MDS去甲基化治疗课件

MDS去甲基化治疗研究进展内容： 一、DNA甲基化与MDS 二、NCCN指南关于MDS的治疗 三、国内MDS的治疗现状 四、去甲基化药物地西他滨治疗MDS的经验与体会DNA甲基化与MDS定义 骨髓增生异常综合征(MDS)是一类疾病: 骨髓中恶性细胞克隆形成并持续存在，产生的血细胞不能发育成熟 从而导致： 外周血细胞水平异常低下（细胞减少症） 血细胞功能和形态异常（发育不良） 恶性克隆中可能存在细胞遗传学异常 恶性克隆细胞逐渐取代正常造血***Themyelodysplasticsyndromes(MDS)areagroupofconditionsthatarecausedbytheabnormalmaturationofblood-formingcellsinthebonemarrow.Asaresult,thebonemarrowcannotproduceasufficientnumberofmaturebloodcells,andthosethatareproduceddonotfunctionnormally.Whiletheproductionoferythrocytes,granulocytes,monocytes,andplateletsmayallbeaffectedinpatientswithMDS,theywillusuallyhavenormalTandBlymphocytes.TheunderlyingcauseofMDSisachromosomalabnormalitythatdevelopsinahaematopoieticstemcellthatchangesitintoamalignantcell.TheabnormalitymayresultfromDNAdamagethatiscausedby,forexample,priorcancertherapyorexposuretoenvironmentaltoxins.Asthiscellreproducesbymitoticdivision,itformsacloneofcellsinwhichtheabnormalitypersists.Thedamagedstemcellpopulationproducesprogenitorblastcellsthatfailtorespondtonormalcontrolsignalsandthusfailtodifferentiateintofunctionalbloodcells.特征 MDS典型特征: 骨髓中异常增高的原始细胞 外周血成熟细胞减少 发育异常的外周血细胞功能异常***InMDS,thepopulationofblastcellsprogressivelyreplacesnormalbonemarrowcells.Asaresult,thenumberofblastcellsinthebonemarrowincreases,whilelevelsofmature,circulatingcellsdecline(cytopenias).Inaddition,manymaturecellsthatarereleasedintothebloodstreamhavevisiblecellularabnormalities(i.e.dysplasias)anddonotfunctionnormally.Thedefectivecellsproducecytokinesthatleadtoincreasedapoptosisinnormalcells.Thisphenomenoncontributestolowlevelsofcirculatingbloodcells.细胞遗传学细胞遗传学异常较常见(>50%)DüsseldorfRegistry:1080例MDS患者染色体异常的发生率goodintermediatepoor***ZytogenetischeAberrationentreteninca.50%auf流行病学 危险因素 老年 男性 曾有抗癌治疗，例如化疗和/或放疗 环境毒素接触史，例如有机溶剂 吸烟 先天性和遗传性疾病，例如范可尼贫血 ~30%为继发MDS 大多数为治疗相关的MDS(t-MDS)***ThegreatestriskfactorforMDSappearstobeolderage,butgenderalsoplaysarole,asMDSisdiagnosedsomewhatmorefrequentlyinmenthaninwomen.OtherimportantriskfactorsforthedevelopmentofMDSincludepriortreatmentforcancer,exposuretoenvironmentaltoxins,cigarettesmoking,congenitalandhereditarydisorders.PatientstreatedwithcertaincancerchemotherapydrugsaremorelikelytodevelopMDS.Inparticular,patientswhohavehadpreviousexposuretomechlorethamine,procarbazine,chlorambucil,etoposide,teniposide,andtoacertainextent,cyclophosphamideordoxorubicin,areatincreasedrisk.Theriskisfurtherincreasedamongpatientswhohavehadcombinationchemotherapyandradiotherapy(chemoradiotherapy).Prolongedorheavyexposuretoenvironmentaltoxins,suchasbenzene,organicsolvents,andcertainpesticides,hasalsobeenlinkedtothedevelopmentofsecondaryMDS.Inaddition,exposuretohigh-doseradiationpredisposesapersontothedisease.Cigarettesmokingistheonlylifestyle-relatedriskfactorforthedevelopmentofMDSandisalsoaknownriskfactorforacutemyeloidleukaemia(AML).CertainrarecongenitaldiseasessuchasFanconianaemiaareassociatedwithsecondaryMDS,andtherehavebeenreportsofMDSoccurringwithinfamilies,suggestingamutationthatcanbeinherited.Theseriskfactorsaccountforabout20-30%ofcasesandareknownassecondaryMDS.TheremainingcasesaresaidtobeprimaryMDS.Therapy-relatedMDSisbyfarthemostcommonformofsecondaryMDS.流行病学 MDS是一类老年性疾病: 70岁以上年龄组最高发 2.1-12.6/100,000每年 ~50/100,000在70+年龄组 MDS在男性中常见 男性发病率随年龄增长显著增高 M:F40岁~1.0 M:F>70岁~2.25GermingUetal.Haematologica2004;89:905-910***MDSisoneofthemostcommonhaematologicaldisorders.RegistrydatashowthatMDSisprimarilyadiseaseoftheelderly,withthehighestincidenceoccurringinpatientsaged80-90years.Theoverallincidenceofthediseasevariesfrom2.1-12.6per100,000populationperyearbutthisrisestoalmost50per100,000perannuminover70yearolds.Overall,thereisanexcessofMDSinmen,butthisismostobviouswithincreasingage.Inpatientsover70years,theincidenceinmenisapproximately54/100,000populationperannumcomparedwith24/100,000populationperannuminwomen.