. This has encouraged the investigation of inhibitors of angiogenesis such as thalidomide, lenalidomide, and inhibitors of vascular endothelial growth factors (VEGF) for individuals with either AML or MDS. •Thalidomide was initially developed to used as to anti reaction of pregnancy, but it was found to have activity in the treatment of patients with multiple myeloma. Using this drug either alone or in combination with Topotecan, Pentoxifyllin, resulted in 30~40% of MDS patients showing a hematopoietic response, usually an improved erythropoiesis. Intensive cytotoxic treatment•At the present time, long-term benefit for individuals with MDS can be achieved only by eradication of the abnormal clone and restoration of normal hematopiesis. As a consequence of the improved supportive care in patients receiving intensive cytotoxic treatment, during the last years the remission rate which is achieved in younger patients with high-risk MDS is comparable with those known from patients with de novo AML. •However, data from EORTC and MD Anderson Cancer Center, neither the chemotherapy nor the transplantation could show a clear benefit for those patients. Intensive cytotoxic treatment•The decision whether aggressive treatment may be of benefit for an individual should include stratification according to their risk factors using the IPSS. Also, the use of hematopoietic growth factors permits more patients to receive intensive cytotoxic treatment. •Nevertheless, the duration of remissions are associated with restoration of polyclonal hemopoiesis, and the achievement of a partial remission after induction therapy may be of clinical benefit for high-risk patients. Overall treatment approach in MDS•The treatment decision should take into consideration–Disease risk according to IPSS–Age of the patients–Performance status of the patients•Based on these results, and keeping in mind the median survival determined by IPSS (low-risk, 5.7 years; intermediate risk, 1.2~3.5 years; high-risk, 0.5 years), four possible treatment strategies are as followsFor younger patients who are candidate of HCT•Individuals up to the (biological) age of approximately 55~60 years are candidate for allogeneic transplantation from HLA-matched (sibling or unrelated) donor. The patients should be carefully informed about the risks of the allogeneic hematopoietic cell transplantation including informing about the necessary, sometimes long-term prophylaxis against graft-versus-host disease. The alternative treatment options should be mentioned in detail. For patients with low- or Int-1 risk •Patients with low or intermeidate-1 risk MDS who have no HLA-identical donor or are older than 60 years with good clinical performance should receive either supportive care or when necessary a trial of erythropoietin. •For non-responder to erythropoietin, the combination therapy of erythropoietin with G-CSF may be effective. •Alternatively, immunosuppressive therapy should be considered. •As their disease progresses, various therapies might be evaluated in the context of ongoing clinical studies. For patients with Int-2 or high risk•Patients with intermediate-2 or high risk MDS, older than 60 years and have a good clinical performance, are candidates for intensive cytotoxic therapy, followed by consolidation therapy and perhaps autologous transplantation. Elder patients or with poor performance•Individuals who are elder and/or in poor clinical condition should receive supportive care and if possible and desired by the patients investigational, outpatient-based therapy (eg demethylating drugs or thalidomide). Summary •MDS is heterogenous, from refractory anemia to progression to AML. The median survival is very different. •Recently development in understanding of the underlying pathogenesis and the classification depended on the outcome of the disease has already improved some of the patients. •Individualization of therapeutic strategies is very important both for prolonging the survival and improving the quality of life for patients with MDS. Myelodysplastic syndromes (MDS)Guo Nongjian, MD, PhDProfessor of Shandong UniversityJinan Central HospitalContent•Definition•History•Etiology•Classifications•Pathogenesis•Diagnosis and differential diagnosis•TreatmentDefinition•Myelodysplastic syndrome (MDS) is a clonal disorder characterized by ineffective hematopoiesis, which led to either fatal cytopebias or acute myelogenous leukemias (AML) •Pathogenetically related to about half of AML cases, especially in older patients•Clinical features of MDS, are usually presented by bone marrow failure•Peripheral blood cytopenias in combination with a hypercellular bone marrow exhibiting dysplastic