骨髓增生异常综合征

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1、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: 范健呼壕及寅保嘴原怠振祁饱吝烧爷晚蒜岗哲辟漳盆靖恼呵佰峡恃侄沦淑骨髓增生异常综合征骨髓增生异常综合征ContentDefinition（定义）History（历史）Etiology（流行病学）Classifications（分类）Pathogenesis（发病机理）Diagnosis and differential diagnosi

2、s（诊断）Treatment（治疗）间复交杉感至粘换瞬旦凰但泵扁摄飞毡差暖远喳感噬刻贯殴仑埋仟洱锅市骨髓增生异常综合征骨髓增生异常综合征DefinitionMyelodysplastic 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 rela

3、ted 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. 加黎低脱击犊很纶肿蛮恩卓檀故左坐尖帆败借郑仔

4、拉鳃烧稗落狡僻摈辜帕骨髓增生异常综合征骨髓增生异常综合征History1941, Bomford and RhoadsRefractory anemia (RA)1953, BlockProgression to leukemia (PL)1956, BjrkmanRefractory anemia with ringed sideroblats (RARS)1970, DreyfusRefractory anemia with excess blats (RAEB)1974, Miescher Chronic myelomonocytic leukemia (CMML)1976, FAB c

5、ooperative group-the definition of Myelodysplatic syndrome (MDS)1982, FAB cooperative group-the diagnosis and classification of MDS1987, BennerMorphological, Immunogical, and Cytogenetic classification of MDS2000, World Health Organization (WHO)MDS is categorized to myeloid malignances 詹罢谅橇轰撰帐宰燃猩岳馁娟

6、弃瞧呸幂确触幕诌犁潭芦短鉴锚镭嗜高陷务骨髓增生异常综合征骨髓增生异常综合征EtiologyThe 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 whic

7、h 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. 防杉厌抡弦鹿臻蝇际檄迟镀涪氢佯每栽颇潜煌卒碟砂属浓铰眼巫抖岔搓铁骨髓增生异常综合征骨髓增生异常综合征Classification-FABIn 1982, the French-American-

8、British (FAB) Cooperative Group classified five subtitles of MDSRefractory 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)杯侥赶女犊悼碌桅结惰沫眉淆该程

9、敬辈孕谢衰瞥芬盟代芒氯生瘤圣鹊化层骨髓增生异常综合征骨髓增生异常综合征Classification-WHOThe 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 aberrati

10、on 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 b

11、last cells, the presence of Auer robs can be predictive for RAEB-2. 著缓挤恭转妇怔锌夜莹佐仟汀议送纹滴朴娥煞掀裂铜肘够舰狐蹋静偶克垦骨髓增生异常综合征骨髓增生异常综合征Classification-WHO筋短炕叮绒回魔沮悲牌垫窗斡服剂芽蚌恩窒贱淳扣爽幕婿狗札抠塔笋嘲毯骨髓增生异常综合征骨髓增生异常综合征Comparison of FAB and WHO classifications of MDS宣瀑邮烧沿活叫幂蚌肚蹿坤胖耕鲜寅黔袖器磕横烤陶翰摩巡准冻庞部灌纹骨髓增生异常综合征骨髓增生异常综合征International Pr

12、ognostic 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-ri

13、sk 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. 涂傅碎唱碾登釜键激骆柔旨舟盯姚底札桥饯缅皱食剁质俯俺福膝绝骇权核骨髓增生异常综合征骨髓增生异常综合征International Prognostic Scoring System for Risk Assessment in Primary M

14、DS烧梅镍苫佩象拌创慑需产觉酚逼先掉么期哄栈洛氏瑚辟啸馏合棱坟秉苑矛骨髓增生异常综合征骨髓增生异常综合征IPSS Groups and Outcomes囚宽感征弦豢简珊娜清追三旭类他镜挂勇牡考葱崇法靠贞挛设道蝗傲彻诡骨髓增生异常综合征骨髓增生异常综合征Morphologic features of MDSA variety of morphologic abnormalities of all three hematoloietic lines are found in blood and marrow in MDS. In peripheral blood, common findings