不同年龄段的发病率全球MDS患病率分布－byTrinityReport*亚太地区占有全球一半以上MDS人口MDS发病率的比较－byTrinityReport*提示：中国MDS的发病率约在2/100,000 Region IncidenceRate(per100,000) IncidenceRate95%CI Incidence2008 US 3.8 3.66-3.94 11,443 Europe 3.6 3.33-3.82 26,085 -G5 3.6 3.33-3.82 10,906 -EuropeII 3.6 3.33-3.82 15,179 AsiaPacific 2.8 2.17-3.43 90,021 -Japan 2.8 2.17-3.43 3,578 -China 2.8 2.17-3.43 37,012 Australia/NewZealand 3.6 3.33-3.82 876 Canada/LatinAmerica 2.9 2.91-2.99 17,544 -Canada 3.8 3.66-3.94 1,269 -LA 2.9 2.56-3.24 16,275 Africa/MiddleEast 2.8 2.17-3.43 36,976亚洲MDS分布－byIPSS分期系统 ThethreestudiesfromAsiareportingIPSSclassificationallsuggestasmallpercentofpatientsinLowriskgroupandalmost50%ofpatientsinInt-1group ComparisonofstudiesfromJapanandotherAsiannationsalsoshowsimilardistributionsfortheFABclassification*一项覆盖北京及上海13家top医院的调研显示：～50％的MDS患者为Int-2及高危患者 StudyGeography: WestAverage: China Korea Japan Low 8% 5% 11% 26% Int-1 48% 52% 42% 35% Int-2 27% 30% 29% 21% High 18% 12% 19% 8%临床表现 MDS可以有症状也可以无症状 症状包括: 疲劳 碰伤 出血 皮疹 呼吸急促 心动过速 体重减轻 发热 厌食 症状大多与血细胞减少有关***ManypatientswhodevelopMDSmayinitiallyhavenoapparentsymptoms,butarediagnosedafterroutinelaboratorytestsuncoverabnormalitiesinthecirculatingbloodcells.Alternatively,patientsmaydevelopsymptomsthatsuggestanunderlyingdisease.EarlysymptomsofMDSmayincludebruising,increasedbleeding(particularlynosebleedsorbleedinggumsduringbrushingoftheteeth),rash,shortnessofbreath,rapidheartrate,weightloss,fever,andlossofappetite.Fatigue,acommonsymptomofmanydifferenttypesofdisorders,isanimportantsymptomofconditionsthatareassociatedwithabnormalbloodcellcountsanddysplasias.FatigueisthemostcommonsymptomofMDS.Thesesymptomsarerelatedtoanumberofpossibledeficienciesincirculatingredbloodcells,whitebloodcells,and/orplatelets.ItisimportanttonotethatnoneofthesymptomsofMDSarespecifictothedisease.Infact,oneofthechallengesindiagnosingMDSisthatanyofthesesymptomsmaybeattributabletootherconditions.表观遗传学（epigenetics）1942年,沃丁顿（C.H.Waddington）首次提出表观遗传学(epigenetics)的概念1.基因序列不发生改变的情况下，基因的表达水平与功能发生改变，并产生可遗传的表型。2.特征:(1)可遗传；(2)可逆性；(3)DNA序列本身不变 表观遗传学的现象： DNA甲基化; 组蛋白修饰; 基因沉默等DNA甲基化DNA甲基化是最早发现的基因表观修饰方式之一 DNA甲基化主要形成5－甲基胞嘧啶（5-mC）和少量的N6-甲基嘌呤（N6-mA）及7－甲基鸟嘌呤（7-mG） DNA甲基化能引起染色质结构、DNA构象、DNA稳定性及DNA与蛋白质相互作用方式的改变，从而控制基因表达。DNA甲基化SAM=S-adenosylmethionine;SAH=S-adenosylhomocysteine.www.mdanderson.org/leukemia/methylation. DNA的甲基化是在DNA甲基化转移酶（DNMTs）的作用下使CpG二核苷酸5'端的胞嘧啶转变为5'甲基胞嘧啶。这种DNA修饰方式并没有改变基因序列，但是它调控了基因的表达DNA甲基转移酶 1)DNMT1,持续性DNA甲基转移酶——作用于仅有一条链甲基化的DNA双链,使其完全甲基化,可参与DNA复制双链中的新合成链的甲基化,DNMT1可能直接与HDAC(组蛋白去乙酰基转移酶)联合作用阻断转录 2)DNMT3a、DNMT3b从头甲基转移酶,它们可甲基化CpG,使其半甲基化,继而全甲基化。从头甲基转移酶可能参与细胞生长分化调控,其中DNMT3b在肿瘤基因甲基化中起重要作用。DNA甲基转移酶作用机理CGCGCGGCGCGCCH3CH3CH3DNMT1CGCGCGGCGCGCCH3CH3CH3CH3CH3CH3CGCGCGGCGCGCCGCGCGGCGCGCCH3CH3CH3CGCGCGGCGCGCCH3CH3CH3CH3CH3CH3DNMT3aDNMT3b全甲基化DNA半甲基化DNACpGIslands1)在基因组的某些区域中，CpG序列密度很高，可以达均值的5倍以上，成为鸟嘌呤和胞嘧啶的富集区，形成所谓的CpG岛2)CpG岛通常位于基因的启动子区或是第一个外显子区.3)健康人中，CpG岛中的CpG位点通常是处于非甲基化状态，而在CpG岛外的CpG位点则通常是甲基化的DNA甲基化与MDS甲基化状态的改变是MDS的一个重要特征,包括：基因组整体甲基化水平降低；CpG岛局部甲基化水平的异常升高； 从而导致的不稳定(如染色体的不稳定、可移动遗传因子的激活、原癌基因的表达)和抑癌基因的不表达。CommonGenesHypermethylatedinAdvancedMDSHyper-MethylatedGene GeneFunction MDS(%) Calcitonin Ca++boneresorption 40–80 p15INK4b Cyclin-depkinaseinhibitor 20–79 p16INK4b Cyclin-depekinaseinhibitor <10 ZO-1Closedasmallringprotein<10FHITOpenreadingframe<10AdaptedfromClausR.andM.Lubbert.Oncogene.2003;22:6489-96.