changes are the hallmark of MDS. History•1941, Bomford and Rhoads—Refractory anemia (RA)•1953, Block—Progression to leukemia (PL)•1956, Björkman—Refractory anemia with ringed sideroblats (RARS)•1970, Dreyfus—Refractory anemia with excess blats (RAEB)•1974, Miescher– Chronic myelomonocytic leukemia (CMML)•1976, FAB cooperative group-the definition of Myelodysplatic syndrome (MDS)•1982, FAB cooperative group-the diagnosis and classification of MDS•1987, Benner—Morphological, Immunogical, and Cytogenetic classification of MDS•2000, World Health Organization (WHO)—MDS is categorized to myeloid malignances Etiology•The incidence curves for populations at risk for AML and MDS are similar in shape, with MDS exceeding AML and with a potential increase for both with advancing age.•Similar to AML, the sex distribution of MDS is approximately equal until age 60, after which a substantial male predominance develops. •MDS-related AML, a subtype of AML, mirrors the incidence of AML, including the progressive male predominance that develops with advancing age beyond 60 years. Classification-FAB•In 1982, the French-American-British (FAB) Cooperative Group classified five subtitles of MDS–Refractory anemia (RA)–Refractory anemia with excess of blasts (RAEB)–Refractory anemia with excess of blasts in transformation (RAEB-T)–Refractory anemia with ringed sideroblasts (RARS)–Chronic myelomonocytic leukemia (CMML)Classification-WHO•The classification based on morphologic criteria was revised resulting in WHO classification, which provides more homogenous MDS categories but eliminates the “RAEB-T” category.•The better prognosis of patients with an isolated cytogenetic aberration at 5q was identified as 5q-•Patients with >10% BM blasts have a shorter median survival and a higher transformation rate to AML as compared to those with ≤10% blasts, RAEB is divided into two subgroups, RAEB-1 and RAEB-2, depending on the number of blasts in BM and PB. •In addition to the number of blast cells, the presence of Auer robs can be predictive for RAEB-2. Classification-WHOComparison of FAB and WHO classifications of MDSInternational Prognostic Scoring System (IPSS)•The initial chromosomal aberration, the age of patients, and the number and severity of the cytopenia are important to evaluate the prognosis of MDS as summarized in IPSS.•The median survival of MDS patients according to this classification ranges from 6 years for low-risk to 6 months for high-risk patients. •Therefore, the implication of this scoring system in any clinical trial evaluating treatment options in MDS is now a standard requirement. International Prognostic Scoring System for Risk Assessment in Primary MDSIPSS Groups and OutcomesMorphologic features of MDS•A variety of morphologic abnormalities of all three hematoloietic lines are found in blood and marrow in MDS. •In peripheral blood, common findings in red cells are macrocytic or dimorphic (macrocytic and normocytic) populations, basophilic stippling, and nucleated red blood cells. Granulocytes may have Pelger-Huet morphology, hepersegmentation, hypogranulation, and immature forms. Platelets may be large, agranular, or vacuolated. •In marrow, additional erythroid changes are megaloblastoid changes (nucleocytoplasmic asynchrony), irregular nuclear shapes, bi- or multinucleation, ringed and abnormal siderob;asts, PAS positivity, and internuclear bridging (INB). Additional granulocytic changes include megaloblastoid or blocked maturation and loss of MPO reactivity. •Megakaryocytes may be small woth single or multiple small nuclei, larger and monolobate, or large with large, hyperchromatic, irregular nuclei. Immature cells in peripheral blood may show most of the same features as marrow cells. DysplasiaHypogranulationMultinuclearityNegative for neutrophil myeloperoxidase Morphologic features of MDSRefractory anemia(marrow clot section)HyperproliferationRefractory anemia(marrow smear)Ineffective erythropoiesisRefractory anemiaWith ringed sideroblasts(iron staining)Morphologic features of MDSRefractory anemiaWith excess blasts(RAEB-1)Marrow blasts 5~9%Refractory anemia with excess blasts(RAEB-2)Marrow blasts 10~19%Transformation (Progression) to leukemiaMarrow blasts≥20%Application of immunophenotyping to MDS•In additional to acquired morphologic functional, cytogenetic, and production abnormalities, marrow cells in MDS frequently demonstrate aberrant patterns of differentiation antigen expression and lineage-aberrant antigen expression. •Flowcytometry (FCM) in MDS using a panel of antibodies similar to those for AL has demonstrated aberrant differentiation patterns in both myeloid and erythroid precursors and lineage-aberrant antigen expression in myeloid precursors in a large percentage of cases.