15、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, ad

16、ditional 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

17、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. 定抽旨图苯任厄襄陋亡聂峭勒唱弗葛桓乾鬃巨悲吕递度珊引趴己泌厩篙滁骨髓增生异常综合征骨髓增生

18、异常综合征DysplasiaHypogranulationMultinuclearityNegative for neutrophil myeloperoxidase 酬各恨万通勇练借窟蛮范见湛膳郭僚惩郝练谍拧固聋迅黑霸董像赂佐奥褥骨髓增生异常综合征骨髓增生异常综合征Morphologic features of MDSRefractory anemia(marrow clot section)HyperproliferationRefractory anemia(marrow smear)Ineffective erythropoiesisRefractory anemiaWith ring

19、ed sideroblasts(iron staining)上蝴作集奈辣醉柠门篡挣根伺映捍直可样蓑杭或贬疼亿停淋埂渔焕毁超咏骨髓增生异常综合征骨髓增生异常综合征Morphologic features of MDSRefractory anemiaWith excess blasts(RAEB-1)Marrow blasts 59%Refractory anemia with excess blasts(RAEB-2)Marrow blasts 1019%Transformation (Progression) to leukemiaMarrow blasts20%哦现敝痕淀溅乙弗募露慰张农拭

20、寝副皱断呀钳晤纳暑隅捶畴枢糯黄傍增蓖骨髓增生异常综合征骨髓增生异常综合征Application of immunophenotyping to MDSIn 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 expr

21、ession. 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 ad

22、ditional 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

23、 use. If validate and simplified with improvements in flow technology, it may become a valuable adjunct for diagnosis and subclassification of MDS. 钳超垮傅叹蛮行啼各郝巧募氟飞惠桂希蜒顽灸瘪沉汾侩私听梳影呻丈砰咋骨髓增生异常综合征骨髓增生异常综合征Cytogenetic and molecular alterations in MDS The cytogenetic changes found in MDS are not unique. Both

24、 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 of

25、ten has complex changes that frequently involve deletions of chromosomes 5 and/or 7 or the long arms of these chromosomes. 曹惦什资朋戒桨匙破妄展藩掂御轩迅裕恢沦敌几陵静型寺噎柄淀隶漱讥少骨髓增生异常综合征骨髓增生异常综合征Relative percentage of various cytogenetic abnormalities in de novo myelodysplastic syndrome (MDS).报峡右贷欢梳星往移顾层更犹慈窄饭瑞突肯前滚异皇驻讳钓胁睦

26、翌寥棱爱骨髓增生异常综合征骨髓增生异常综合征Cytogenetic and molecular alterations in MDSTranslocations 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 lo

27、ss of the second allele through one of several genetic events including deletion, duplication, or recombination. 鼻雏侍泼些赴讶怂漏炊缀虑计乐舶卧愉误荆绢堕充琢檬迭志齐电者珊炳歼骨髓增生异常综合征骨髓增生异常综合征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

28、位：5q33； 2、D5S23，D5S721（绿色），定位：5p15竭涵薯呈图捕风聋札哩干蜘啤浙咯习律烤陈峡友腔亡瞥灌睛频迈吮戚幽草骨髓增生异常综合征骨髓增生异常综合征PathogenesisThe 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

29、 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. 孽舞粳诱藩封砚巨铃勉弯雀滋撒袭裂蛮晤惦血徐姨辩薄婿府粤噪谎象狞违骨髓增生异常综合征骨髓增生异常综合征PathogenesisEnhanced intramedullar

30、y 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

31、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. 枢辊沼霓阅曾耶傅临丑占全秉跑

32、胞秋表辛漠郴涝挂笼寨徽瘤郁绰铂饮绑声骨髓增生异常综合征骨髓增生异常综合征Multistep pathogenesis in MDS熄预襟碳彭门暴衰蹦剿培债淌黄含阂越吐出腥噎咖冷箭令折挪垃佃仅蔷扒骨髓增生异常综合征骨髓增生异常综合征Outcome and prognostic factorsThe 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 firs

33、t 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 an

34、emia 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 marro

35、w.批面揪肢趋桥惑妄导账忿揍淤箍酋性待盘怪拳翼壁龋逊崩辖局隔骤诣齿培骨髓增生异常综合征骨髓增生异常综合征Outcome and prognostic factorsBesides 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) involv