*SLIDESCURRENTATTIMEOFPRINT*ThetumorsuppressorgenesthatundergoaberrantCpGislandmethylationinhumancanceraffectallthecellularpathwaysandhaverelevantconsequences.AbrieflistofthemostsignificantgenesinactivatedbyDNAhypermethylationinadvancedMDSandAMLisdepictedonthisslide.Someofthemostfrequentlyevaluatedgenesarethecyclin-dependentkinaseinhibitors,p15,p16,p21,andp57.Thep15INK4bandp16INK4agenesencodethecyclin-dependentkinases4and6andcontroltheprogressionofthecellcyclefromG1totheSPhase.1Inactivationofthesegeneshasbeendetectedinmanycancers,leadingtoinappropriatecellcycleprogression.2,3DNAhypermethylationofCpGislandsofthep15promoterregionhasbeenreportedinMDSandisassociatedwithlossofp15expression.4,5Therehasalsobeenacloseassociationbetweenthepercentageofbonemarrowblastsandp15hypermethylation.4,5ReferencesforSlideNotes:SerranoM,HannonGJ,BeachD.Nature.1993;366:704-707.NoboriT,MiuraK,WuDJ,etal.Nature.1994;368:753-756.KambA,GruisNA,Weaver-FeldhausJ,etal.Science.1994;264:436-440.QuesnelB,GuillermG,VereecqueR,etal.Blood.1998;91:2985-2990.UchidaT,KinoshitaT,NagaiH,etal.Blood.1997;90:1403-1409.p15INK4b 定位于染色体9P21位点附近 编码细胞周期蛋白依赖激酶抑制因子（CDKI），控制细胞周期过程。 P15的失活，引起G1期缩短，细胞周期加速，特别是DNA在没有修复前过早的进入S期。故P15及其产物是抑制细胞生长的重要途径，特别是负向调节造血细胞增生和阻止其恶性转化中起到重要作用。P15INK4b作用机理CD-CDK4/6（细胞周期蛋白依赖激酶复合物）RB蛋白（视网膜母细胞瘤蛋白）磷酸化促进P15基因CDK1(细胞周期蛋白依赖激酶抑制因子)STOPAssociationBetweenSurvivalandp15MethylationStatusinMDSQuesnel,etal.Blood.1998;91:2985.MethylatedUnmethylatedP=0.049*SLIDESCURRENTATTIMEOFPRINT*PrognosisofMDSpatientshasbeenlinkedtop15INK4b.Patientswithp15INK4bgenemethylationhadasignificantlyshortersurvivalthanunmethylatedcases(median18vs48months,P=0.049,log-ranktest).1Patientswithhypermethylationatthetimeofdiagnosiswerefoundtohavesignificantlyshortersurvivalthanthosepatientswithnormalmethylation.2Theinvestigatorsalsoassessedp15methylationpatternsin“lowrisk”disease(RAandRARS)withoutexcessblastsversusthoseseenin“highrisk”MDS(RAEB,RAEB-T,andCMML).p15methylationwasnotdetectablethroughoutthecourseof“lowrisk”disease;however,in“highrisk”MDS,theincidencerangedfrom23%atdiagnosisto30%atadvancedstates.InAMLthatpreviouslyevolvedfromMDS,p15hypermethylationisashighas60-75%.2Thismightindicatethep15hypermethylationisamarkerofleukemictransformationinMDS.Inadditionhypermethylationofthecalcitoningenehasalsobeenfoundin65%ofpatientswithMDS.3ReferencesforSlideNotes:Quesnel,etal.Blood.1998;91:2985TienHF,TangJH,TsayW,etal.BrJHaematol.2001;112:148-154.DhodapkarM,GrillJ,LustJA.LeukRes.1995;19:719-726.2010年第二版NCCN指南关于MDS的治疗 目录 工贸企业有限空间作业目录特种设备作业人员作业种类与目录特种设备作业人员目录1类医疗器械目录高值医用耗材参考目录 原发MDS分型系统 治疗 低危中危-1的治疗 中危-2高危的治疗 原发MDS分型系统MDS的FAB分类 FAB分型 外周血原始细胞% 骨髓原始细胞% 难治性贫血（RA） <1 <5 环形铁粒幼细胞性难治性贫血伴（RARS） <1 <5 难治性贫血伴原始细胞增多（RAEB） <5 5~20 难治性贫血伴原始细胞增多转变型（RAEB-t） >=5 21~30 慢性粒-单核细胞白血病(CMML)（单核细胞>1,000/mcl血） <5 5~20原发MDS分型系统2008WHO分型 分    类 外周血    骨 髓  难治性血细胞减少伴有单系增生异常（RCUD） 一系或两系血细胞减少 一系细胞增生异常≥10%，原始细胞<5% 环形铁粒幼细胞性贫血（RARS） 贫血，无原始细胞 只有红系发育异常，原始细胞<5%，铁粒幼细胞≥15% 难治性血细胞减少伴有多系增生异常（RCMD）j 血细胞减少，单核细胞<1×109/L ≥2系细胞增生异常且>10%，原始细胞<5%，铁粒幼细胞≥15% 难治性贫血伴有原始细胞增多1型（RAEB-1） 血细胞减少，原始细胞<2%~4%，单核细胞<1×109/L 单系或多系增生异常，无Auer小体，原始细胞5%~9% 难治性贫血伴有原始细胞增多1型（RAEB-2） 血细胞减少，原始细胞5%~19%，单核细胞<1×109/L 单系或多系增生异常，有或无Auer小体，原始细胞10%~19% MDS未能分类（MDS-U） 血细胞减少 单系或无增生异常，但有典型的MDS的细胞遗传学异常，原始细胞<5% MDS伴孤立的del（5q） 贫血，血小板正常或增加 只有红系增生异常，原始细胞<5%，孤立del（5q）骨髓增生异常综合征/骨髓增殖性肿瘤（MDS/MPN）的WHO分型 分型 外周血 骨髓 慢性粒单核细胞白血病（CMML-1） 单核细胞>1×109/l原始细胞<5% ≥1系的病态造血原始细胞<10% CMML-2 单核细胞>1×109/l原始细胞5%-19%或者有Auer小体 ≥1系的病态造血原始细胞10%-19%或者有Auer小体 不典型的慢性髓细胞白血病，Bcr-Abl阴性 白细胞13×109/l，中性粒细胞前体细胞>10%原始细胞<20% 细胞计数高，原始细胞<20% 幼年型粒单细胞白血病 单核细胞绝对值>1×109/l原始细胞<20% 单核细胞绝对值>1×109/l原始细胞<20% MDS/MPN，未分类型 既有病态造血，又有骨髓增殖性疾病的特点，但是不符合MDS或者MPN 既有病态造血，又有骨髓增殖性疾病的特点初发MDS的分型系统IPSS 存活及AML演变        分          值 预后因素 0 0.5 1．0 1.5 2．