•This approach may provide additional information to confirm diagnosis of MDS in difficult cases and may possibly contribute to subclassification of MDS. •However, evaluation of both myeloid and erythroid lineages for this purpose requires use of a large panel of antigens, and this approach has not yet gained widespread clinical use. •If validate and simplified with improvements in flow technology, it may become a valuable adjunct for diagnosis and subclassification of MDS. Cytogenetic and molecular alterations in MDS •The cytogenetic changes found in MDS are not unique. Both structural and numerical cytogenetic changes may occur. •The most frequent chromosomal abnormalities in MDS involved deletions of chromosomes 5, 7, 11, 12, and 20 and/or trisomy 8. •The incidence of chromosomal abnormalities is about 30%~50% in primary MDS and 80% in mutagen-related MDS. •The latter often has complex changes that frequently involve deletions of chromosomes 5 and/or 7 or the long arms of these chromosomes. •Relative percentage of various cytogenetic abnormalities in de novo myelodysplastic syndrome (MDS).Cytogenetic and molecular alterations in MDS•Translocations are rare in MDS. •MDS-related chromosomal deletions suggest that tumor suppressor genes or DNA repair genes are altered in this group of disease. •Usually these changes require two hits: mutation of the target gene and loss of the second allele through one of several genetic events including deletion, duplication, or recombination. FISH for 5q deletion位于5q31上的红色信号只有一个，表示5q31缺失。

探针：1、EGR1（红色），定位：5q31； 2、D5S23，D5S721（绿色），定位：5p15位于5q33上的红色信号只有1个，表示5q33缺失探针：1、CSF1R（红色），定位：5q33； 2、D5S23，D5S721（绿色），定位：5p15Pathogenesis•The underlying causes of primary MDS are still being defined. •A proposal for multistep pathogenesis of MDS is shown. •After initial damage of the progenitor cell by a toxin or spontaneous mutation, several additional laterations may affect these cells providing them with a growth advantage. •These alterations can influence expression of cell cycle-related genes, transceiption factors as well as tumor suppressor genes. Pathogenesis•Enhanced intramedullary apoptosis may contribute to the ineffective hematopoiesis in MDS. •The activity of the caspases 1 and 3 was found to be increases in bone marrow cells from patients with low-risk MDS. •Early MDS was described to be associated with an elevated ration of apoptosis to proliferation, but the mechanisms for this finding are not yet established. •Recently, microarray analyses can provide sufficient data to detect genes or gene patterns that associated with MDS, for example, hypermethylation. The approach may have a strong impact on the further classification and risk definition of MDS. Multistep pathogenesis in MDSOutcome and prognostic factors•The evaluation of disease risk and outcome of patients with MDS is one of the most critical points. •The introduction of IPSS could demonstrate for the first time that multiple parameters including chromosomal changes, bone marrow blast cells, and the number of cytopenias are required to predict for the survival and transformation rate to AML. •In patients with IPSS low or intermediate-1 risk, the disorder can be stable for years without worsening of anemia or symptoms. The median survival is about 6 years. •In such patients, iron overloaded is a common problem in polytransfused patients leading to secondary hemosiderosis and sometimes to hemochromatosis. •The survival time is considerably shorter for patients with increased blasts in the bone marrow.Outcome and prognostic factors•Besides the application of classical morphological and cytogenetical techniques, the introduction of mutational and epigenetic (DNA-methylation) analysis of key genes (eg FILT3, CHK2, p14ARF, p15INK4b, p16INK4a) involved into the cell cycle provided evidence for the risk evaluation in MDS. •Furthermore, it has been recently shown that gene expression profiling of hematopoietic stem cells od patients with MDS can distinguish between low- and high-risk patients with high accuracy. •The knowledge about the risk classification of MDS at time of initial diagnosis could result in more individule treatment strategies in patients with MDS. Differential Diagnosis•The clinical diagnosis of typical MDS according to FAB criteria is often straightfoward and presents no difficulty. While the diagnosis may be suspected on the basis of the history and the peripheral blood findings, morphological examination of BM is essential to establish the diagnosis. •Exclusion of hypoplastic/aplastic anemia may be difficult in hypocellular MDS. •Rarely, disorders with