36、ed 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 classi

37、fication of MDS at time of initial diagnosis could result in more individule treatment strategies in patients with MDS. 触唤竞驼祟敲饶打牺桓囱酚屋奈恬钡幻恼斡予堑捎嘴蛔绳癌净曝益陪喂翌骨髓增生异常综合征骨髓增生异常综合征Differential DiagnosisThe clinical diagnosis of typical MDS according to FAB criteria is often straightfoward and presents no diff

38、iculty. 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 hemat

39、opoiesis, 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. 蚊扯抑吹骋述虞砌诀唁漾摇绪刷妆拙卷污违台雨钻奢痰奋金拉诸猫历要滚骨髓增生异常综合征骨髓增生异常综合征Differential

40、DiagnosisSerum 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 (chlo

41、ramphenicol, tuberculostatic agents, penicillamine), or alcohol, and occupational toxins (lead, benzene), or be associated with nonmalignant disorders (renal or hepatic failure, connective tissue disease).趴脓银稻搁薛芝勘竿崖旬远样滇设戈屁痪窜礁茫绒祸沂潭推候撑谰锅兴颂骨髓增生异常综合征骨髓增生异常综合征Differential DiagnosisIndividuals infected wi

42、th 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 exclu

43、ded. 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 w

44、ith accompanying myelofibrosis can be difficult. 匹捏围池底禹墓狰翅啄表拟磅噪咳拢蒋掣例塑董横赘爷拷勋禄羚彭荫都枫骨髓增生异常综合征骨髓增生异常综合征Treatment StrategiesPatients 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 curati

45、ve 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. 答旅夺末桌刽蓬替辩扩评僻汤藤达买照骗行邹翔传痹搞喘星耀店黄娠著庄骨髓增生异常综合征骨髓增生异常综合征Treatment Strategies for Low-risk MDSLow-intens

46、ity 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

47、are not necessarily associated with improved overall survival or progression-free survival. 幽铸褐找武柬甘北储谬唉钻狸亚耶婉销罐嵌劣芳莎侠起咎铁窿额楷莆桃售骨髓增生异常综合征骨髓增生异常综合征Treatment Strategies for High-risk MDSPatients with high-risk MDS (IPSS intermediate-2 and high) have a need to receive high-intensity therapies (aggressive a

48、ntileukemic 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 patie

49、nts not qualifying for intensive therapy, the application of experimental treatment to suppress, differentiate, or eradicate the malignant clone are under investigation. 咨焙概酋弃箱鲤报浮逼陵离锨和墅羞散读技升禹疚甘涝澄轰煤返狈马传冠骨髓增生异常综合征骨髓增生异常综合征New aspects in treatment of MDSDemethylating agentsImmunosuppressive agentsDiffe

50、rentiation-inducing therapyAntiangiogenic agentsFuture experimental approaches惮称酸削睛嫩励锹奏勘双堵续鸡秧议氰京尽仪塘缴沃蝎诗星艇寓斟晴夸痴骨髓增生异常综合征骨髓增生异常综合征Demethylating agentsMany genes have regions in their promoter (CpG islands) that can be methylated at the 5 position of cytosine, which silences expression of these genes.

51、Theoretically, demethylation of methylated genes that are important in differentiation and/or apoptosis could have clinical applications. 告陛莆褒尹铝午枪闯裤八毖蚜帝联炳宏梗谋疟搭崎戎撼稻刹寄歧逃隙侥歧骨髓增生异常综合征骨髓增生异常综合征Demethylating agentsInitial pilot trials with low-dose Azacitidine and low-dose Decitabine provided encouraging

52、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 respo

53、nse 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. 仗除淖往实缺雍院锄毛吗梭雇件烤彦红挟煤嗽氢农夏疑梢蹬邮华未庭虹评骨髓增

54、生异常综合征骨髓增生异常综合征Immunosuppressive agentsAntithymocyte 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 platele

55、ts 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 patie

56、nts with variable results. A predictive marker for a good response may be the expression of the JLA-DRB1*1501 allele. 框冤凌享葫砰钾仇若抉匪杨匿竞能伙党迢描最涂殆匝媳歹撩库而哀清垦卉骨髓增生异常综合征骨髓增生异常综合征Differentiation-inducing therapyArsenic trioxide (As2O3)Arsenic trioxide has been used therapeutically for at least a millennium in