0 骨髓原始细胞数%r <5 5~10 --- 11~20 21~30 核型s 好 中等 差     细胞减少的系列t 0/1 2/3      初发MDS的分型系统IPSS 危险类型IPSS分型%  积分 不治疗中位生存期（年） 不治疗25%转化为急性白血病的时间(年) 低(33) 0 5.7 9.4 中危-1(38) 0.5-1.0 3.5 3.3 中危-2(22) 1.5-2.0 1.1 1.1 高危(7) ≥2.5 0.4 0.2IPSS危险度*分类—患者分布 StudyGeography: WestAverage: China Korea Japan Low 8% 5% 11% 26% Int-1 48% 52% 42% 35% Int-2 27% 30% 29% 21% High 18% 12% 19% 8%***Slide31.MDS:IPSSRiskCategories—PatientDistribution ThemajorityofpatientsdiagnosedwithMDSareclassifiedineithertheLow(31%)ortheInt-1(39%)IPSSriskcategories,basedonthenumericIPSSscore,whichinturnisbasedonblastpercentage,karyotypicabnormalities,andnumberofcytopeniasGreenbergPetal.Blood.1997;89:2079**可编辑TreatmentLOW,INT-1*Lenalidomidewasaddedasatreatmentrecommendationtobeconsideredforsymptomaticallyanemicnon-del(5q)patientswhoseanemiadidnotrespondtoinitialtherapy.TreatmentINT-2,HIGH*Footnote”v”wasrevisedtostate--Basedonage,performancestatus,majorcomorbidconditions,psychosocialstatusandavailabilityofcaregiver国内MDS的治疗现状 国内关于MDS治疗的专家意见MDS患者选择治疗 方案 气瓶 现场处置方案 .pdf气瓶 现场处置方案 .doc见习基地管理方案.doc关于群访事件的化解方案建筑工地扬尘治理专项方案下载 的基本原则是个体化：对于大多数病程平稳、主要表现顽固性血细胞减少，而基本上没有恶性表征的患者，治疗目标则应是提高血细胞数量和保持较好的生活质量；对于有明确白血病基本表征的患者，治疗目标是杀灭恶性克隆，恢复正常造血功能。 在给一个确诊的MDS患者作治疗决策时，主要考虑以下3点： ①患者的国际预后积分系统(IPSS)危度分组 ②患者的年龄 ③患者的体能状况儿童MDS的治疗1绝大部分儿童MDS应将SCT作为首选治疗。 7号染色单体或复杂染色体核型异常RC患儿，如有HLA匹配的同胞供体或无关供体，应在确诊后尽早进行SCT，其他RC患儿如有HLA匹配的同胞供体也应在确诊后尽早进行SCT。对晚期MDS应在确诊后尽早进行HLA完全匹配的同胞供体和无关供体或1个位点不合的无关供体SCT。如果疾病进展可考虑单倍体SCT。现有 资料 新概念英语资料下载李居明饿命改运学pdf成本会计期末资料社会工作导论资料工程结算所需资料清单 表明这些患者在移植前是否接受强化疗及骨髓原始粒细胞的比例对患者移植后生存率和复发率并无影响。2药物治疗，如免疫抑制药(环孢霉素、ATG)和DNA甲基化酶抑制药(5-AC和DAC)，除有ATG治疗儿童MDS的小系列报道外，其他药物极少有用于儿童MDS的治疗。国内常用药另外还有：沙利度胺罗盖全胸腺五肽小剂量激素类（泼尼松美卓乐）免疫球蛋白常用中药制剂益血生胶囊多糖蛋白片参归养血片复方皂矾丸再造生血片知柏地黄丸三七片云南白药去甲基化药物地西他滨治疗MDS经验与体会MDS抗甲基化治疗 甲基化的频率随着MDS疾病的进展而增加。 去甲基化药物在体内和体外均能通过抑制DNA甲基转移酶1（DNMT1）使抑癌基因恢复正常去甲基化状态，重新激活那些由于DNA过度甲基化而失活的基因，使细胞恢复正常终末分化、衰老或凋亡。MechanismofEpigeneticTherapyCourtesyofIssa,JPDecitabinePhase3StudyDesignOpen-label,1:1randomized,multi-centerstudyintheUSandCanadaEligiblePatients(n=170)Decitabine+SupportiveCare*(n=89)RANDOMIZEDSupportiveCare*(n=81)Stratification IPSSClassification PriorChemotherapy StudyCenterStudyD-0007*Antibiotics,GrowthFactorsand/orTransfusionsSabaHI,etal.JClinOncol.2005;23(suppl16S):570s.Abstract6543..*SLIDESCURRENTATTIMEOFPRINT*BetweenJulyof2001andApril2003,atotalof170patientswereenrolledandrandomizedtoreceivebestsupportivecare(includingantibiotics,growthfactorand/ortransfusions)anddecitabineversusbestsupportivecaremeasuresalone.Enrollmentoccurredat23centersincluding1Canadianinstitutionand22USsites.Eighty-ninepatientswereinthedecitabinearmand81inthesupportivecarearm.Response*toDecitabine(ITT)StudyD-0007*ChesonBDBlood.200096:3671-3674.SabaHI,etal.JClinOncol.2005;23(suppl16S):570s.Abstract6543. IWGResponseRate Decitabine(n=89) SupportiveCare(n=81) OverallResponseRate(CR+PR) Completeresponse(CR) Partialresponse(PR) Hematologicimprovement(HI) 15(17%)**8(9%)7(8%)12(13%) 0(0%)0(0%)0(0%)6(7%) **P-value<.001fromtwo-sidedFisher’sExactTest*SLIDESCURRENTATTIMEOFPRINT*BasedonablindedcentralreviewusingtheInternationalWorkinggroupcriteriaforresponse,theoverallresponseratewas17%inthedecitabinegroupcomparedto0%intheSupportiveCaregroup,whichwashighlysignificant.9%ofpatientsondecitabinehadacompleteresponseand8%,apartialresponse.Anadditional13%ofdecitabine-treatedpatientshadhematologicimprovement.Themediantimetoresponsewas3.3monthsandthemediandurationofresponsewas10.3months.Whilethemediannumberofcyclesreceivedperpatientwasthree,bestresponsewasobservedafter2cyclesoftreatment.MedianTimetoAMLorDeathStudyD-0007+CensoredDataSabaHI,etal.JClinOncol.2005;23(suppl16S):570s.Abstract6543. MDSGroup DecitabineMonths(range) SupportiveCareMonths(range) Log-rankP-value Allpatients 12.1(0.3+–22.3)n=89 7.8(0.3–21.0+)n=81 .160 Treatmentnaïve 12.3(0.3+–20.1+)n=69 7.3(0.3–21.0+)n=65 .082 Int-2/Highrisk 12.0(0.4+–22.3)n=61 6.8(0.3–21.0+)n=57 .028 Highrisk 