hypoplastic hematopoiesis, for example, amegakaryocytic thrombocytopenia, chronic neutropenia, and aplastic anemia can evolve into acute leukemia and must be distinguished from MDS. In these cases, chromosomal abnormalities may be helpful to verify MDS. Differential Diagnosis•Serum vitamin B12 and folate levels are often measured to exclude these vitamin deficiencies. •In younger patients, congenital dyserythropoietic anemias and pure red cell anemia must be considered, the latter can be associated with MDS. •Sideroblastic changes may also be caused by drugs (chloramphenicol, tuberculostatic agents, penicillamine), or alcohol, and occupational toxins (lead, benzene), or be associated with nonmalignant disorders (renal or hepatic failure, connective tissue disease).Differential Diagnosis•Individuals infected with human immunodeficiency virus can have morphological features of MDS in their bone morrow and they have to be distinguished from primary MDS. •Disorders that result in peripheral destruction of the mature cells (immune phenomena, infectious agents, mechanical hemolysis, hypersplenism) must be excluded. •The distinction between CMML and chronic myelogenous leukemia (CML) can sometimes present diagnostic difficulties. Cytogenetic (Philadelphia chromosome) and molecular (bcr-abl-translocation) studies will help in such cases. •On the other hand, the distinction between osteomyelofibrosis and MDS with accompanying myelofibrosis can be difficult. Treatment Strategies•Patients with MDS are mainly older patients suffering from accompanying diseases. Therefore, various strategies have been used to treat patients with MDS. •Rather than offer a curative therapeutic option (which is allogeneic hematopoietic cell transplantation), the main therapeutic goal in patients with MDS is to improve the hematopoiesis and ensure the age-related quality of life. Treatment Strategies for Low-risk MDS•Low-intensity therapies, defined as treatments capable of permitting an outpatient management, are often directed at patients with low-risk MDS (IPSS low and intermediate-1). •Using such strategies, the goal is to improve hematopoiesis and to minimize the number of red blood cell transfusions. •Such strategies are not necessarily associated with improved overall survival or progression-free survival. Treatment Strategies for High-risk MDS•Patients with high-risk MDS (IPSS intermediate-2 and high) have a need to receive high-intensity therapies (aggressive antileukemic chemotherapy and/or hematopoietic cell transplantation) to eliminate the expanded clonal cells and to induce hematological responses. •As a result of the high median age of patients with MDS, only about one-third of high-risk MDS patients can enter intensive cytotoxic treatment. •For patients not qualifying for intensive therapy, the application of experimental treatment to suppress, differentiate, or eradicate the malignant clone are under investigation. New aspects in treatment of MDS•Demethylating agents•Immunosuppressive agents•Differentiation-inducing therapy•Antiangiogenic agents•Future experimental approachesDemethylating agents•Many genes have regions in their promoter (CpG islands) that can be methylated at the 5’ position of cytosine, which silences expression of these genes. •Theoretically, demethylation of methylated genes that are important in differentiation and/or apoptosis could have clinical applications. Demethylating agents•Initial pilot trials with low-dose Azacitidine and low-dose Decitabine provided encouraging results that were confirmed in multicenter studies. •The results of a multicenter phase II trial with low-dose intravenous Decitabine (45 mg/m2 for 3 days every 6 weeks) were reported for 66 mostly elderly patients with advanced (24% Int-1, 38% Int-2, 38% high-risk) MDS. The overall hematologic response rate was 49%, which included a response of 64% for high-risk individuals. •Cytogenetic remission following treatment with Decitabine have been noted in 31% of patients with an abnormal karyotype, and 38% with complex karyotype and/or chromosome 7 abnormalities. Immunosuppressive agents•Antithymocyte globulin (ATG)–ATG has been successfully in the treatment of severe aplastic anemia. In a large study, 42 transfusion-dependent MDS patients received ATG (40mg/kg/day for 4 days). RBC transfusion independence occurred in 16 individuals, and platelets increased in 14 of them. Three individuals with RA had a complete remission. The response rate was 64% in the low-risk individuals and 33% in those with high-risk MDS. •Cyclosporin A (CSA)–CSA can be effective in improving anemia in autoimmune disorders. Several small studies used CSA for MDS patients with