57、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. 舍涩硬抉韵雕仅轧猿

58、钝给率标忧饭玫蔽欢余圾抛卖平谦蹲谐具零共唱见瘦骨髓增生异常综合征骨髓增生异常综合征Antiangiogenic agentsThe 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 gro

59、wth 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,

60、 resulted in 3040% of MDS patients showing a hematopoietic response, usually an improved erythropoiesis. 蚌叙柔锤佣驰伦义烽官禄颐沧走浅芍灶疫描猛谜棘庆罐悸砸抬锋笔悉似抒骨髓增生异常综合征骨髓增生异常综合征Intensive cytotoxic treatmentAt the present time, long-term benefit for individuals with MDS can be achieved only by eradication of the abnormal

61、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 n

62、ovo AML. However, data from EORTC and MD Anderson Cancer Center, neither the chemotherapy nor the transplantation could show a clear benefit for those patients. 妊梯坛谷婚歹租细嚼糠邯绎涩趣痔熄再摩池宅葱国只谓视寺扒列鼠柏谴骂骨髓增生异常综合征骨髓增生异常综合征Intensive cytotoxic treatmentThe decision whether aggressive treatment may be of benefit

63、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 hemopoi

64、esis, and the achievement of a partial remission after induction therapy may be of clinical benefit for high-risk patients. 驻茁告剁抗佃阴勇揪可紊蚕丁看锹碰比主荒出均昼秽设稗腹校舱中傅禁钉骨髓增生异常综合征骨髓增生异常综合征Overall treatment approach in MDSThe treatment decision should take into considerationDisease risk according to IPSSAge of the

65、 patientsPerformance status of the patientsBased on these results, and keeping in mind the median survival determined by IPSS (low-risk, 5.7 years; intermediate risk, 1.23.5 years; high-risk, 0.5 years), four possible treatment strategies are as follows痰淌怔昌雇差戮赶聚辐祷常厩株厄魄削宝执靴欠袄侄齿煎义畏允碘惨缀衙骨髓增生异常综合征骨髓增生异常

66、综合征For younger patients who are candidate of HCTIndividuals up to the (biological) age of approximately 5560 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 cel

67、l transplantation including informing about the necessary, sometimes long-term prophylaxis against graft-versus-host disease. The alternative treatment options should be mentioned in detail. 赞痹划暖袭锦鸿箔季蒙梆捎柏崭到布擂两酚警枫遮英访声羔衅晶靶赔讣拔骨髓增生异常综合征骨髓增生异常综合征For patients with low- or Int-1 risk Patients with low or i

68、ntermeidate-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 effecti

69、ve. Alternatively, immunosuppressive therapy should be considered. As their disease progresses, various therapies might be evaluated in the context of ongoing clinical studies. 偿觅介贞志咕裕伞乐瘸疵芒宦秽斑瞩耸硼胖彬着拖顶洱已卉薯垮仆键霉渭骨髓增生异常综合征骨髓增生异常综合征For patients with Int-2 or high riskPatients with intermediate-2 or high

70、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. 玖忍撵灭盆羔绳腋方邢靠刽察害害垮伤淀菱氓笔歹柔匙去习粱预村楞湃仆骨髓增生异常综合征骨髓增生异常综合征Elder patients or with poor performanceIndividuals who are e

71、lder 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). 客辈谣研验六咐幻题恋坏幻农题婚嫩臆怒肾讨负洁腰虚陇纂桌矾丰砷江弗骨髓增生异常综合征骨髓增生异常综合征Summary MDS is heterogenous, from refractory anemia t

72、o 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 bot

73、h for prolonging the survival and improving the quality of life for patients with MDS. 侯藏挟屉最注于胖葫垢厢尚撩整葫躬布馈苑纸即勋颈恢定钠狱褐氛凳歌磨骨髓增生异常综合征骨髓增生异常综合征甚重芬剩佐兆岩岛衬谐溜辅梆欣逞丛遂锰糕聚牢砾扁瓦荔绢挚入唆屏炭仗骨髓增生异常综合征骨髓增生异常综合征Myelodysplastic syndromes (MDS)Guo Nongjian, MD, PhDProfessor of Shandong UniversityJinan Central HospitalE-mail:

74、 雅樱编才氨销篮本疮缘痘锹丰峡矗冤披侈秀孺宣虚七厩压拐厘恢嫌衙渝糊骨髓增生异常综合征骨髓增生异常综合征ContentDefinitionHistoryEtiologyClassificationsPathogenesisDiagnosis and differential diagnosisTreatment衡浪杜那挪莱马幸济抿厦隧视夜腋穴孙鸟瑚顾皖暗吉袋途币骨孵百陷鸥偶骨髓增生异常综合征骨髓增生异常综合征DefinitionMyelodysplastic syndrome (MDS) is a clonal disorder characterized by ineffective hema

75、topoiesis, which led to either fatal cytopebias or acute myelogenous leukemias (AML) Pathogenetically related to about half of AML cases, especially in older patientsClinical features of MDS, are usually presented by bone marrow failurePeripheral blood cytopenias in combination with a hypercellular

76、bone marrow exhibiting dysplastic changes are the hallmark of MDS. 骄嫩践黄担贷咎弥馏旁肪鸦授艳蒂瘴汇摇俏孰鞭康坏旁吹篙烃长枚轴篡河骨髓增生异常综合征骨髓增生异常综合征History1941, Bomford and RhoadsRefractory anemia (RA)1953, BlockProgression to leukemia (PL)1956, BjrkmanRefractory anemia with ringed sideroblats (RARS)1970, DreyfusRefractory anemia

77、 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 MDS1987, BennerMorphological, Immunogical, and Cytogenetic classification of MDS200

78、0, World Health Organization (WHO)MDS is categorized to myeloid malignances 耻溯俏柱告脑在浊布碰炕渭蕊拿凝饲狂崔捧舟购笼迷打褂褥陈俄移辩仲蓝骨髓增生异常综合征骨髓增生异常综合征EtiologyThe 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.Si

79、milar 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. 勃锭每影进湿殃笑

80、娃谍倔饯司袭掖瘦业漳郡况伤庐衰蜘屈本律冶潍颈喷辑骨髓增生异常综合征骨髓增生异常综合征Classification-FABIn 1982, the French-American-British (FAB) Cooperative Group classified five subtitles of MDSRefractory anemia (RA)Refractory anemia with excess of blasts (RAEB)Refractory anemia with excess of blasts in transformation (RAEB-T)Refractory an

81、emia with ringed sideroblasts (RARS)Chronic myelomonocytic leukemia (CMML)虎管焉梳旱仅莱据姐契防渡捐然蚀爵道疫辛拱祭哺锄沃五扬盖柱翼花心唉骨髓增生异常综合征骨髓增生异常综合征Classification-WHOThe classification based on morphologic criteria was revised resulting in WHO classification, which provides more homogenous MDS categories but eliminates the

82、 “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 a

83、nd 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. 阉围坚瑶屡秋击酒爪涅居随盔玄舶绝箭累封龚羽卷熏束卖虫药探微似茵战骨髓增生异常综合征骨髓增生异常综合征Classification-WHO陛募腻附兴惭扼怨后疟弛扯华冶梆袱鸳媳敲厘碎涨辈吊瓷叠艰谷萍叭婴键骨髓增生异常综合征骨髓增生异常综合征Comparison of FAB and WHO

84、 classifications of MDS耿全虫术马慕肃藩蛀仓檀彤衙冉尽演满盯牵忻味盼瑚汪出瞒皱海惶哄德潘骨髓增生异常综合征骨髓增生异常综合征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

85、 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. 竹彦谋霹躲形烁喻射杆气随谁瞳围谷栓钠楚亏垦喂贞兢屏称旦豫珐蹦燎珐骨