9.3(0.4+–19.9)n=23 2.8(0.3–13.5)n=21 .010*SLIDESCURRENTATTIMEOFPRINT*IntheIntenttoTreatanalysisofallpatients,theseparationofthecurveswasclinicallymeaningfulbutwasnotstatisticallysignificantaftercorrectionfortheprimaryendpoint.Similarresultswerereportedintreatmentnaïvepatients(n=134)Whenthedataforthesubgroupswereseparatelyexamined,thisbecamemorepronouncedinthesubsetofpatients,withIntermediate-2andHighRiskMDSandinthehigh-risksubgroup.Impressively,forthepatientswithhighriskdisease(n=44),resultswereclinicallyandstatisticallysignificantwithap-valueof0.010.Thelog-ranktestputsequalweightoneachobservationandismoresensitivetoexposureswithaconsistentrelativerisk.TimetoAMLorDeathwasmeasuredfromthedateofrandomizationtothedateonwhichAMLordeathwasestablished.Censoreddata=patientslosttofollow-up,thosewhowithdrewconsent,orwhohadnotreachedthespecifiedevent(i.e.AMLordeath)werecensoredfordiseaseprogressionatthelastvisit.Note:ThissamedataisdepictedonKaplanMeiercurvesinsubsequentslides.TimetoAMLorDeathAllPatients(n=170)2-sidedlog-ranktestforhomogeneityofsurvivaldistributions,P=.160SabaHI,etal.JClinOncol.2005;23(suppl16S):570s.Abstract6543.Decitabine(n=89)SupportiveCare(n=81)0204060801000100200300400500600700Survival(days)withoutAMLPercentalivewithoutAML*SLIDESCURRENTATTIMEOFPRINT*IntheIntenttoTreatanalysisofallpatients,theseparationofthecurveswasclinicallymeaningfulbutwasnotstatisticallysignificantaftercorrectionfortheprimaryendpoint.Whenthedataforthesubgroupswereseparatelyexamined,thisbecamemorepronouncedinthesubsetofpatientswithIntermediate-2andhighriskMDSandinthehigh-risksubgroup.TimetoAMLorDeathInt-2&HighRiskPatients(n=118)2-sidedlog-ranktestforhomogeneityofsurvivaldistributions,P=.028Decitabine(n=61)SupportiveCare(n=57)SabaHIandWijermansPWSeminHematol.2005;42(3Suppl2):S23-310204060801000100200300400500600700Survival(days)withoutAMLPercentalivewithoutAML*SLIDESCURRENTATTIMEOFPRINT*WhenanalyzingthetimetoAMLordeathinpatientswithintermediate-2andhighriskdiseaseresultstheseparationofthecurveswasclinicallymeaningfulbutwasnotstatisticallysignificant(p=0.028).TimetoAMLorDeathHighRiskPatients(n=44)StudyD-00072-sidedlog-ranktestforhomogeneityofsurvivaldistributions,p=0.010Decitabine(n=23)SupportiveCare(n=21)SabaHIandWijermansPWSeminHematol.2005;42(3Suppl2):S23-310204060801000100200300400500600700Survival(days)withoutAMLPercentalivewithoutAML*SLIDESCURRENTATTIMEOFPRINT*WhenanalyzingthetimetoAMLordeathinpatientswithhighriskdisease(n=44),resultswereclinicallyandstatisticallysignificantwithap-valueof0.010.Phase3AdverseEventsGrades3&4StudyD-0007SabaHI,etal.JClinOncol.2005;23(suppl16S):570s.Abstract6543 Decitabinen=83(%) SupportiveCaren=81(%) MedDRAPreferredTerm Grade3 Grade4 Grade3 Grade4 Bloodandlymphaticsystemdisorders 中性粒细胞教减少 8(10) 64(77) 20(25) 20(25) 血小板减少 18(22) 52(63) 22(27) 13(16) 贫血 9(11) 1(1) 11(14) 1(1) 发热性中性粒细胞减少 14(17) 5(6) 3(4) 0(0) 白细胞减少 7(8) 12(14) 4(5) 2(2) Gastrointestinaldisorders 恶心 1(1) 0(0) 3(4) 0(0) 便秘 2(2) 0(0) 1(1) 0(0) 腹泻 0(0) 0(0) 1(1) 1(1) 腹痛 2(2) 0(0) 3(4) 0(0) 口腔黏膜瘀斑 2(2) 0(0) 1(1) 0(0)适应症 地西他滨适用于IPSS评分系统中中危-2和高危的初治，复治MDS患者，包括原发性和继发性的MDS，按照FAB分型所有的亚型：RA，RARS,RAEB，RAEB-t,CMML. 2006年，美国FDA批准了地西他滨注射液的上市 申请 关于撤销行政处分的申请关于工程延期监理费的申请报告关于减免管理费的申请关于减租申请书的范文关于解除警告处分的申请 。 副作用：主要表现为骨髓抑制。