variable results. A predictive marker for a good response may be the expression of the JLA-DRB1*1501 allele. Differentiation-inducing therapy•Arsenic trioxide (As2O3)–Arsenic trioxide has been used therapeutically for at least a millennium in China. It was employed in the middle of the last century in the Western countries for treatment of chronic myelogenous leukemia (CML). Most recently, it has produced very good response in acute promyelocytic leukemia (APL). Clinical studies to evaluate Arsenic trioxide in MDS are underway. Antiangiogenic agents•The bone marrow of individuals with MDS contains an abnormally high number of blood vessels. This has encouraged the investigation of inhibitors of angiogenesis such as thalidomide, lenalidomide, and inhibitors of vascular endothelial growth factors (VEGF) for individuals with either AML or MDS. •Thalidomide was initially developed to used as to anti reaction of pregnancy, but it was found to have activity in the treatment of patients with multiple myeloma. Using this drug either alone or in combination with Topotecan, Pentoxifyllin, resulted in 30~40% of MDS patients showing a hematopoietic response, usually an improved erythropoiesis. Intensive cytotoxic treatment•At the present time, long-term benefit for individuals with MDS can be achieved only by eradication of the abnormal clone and restoration of normal hematopiesis. As a consequence of the improved supportive care in patients receiving intensive cytotoxic treatment, during the last years the remission rate which is achieved in younger patients with high-risk MDS is comparable with those known from patients with de novo AML. •However, data from EORTC and MD Anderson Cancer Center, neither the chemotherapy nor the transplantation could show a clear benefit for those patients. Intensive cytotoxic treatment•The decision whether aggressive treatment may be of benefit for an individual should include stratification according to their risk factors using the IPSS. Also, the use of hematopoietic growth factors permits more patients to receive intensive cytotoxic treatment. •Nevertheless, the duration of remissions are associated with restoration of polyclonal hemopoiesis, and the achievement of a partial remission after induction therapy may be of clinical benefit for high-risk patients. Overall treatment approach in MDS•The treatment decision should take into consideration–Disease risk according to IPSS–Age of the patients–Performance status of the patients•Based on these results, and keeping in mind the median survival determined by IPSS (low-risk, 5.7 years; intermediate risk, 1.2~3.5 years; high-risk, 0.5 years), four possible treatment strategies are as followsFor younger patients who are candidate of HCT•Individuals up to the (biological) age of approximately 55~60 years are candidate for allogeneic transplantation from HLA-matched (sibling or unrelated) donor. The patients should be carefully informed about the risks of the allogeneic hematopoietic cell transplantation including informing about the necessary, sometimes long-term prophylaxis against graft-versus-host disease. The alternative treatment options should be mentioned in detail. For patients with low- or Int-1 risk •Patients with low or intermeidate-1 risk MDS who have no HLA-identical donor or are older than 60 years with good clinical performance should receive either supportive care or when necessary a trial of erythropoietin. •For non-responder to erythropoietin, the combination therapy of erythropoietin with G-CSF may be effective. •Alternatively, immunosuppressive therapy should be considered. •As their disease progresses, various therapies might be evaluated in the context of ongoing clinical studies. For patients with Int-2 or high risk•Patients with intermediate-2 or high risk MDS, older than 60 years and have a good clinical performance, are candidates for intensive cytotoxic therapy, followed by consolidation therapy and perhaps autologous transplantation. Elder patients or with poor performance•Individuals who are elder and/or in poor clinical condition should receive supportive care and if possible and desired by the patients investigational, outpatient-based therapy (eg demethylating drugs or thalidomide). Summary •MDS is heterogenous, from refractory anemia to progression to AML. The median survival is very different. •Recently development in understanding of the underlying pathogenesis and the classification depended on the outcome of the disease has already improved some of the patients. •Individualization of therapeutic strategies is very important both for prolonging the survival and improving the quality of life for patients with MDS. 。