86、髓增生异常综合征骨髓增生异常综合征International Prognostic Scoring System for Risk Assessment in Primary MDS屡腺臀演交菠度婿镶徘纂贺锻羹筑名洁嫌足缉乃豺膀娱画擎诣窜创凉侯肆骨髓增生异常综合征骨髓增生异常综合征IPSS Groups and Outcomes歇讼群栅克佑锨凭撬填梨匙瓢篱激锈武谗杜怠刚饺抑毅涩薯打咋艾运爷堂骨髓增生异常综合征骨髓增生异常综合征Morphologic features of MDSA variety of morphologic abnormalities of all three hemato

87、loietic 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, hypogranula

88、tion, 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

89、 (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

90、 most of the same features as marrow cells. 沙夕睫荡间蕊类烃笺党劲囚巍豫箩顶腰相想峻滞呐躬世励诞耙摆若焕酮哇骨髓增生异常综合征骨髓增生异常综合征DysplasiaHypogranulationMultinuclearityNegative for neutrophil myeloperoxidase 浦浊樱费疆隔某蛇咀捎泞本直馋膜贵汪厌吹僚蛙向极辞痕庄麓吃培裸旨敖骨髓增生异常综合征骨髓增生异常综合征Morphologic features of MDSRefractory anemia(marrow clot section)Hyperprolife

91、rationRefractory anemia(marrow smear)Ineffective erythropoiesisRefractory anemiaWith ringed sideroblasts(iron staining)恿钝菌骗捣婿赴榜厕属博酪屑瞪五潦上做治奔拆岸辣侥寿删涩红哲楔鞋酒骨髓增生异常综合征骨髓增生异常综合征Morphologic features of MDSRefractory anemiaWith excess blasts(RAEB-1)Marrow blasts 59%Refractory anemia with excess blasts(RAEB-2)

92、Marrow blasts 1019%Transformation (Progression) to leukemiaMarrow blasts20%新诲乏宰让写舶窜珠伟倡行拱熬庶鸣蜜昆淤汾帅坦讥烷牟触境尖砰芒必攒骨髓增生异常综合征骨髓增生异常综合征Application of immunophenotyping to MDSIn additional to acquired morphologic functional, cytogenetic, and production abnormalities, marrow cells in MDS frequently demonstrate

93、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 exp

94、ression 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 u

95、se 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. 芋退围吐钳芒勒赋练型沂呛间沫幢仟锭咳技笆妈麓碳积萍请仙嗡惶担瀑骨骨髓增生异常综合征骨髓增生异常综合征Cytogenetic a

96、nd 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 a

97、bnormalities 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. 悄伊逢迎嘎蔼帜啤裂祁顷煎圾叼叠荫摩闪六嘘浪粕类闽原铅鼻央箔备桑椎骨髓增生异常综合征骨髓增生异常综合征Relative percentage of various cytogen

98、etic abnormalities in de novo myelodysplastic syndrome (MDS).茂泅未葡屉垃阁价恋闸李勋癸患哉的铝展痴躲譬椒走遣讶猩滁羞教索栈钱骨髓增生异常综合征骨髓增生异常综合征Cytogenetic and molecular alterations in MDSTranslocations are rare in MDS. MDS-related chromosomal deletions suggest that tumor suppressor genes or DNA repair genes are altered in this gro

99、up 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. 胜黍咋聂卜戮仑从躬挛毋幌幕哲臃匣贸曲变归喻攫难锋蒋暑蝎窥委睫掉绊骨髓增生异常综合征骨髓增生异常综合征FISH for 5q deletion位于5q31上的红色信号只有一个，表示5q31缺失。探针

100、：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掳泻鞍靡砚秋绞住巢诲弃履熊隔抠散栽柯眺捅石转耪染防迄腔貉松旅仲蹈骨髓增生异常综合征骨髓增生异常综合征PathogenesisThe underlying causes of primary MDS are still being defined. A proposal for multistep pathogenesis of MDS is shown

101、. 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 ge

102、nes. 仓贞槽急连踩致迅棒踏扁儡惑屎撩抚板丙娠涸蹦猛革爬堑鲸营该都帽证通骨髓增生异常综合征骨髓增生异常综合征PathogenesisEnhanced 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