AZA-001phaseIIIstudyAZA75mg/m2/dx7dq28d(n=179)CCR(n=179)Randomization BestSupportiveCare(BSC)only LowDoseAra-C(LDAC,20mg/m2/dx14dq4-6weeks) StdChemo(7+3)CentralPathReviewCCRSelection358ptswithhigherriskMDS(RAEB,RAEB-T,CMML)IPSSint2orhighFenaux.Blood110:abst817,2007 Medianage69yrs IPSS:high47%,int-240%,NC13% AZAmedian9cycles medianFU21mo**AtScreening:Thecentralreviewer’sassessmentswereusedinrealtimetodetermineeligibilityofFABdiagnosesCCRselection::Toavoidpotentialbias,theintendedtreatmentselectionfromtheconventionalcareregimensbytheinvestigatorwastoberecordedforallpatientspriortorandomizationtoeitherazacitidineorconventionalcaretreatment;treatmentassignmentwasnotsubsequentlychangedafterrandomizationBSCinalltreatmentarmsRecommendedminimumtreatmentduration: AZA6cycles LDAC4cycles SCTAfterinduction,patientswhoattainedCRorPRusingIWGcriteriaforAMLcouldreceiveatleast 1 andnotmorethan2consolidationcyclesOverallSurvivalAzacitidinevsCCRFenaux.Blood110:abst817,2007P=0.0001*9.4monthsdifference适应症 2004年5月，阿扎胞苷（商品名：维达扎）由Pharmion公司开发上市成为首个获得FDA批准的表观遗传药物。尤适应于中危2型或高危疾病的MDS患者。 用于乳腺癌、肠癌、黑色素瘤等有一定疗效。Decitabinevs.Azacitidine Azacitidine和Decitabine均为胞嘧啶甲基化的有效抑制物。可与DNA结合，抑制DNMT（DNA甲基转移酶）的活性，随着细胞分裂次数的增加，DNA甲基化程度进行性的降低，使因高度甲基化而失活的基因表达上调。*Decitabinevs.Azacitidine Decitabine拥有更快的起效时间和更高的MDS克隆细胞清除率。 Decitabine可能拥有更高的CR。 两者的比较研究还在进行中。去甲基化药物无效 目前认为：一旦出现下述情况即认为属“去甲基化药物无效”，包括：缺乏CR、PR及血液学改善或直接进展至AML，尤其是外周血细胞计数的失调控（增殖）或阻止继续治疗的过度毒性。判断治疗失败之前的最小疗程数为4-6个。小结 1染色体 分析 定性数据统计分析pdf销售业绩分析模板建筑结构震害分析销售进度分析表京东商城竞争战略分析 对地西他滨治疗的选择有重要帮助，或地西他滨能够改善骨髓染色体核型。 2地西他滨治疗后中性粒细胞减少引起的感染必须重视和积极预防。 3国内或省内应该开展地西他滨治疗MDS长期生存研究。**可编辑***Themyelodysplasticsyndromes(MDS)areagroupofconditionsthatarecausedbytheabnormalmaturationofblood-formingcellsinthebonemarrow.Asaresult,thebonemarrowcannotproduceasufficientnumberofmaturebloodcells,andthosethatareproduceddonotfunctionnormally.Whiletheproductionoferythrocytes,granulocytes,monocytes,andplateletsmayallbeaffectedinpatientswithMDS,theywillusuallyhavenormalTandBlymphocytes.TheunderlyingcauseofMDSisachromosomalabnormalitythatdevelopsinahaematopoieticstemcellthatchangesitintoamalignantcell.TheabnormalitymayresultfromDNAdamagethatiscausedby,forexample,priorcancertherapyorexposuretoenvironmentaltoxins.Asthiscellreproducesbymitoticdivision,itformsacloneofcellsinwhichtheabnormalitypersists.Thedamagedstemcellpopulationproducesprogenitorblastcellsthatfailtorespondtonormalcontrolsignalsandthusfailtodifferentiateintofunctionalbloodcells.***InMDS,thepopulationofblastcellsprogressivelyreplacesnormalbonemarrowcells.Asaresult,thenumberofblastcellsinthebonemarrowincreases,whilelevelsofmature,circulatingcellsdecline(cytopenias).Inaddition,manymaturecellsthatarereleasedintothebloodstreamhavevisiblecellularabnormalities(i.e.dysplasias)anddonotfunctionnormally.Thedefectivecellsproducecytokinesthatleadtoincreasedapoptosisinnormalcells.Thisphenomenoncontributestolowlevelsofcirculatingbloodcells.***ZytogenetischeAberrationentreteninca.50%auf***ThegreatestriskfactorforMDSappearstobeolderage,butgenderalsoplaysarole,asMDSisdiagnosedsomewhatmorefrequentlyinmenthaninwomen.OtherimportantriskfactorsforthedevelopmentofMDSincludepriortreatmentforcancer,exposuretoenvironmentaltoxins,cigarettesmoking,congenitalandhereditarydisorders.PatientstreatedwithcertaincancerchemotherapydrugsaremorelikelytodevelopMDS.Inparticular,patientswhohavehadpreviousexposuretomechlorethamine,procarbazine,chlorambucil,etoposide,teniposide,andtoacertainextent,cyclophosphamideordoxorubicin,areatincreasedrisk.Theriskisfurtherincreasedamongpatientswhohavehadcombinationchemotherapyandradiotherapy(chemoradiotherapy).Prolongedorheavyexposuretoenvironmentaltoxins,suchasbenzene,organicsolvents,andcertainpesticides,hasalsobeenlinkedtothedevelopmentofsecondaryMDS.Inaddition,exposuretohigh-doseradiationpredisposesapersontothedisease.Cigarettesmokingistheonlylifestyle-relatedriskfactorforthedevelopmentofMDSandisalsoaknownriskfactorforacutemyeloidleukaemia(AML).CertainrarecongenitaldiseasessuchasFanconianaemiaareassociatedwithsecondaryMDS,andtherehavebeenreportsofMDSoccurringwithinfamilies,suggestingamutationthatcanbeinherited.Theseriskfactorsaccountforabout20-30%ofcasesandareknownassecondaryMDS.TheremainingcasesaresaidtobeprimaryMDS.Therapy-relatedMDSisbyfarthemostcommonformofsecondaryMDS.***MDSisoneofthemostcommonhaematologicaldisorders.RegistrydatashowthatMDSisprimarilyadiseaseoftheelderly,withthehighestincidenceoccurringinpatientsaged80-90years.Theoverallincidenceofthediseasevariesfrom2.1-12.6per100,000populationperyearbutthisrisestoalmost50per100,000perannuminover70yearolds.Overall,thereisanexcessofMDSinmen,butthisismostobviouswithincreasingage.Inpatientsover70years,theincidenceinmenisapproximately54/100,000populationperannumcomparedwith24/100,000populationperannuminwomen.***ManypatientswhodevelopMDSmayinitiallyhavenoapparentsymptoms,butarediagnosedafterroutinelaboratorytestsuncoverabnormalitiesinthecirculatingbloodcells.Alternatively,patientsmaydevelopsymptomsthatsuggestanunderlyingdisease.EarlysymptomsofMDSmayincludebruising,increasedbleeding(particularlynosebleedsorbleedinggumsduringbrushingoftheteeth),rash,shortnessofbreath,rapidheartrate,weightloss,fever,andlossofappetite.Fatigue,acommonsymptomofmanydifferenttypesofdisorders,isanimportantsymptomofconditionsthatareassociatedwithabnormalbloodcellcountsanddysplasias.FatigueisthemostcommonsymptomofMDS.Thesesymptomsarerelatedtoanumberofpossibledeficienciesincirculatingredbloodcells,whitebloodcells,and/orplatelets.ItisimportanttonotethatnoneofthesymptomsofMDSarespecifictothedisease.Infact,oneofthechallengesindiagnosingMDSisthatanyofthesesymptomsmaybeattributabletootherconditions.*SLIDESCURRENTATTIMEOFPRINT*ThetumorsuppressorgenesthatundergoaberrantCpGislandmethylationinhumancanceraffectallthecellularpathwaysandhaverelevantconsequences.AbrieflistofthemostsignificantgenesinactivatedbyDNAhypermethylationinadvancedMDSandAMLisdepictedonthisslide.Someofthemostfrequentlyevaluatedgenesarethecyclin-dependentkinaseinhibitors,p15,p16,p21,andp57.Thep15INK4bandp16INK4agenesencodethecyclin-dependentkinases4and6andcontroltheprogressionofthecellcyclefromG1totheSPhase.1Inactivationofthesegeneshasbeendetectedinmanycancers,leadingtoinappropriatecellcycleprogression.2,3DNAhypermethylationofCpGislandsofthep15promoterregionhasbeenreportedinMDSandisassociatedwithlossofp15expression.4,5Therehasalsobeenacloseassociationbetweenthepercentageofbonemarrowblastsandp15hypermethylation.4,5ReferencesforSlideNotes:SerranoM,HannonGJ,BeachD.Nature.1993;366:704-707.NoboriT,MiuraK,WuDJ,etal.Nature.1994;368:753-756.KambA,GruisNA,Weaver-FeldhausJ,etal.Science.1994;264:436-440.QuesnelB,GuillermG,VereecqueR,etal.Blood.1998;91:2985-2990.UchidaT,KinoshitaT,NagaiH,etal.Blood.1997;90:1403-1409.*SLIDESCURRENTATTIMEOFPRINT*PrognosisofMDSpatientshasbeenlinkedtop15INK4b.Patientswithp15INK4bgenemethylationhadasignificantlyshortersurvivalthanunmethylatedcases(median18vs48months,P=0.049,log-ranktest).1Patientswithhypermethylationatthetimeofdiagnosiswerefoundtohavesignificantlyshortersurvivalthanthosepatientswithnormalmethylation.2Theinvestigatorsalsoassessedp15methylationpatternsin“lowrisk”disease(RAandRARS)withoutexcessblastsversusthoseseenin“highrisk”MDS(RAEB,RAEB-T,andCMML).p15methylationwasnotdetectablethroughoutthecourseof“lowrisk”disease;however,in“highrisk”MDS,theincidencerangedfrom23%atdiagnosisto30%atadvancedstates.InAMLthatpreviouslyevolvedfromMDS,p15hypermethylationisashighas60-75%.2Thismightindicatethep15hypermethylationisamarkerofleukemictransformationinMDS.Inadditionhypermethylationofthecalcitoningenehasalsobeenfoundin65%ofpatientswithMDS.3ReferencesforSlideNotes:Quesnel,etal.Blood.1998;91:2985TienHF,TangJH,TsayW,etal.BrJHaematol.2001;112:148-154.DhodapkarM,GrillJ,LustJA.LeukRes.1995;19:719-726.