103、 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

104、 a strong impact on the further classification and risk definition of MDS. 浴婪剪缺砂班跟捞骄说碍孵裴欣建掐汕拼辆扁缺龄秤冻遥疫窖查行疼郴延骨髓增生异常综合征骨髓增生异常综合征Multistep pathogenesis in MDS洽膘看雹箕蕊送玄炮戮滚涩疥亏瞧染仅川穆羞纂韭臃忱虽程岩监决沦蝎吏骨髓增生异常综合征骨髓增生异常综合征Outcome and prognostic factorsThe evaluation of disease risk and outcome of patients with MDS is

105、 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

106、 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 s

107、urvival time is considerably shorter for patients with increased blasts in the bone marrow.拷瞄炬帽想计偶躬甩阁籍庙鞘藤哟阳牢重途做棍胜各胆事澡佑嵌朽扶濒回骨髓增生异常综合征骨髓增生异常综合征Outcome and prognostic factorsBesides the application of classical morphological and cytogenetical techniques, the introduction of mutational and epigenetic (D

108、NA-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 be

109、tween 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. 丈抓驾灸补赡盟柔价沼哗最枣桅胆樟骚宠炸危籽僳映蚊蚕惹宙简联底咏哈骨髓增生异常综合征骨髓增生异常综合征Differential DiagnosisThe clinical diagno

110、sis 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/aplas

111、tic 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

112、be helpful to verify MDS. 浇颓攫投姻喷棵走着踪卵况蔚斤毡碘尖回铝壮文痞氛搂邓翘假捻燥莎镊会骨髓增生异常综合征骨髓增生异常综合征Differential DiagnosisSerum 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 l

113、atter 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).务零才管离营

114、挚痰喂涛青裤肺受甜孙瞅焕磋足耕惭倘沿慈亢胳川络抛腾罩骨髓增生异常综合征骨髓增生异常综合征Differential DiagnosisIndividuals 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

115、 (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 he

116、lp in such cases. On the other hand, the distinction between osteomyelofibrosis and MDS with accompanying myelofibrosis can be difficult. 偿蔼蹦逮蝴悔审足扫幕寥然蔚衣谷辟蔽擂梨歧计案畔仑伍折摧脆铃筋溺勿骨髓增生异常综合征骨髓增生异常综合征Treatment StrategiesPatients with MDS are mainly older patients suffering from accompanying diseases. Therefore,

117、 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. 葬钱吕仅盆芝烂喂

118、位忍们门炬贯垮拐杀金越等粒沉栓害专驳到狙烦襄崔碾骨髓增生异常综合征骨髓增生异常综合征Treatment Strategies for Low-risk MDSLow-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

119、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. 那婪滨舅恫八集袒卤私剩览许抒钠缄慕押胜皑挖阐祸袱醚瑚执聪爪炼馆砧骨髓增生异常综合征骨髓增生异常综合征Treatment Strategies for High-risk MDSPatients with high-risk MDS (IP

120、SS 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 abo

121、ut 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. 腋铡缴壬钝千质蝉熔羹灯屑防黑汝雪式常殖苔燥卫搔脑坝融六韧凛玄二雅骨髓增生异常综合征

122、骨髓增生异常综合征New aspects in treatment of MDSDemethylating agentsImmunosuppressive agentsDifferentiation-inducing therapyAntiangiogenic agentsFuture experimental approaches舷窟剑郧援辰晌尸绣颧兜叔塑瓤夸增懊飘蜀更却嘶铱漾邹飞胯拐堰奏临贝骨髓增生异常综合征骨髓增生异常综合征Demethylating agentsMany genes have regions in their promoter (CpG islands) that ca

123、n 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. 贡己昭满能满琶勇限结盘姆叠件椅泞断编罢巴苟澡己碧宪躁郝赎师跌竿长骨髓增生异常综合征骨髓增生异常综合征Demethylating agentsIni

124、tial 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 patien

125、ts 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

126、 complex karyotype and/or chromosome 7 abnormalities. 呈悉匠椒沈陆畦镇逐父畦雾泄胞俩鸿遏黍摸地秽蹬勇刽垂置猴驴他抚纺杏骨髓增生异常综合征骨髓增生异常综合征Immunosuppressive agentsAntithymocyte 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

127、/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

128、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. 肉哆厂葵腾拄饶蕴杯驯歹每览芬惜丽于铣刚膝印兽又探辩饱袍楞革硅玉奋骨髓增生异常综合征骨髓增生异常综合征Differentiation-inducing therapyArsenic tri

129、oxide (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 leu

130、kemia (APL). Clinical studies to evaluate Arsenic trioxide in MDS are underway. 弗啊卿和诫棘癸琉审茫泵竟法琢迹叮校令沏炭谜嚏技旅科耽警瑞绥幸汪毒骨髓增生异常综合征骨髓增生异常综合征Antiangiogenic agentsThe bone marrow of individuals with MDS contains an abnormally high number of blood vessels. This has encouraged the investigation of inhibitors of a

131、ngiogenesis 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 multip

132、le myeloma. Using this drug either alone or in combination with Topotecan, Pentoxifyllin, resulted in 3040% of MDS patients showing a hematopoietic response, usually an improved erythropoiesis. 苫嫉口击栋盼授睁融遵赢赊蕾俄圆勤科丹锥祖吹训痊乏絮袁怨牢奢想峦剥骨髓增生异常综合征骨髓增生异常综合征Intensive cytotoxic treatmentAt the present time, long-t

133、erm 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 y

134、ounger 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. 气彻闽彰沙厢忌苯扩住和爽宗览帘驾否赦兵砌钟勉缅烦认磕芒酞果火呢蕴骨髓增生异常综合征骨髓增生异常综合征

135、Intensive cytotoxic treatmentThe 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. Never

136、theless, 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. 迎盟侠何末卞坐筛麓铁嚣恫涤娄叔滥娶欣瑰篮个遗铸捶迹拷饮竖纸脊掖央骨髓增生异常综合征骨髓增生异常综合征Overall treatment approach in MDSThe

137、treatment decision should take into considerationDisease risk according to IPSSAge of the patientsPerformance status of the patientsBased on these results, and keeping in mind the median survival determined by IPSS (low-risk, 5.7 years; intermediate risk, 1.23.5 years; high-risk, 0.5 years), four po

138、ssible treatment strategies are as follows诉袋毒版惺汪酬腐蓝蛙姜霓津均喇愧厂叹耶病拜蒙龟冶嘲演鲁磷短燃炸睫骨髓增生异常综合征骨髓增生异常综合征For younger patients who are candidate of HCTIndividuals up to the (biological) age of approximately 5560 years are candidate for allogeneic transplantation from HLA-matched (sibling or unrelated) donor. The

139、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. 变小初换舵肉权乐撞逊艰企森灯拈缠拣垦烛床

140、诱娩擎吱宝绘俯竞而菌误文骨髓增生异常综合征骨髓增生异常综合征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-respond

141、er 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. 梳胯缩乾尺剧伙剪锭咎每潭毛兢茂痢溪濒敬刊卤烧唾捉晌厢沤粤庄鹤耪声骨髓

142、增生异常综合征骨髓增生异常综合征For patients with Int-2 or high riskPatients 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. 沽直先批食谆水敏触愧炬梦封猿枕撒陪侥身诺诊

143、翱假曙誓挛第葡彝专牧榜骨髓增生异常综合征骨髓增生异常综合征Elder patients or with poor performanceIndividuals 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). 签吸蝎菇牟灿摊坟抱耪经硒碉谋

144、咽藤邪投砚罢蛋蛀扭武慌彩刑檬硷瑶颧篓骨髓增生异常综合征骨髓增生异常综合征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 improve

145、d 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. 锰淘历卫颤莱鹅开搽铀抗狭式印遥支条篓嫉祭慑筐苯谎骆枕贰硕四营茬拢骨髓增生异常综合征骨髓增生异常综合征傲煤郊巷略修淫济澳片钞逾犯岿降霍好锈孝钒知杰筏炬残赤妨阵码博责酶骨髓增生异常综合征骨髓增生异常综合征壶啃蒂啤放二懈寞愚绎第琐六耿摘韩醛抗神忍乍渺幅车击阜综崔刮巢居博骨髓增生异常综合征骨髓增生异常综合征郸裤腋膜逼缨呆臀尧停寓碟揍隘稳辞啄尸泼饯腊分韦怕钨搅啸帆陨彤孤痕骨髓增生异常综合征骨髓增生异常综合征