***Slide31.MDS:IPSSRiskCategories—PatientDistribution ThemajorityofpatientsdiagnosedwithMDSareclassifiedineithertheLow(31%)ortheInt-1(39%)IPSSriskcategories,basedonthenumericIPSSscore,whichinturnisbasedonblastpercentage,karyotypicabnormalities,andnumberofcytopeniasGreenbergPetal.Blood.1997;89:2079*Lenalidomidewasaddedasatreatmentrecommendationtobeconsideredforsymptomaticallyanemicnon-del(5q)patientswhoseanemiadidnotrespondtoinitialtherapy.*Footnote”v”wasrevisedtostate--Basedonage,performancestatus,majorcomorbidconditions,psychosocialstatusandavailabilityofcaregiver*SLIDESCURRENTATTIMEOFPRINT*BetweenJulyof2001andApril2003,atotalof170patientswereenrolledandrandomizedtoreceivebestsupportivecare(includingantibiotics,growthfactorand/ortransfusions)anddecitabineversusbestsupportivecaremeasuresalone.Enrollmentoccurredat23centersincluding1Canadianinstitutionand22USsites.Eighty-ninepatientswereinthedecitabinearmand81inthesupportivecarearm.*SLIDESCURRENTATTIMEOFPRINT*BasedonablindedcentralreviewusingtheInternationalWorkinggroupcriteriaforresponse,theoverallresponseratewas17%inthedecitabinegroupcomparedto0%intheSupportiveCaregroup,whichwashighlysignificant.9%ofpatientsondecitabinehadacompleteresponseand8%,apartialresponse.Anadditional13%ofdecitabine-treatedpatientshadhematologicimprovement.Themediantimetoresponsewas3.3monthsandthemediandurationofresponsewas10.3months.Whilethemediannumberofcyclesreceivedperpatientwasthree,bestresponsewasobservedafter2cyclesoftreatment.*SLIDESCURRENTATTIMEOFPRINT*IntheIntenttoTreatanalysisofallpatients,theseparationofthecurveswasclinicallymeaningfulbutwasnotstatisticallysignificantaftercorrectionfortheprimaryendpoint.Similarresultswerereportedintreatmentnaïvepatients(n=134)Whenthedataforthesubgroupswereseparatelyexamined,thisbecamemorepronouncedinthesubsetofpatients,withIntermediate-2andHighRiskMDSandinthehigh-risksubgroup.Impressively,forthepatientswithhighriskdisease(n=44),resultswereclinicallyandstatisticallysignificantwithap-valueof0.010.Thelog-ranktestputsequalweightoneachobservationandismoresensitivetoexposureswithaconsistentrelativerisk.TimetoAMLorDeathwasmeasuredfromthedateofrandomizationtothedateonwhichAMLordeathwasestablished.Censoreddata=patientslosttofollow-up,thosewhowithdrewconsent,orwhohadnotreachedthespecifiedevent(i.e.AMLordeath)werecensoredfordiseaseprogressionatthelastvisit.Note:ThissamedataisdepictedonKaplanMeiercurvesinsubsequentslides.*SLIDESCURRENTATTIMEOFPRINT*IntheIntenttoTreatanalysisofallpatients,theseparationofthecurveswasclinicallymeaningfulbutwasnotstatisticallysignificantaftercorrectionfortheprimaryendpoint.Whenthedataforthesubgroupswereseparatelyexamined,thisbecamemorepronouncedinthesubsetofpatientswithIntermediate-2andhighriskMDSandinthehigh-risksubgroup.*SLIDESCURRENTATTIMEOFPRINT*WhenanalyzingthetimetoAMLordeathinpatientswithintermediate-2andhighriskdiseaseresultstheseparationofthecurveswasclinicallymeaningfulbutwasnotstatisticallysignificant(p=0.028).*SLIDESCURRENTATTIMEOFPRINT*WhenanalyzingthetimetoAMLordeathinpatientswithhighriskdisease(n=44),resultswereclinicallyandstatisticallysignificantwithap-valueof0.010.**AtScreening:Thecentralreviewer’sassessmentswereusedinrealtimetodetermineeligibilityofFABdiagnosesCCRselection::Toavoidpotentialbias,theintendedtreatmentselectionfromtheconventionalcareregimensbytheinvestigatorwastoberecordedforallpatientspriortorandomizationtoeitherazacitidineorconventionalcaretreatment;treatmentassignmentwasnotsubsequentlychangedafterrandomizationBSCinalltreatmentarmsRecommendedminimumtreatmentduration: AZA6cycles LDAC4cycles SCTAfterinduction,patientswhoattainedCRorPRusingIWGcriteriaforAMLcouldreceiveatleast 1 andnotmorethan2consolidationcycles*9.4monthsdifference