mds的診斷與治療

1、中國(guó)醫(yī)學(xué)科學(xué)院血液學(xué)研究所血液病醫(yī)院秦鐵軍 電話：13332095356,骨髓增生異常綜合征,Sunday, March 10, 2024,MDS的定義與最低診斷標(biāo)準(zhǔn),定義a group of clonal haematopoietic stem cell diseasescharacterized bycytopenia(s).dysplasia in one or more of the major myeloid

2、cell lines. Ineffective haematopoiesisIncreased risk of development of AML,Monday, August 09, 2010,thresholds for cytopenias,Cytopenias Haemoglobin < 100g/LAbsolute neutrophil count (ANC)<1.8xl09/LPlatelets &l

3、t; 100xl09/LDefinitive morphologic and/or cytogenetic findings support the diagnosis of MDS even if values above these thresholds,Monday, August 09, 2010,流行病學(xué)(Epidemiology),Median age 70 yearsincidence of 3-5/100

4、000 persons>20/100 000 among those over the age of 70 yearsmale predominance,Clinical features,Symptoms related to cytopenia(s)Anemic and transfusion-dependentNeutropenia and/or thrombocytopenia --Less frequentIn

5、frequently organomegaly,Monday, August 09, 2010,The morphological of MDS,principally based onpercent of blasts in the BM and PBtype and degree of the dysplasiapresence of ring sideroblasts500-cell differential of all

6、 nucleated cells in the BM smear 200-leukocyte differential in the PBnecessity of high quality slide preparations and the stain,Monday, August 09, 2010,骨髓和外周血涂片,高質(zhì)量的制片和染色新鮮標(biāo)本(抗凝標(biāo)本不應(yīng)超過2小時(shí)) 計(jì)數(shù)500個(gè)細(xì)胞 粒紅比≤1:1時(shí)計(jì)數(shù)500個(gè)非紅

7、系細(xì)胞，不包括淋巴細(xì)胞、漿細(xì)胞、肥大細(xì)胞原始細(xì)胞比例應(yīng)為非紅系比例環(huán)形鐵粒幼細(xì)胞比例 >15%時(shí)，即認(rèn)為是紅系發(fā)育異常,Monday, August 09, 2010,Morphologic manifestation of dysplasia(1),DyserythropoiesisNuclear核出芽(nuclear budding)核間橋(internuclear bridging)核破裂(Karyorrhex

8、is)多核(Multinuclearity)核多分葉(nuclear hyperlobation)巨幼樣變(megaloblastic changes)Cytoplasmic環(huán)狀鐵粒幼紅細(xì)胞(Ring sideroblast)空泡形成(Vacuolization)糖原染色陽性(Periodic acid-Schiff positivity),Monday, August 09, 2010,Morphologic manif

9、estation of dysplasia(2),Dysgranulopoiesis細(xì)胞體積過小或過大(Small or unusually large size)核少分葉Nuclear hypolobation(pseudo Pelger-Huet; pelgeroid)不規(guī)則的分葉過多(Irregular hypersegmentation)少顆粒(Decreased granules; agranularity)Pse

10、udo Chediak-Higashi granules奧氏小體Auer rods,Monday, August 09, 2010,Morphologic manifestation of dysplasia(3),Dysmegakaryocytopoiesis小巨核細(xì)胞(Micromegakaryocytes)核少分葉(Nuclear hypolobation in all size)Mutinucleation(normal

11、 megakaryocytes are uninucleate with lobulated nuclei)Multiple , widely-separated nucleiMore readily appreciated in BM sections than smears,Monday, August 09, 2010,Recommended Qualifications of Dysplasia,Dyserythropoie

12、sis and dysgranulopoiesisRequisite percentage of cells manifesting dysplasia ≥10% in the erythroid precursors and granulocytesSignificant megakaryocyte dysplasia≥ 10% dysplastic megakaryocytes based on evaluation of a

13、t least 30 megakaryocytes in smears or sectionsthe most reliable dysplastic findingsMicromegakaryocytes and multinucleate megakaryocytes,Monday, August 09, 2010,The relationship between cytopenias, type of dysplasia, a

14、nd classification in MDS,General precautions,No MDS without the clinical and drug historyNot reclassified while the patient is on growth factor therapyCytopenia(s) in the absence of dysplasia should not be interpreted

15、 as MDSNo dysplasia + certain cytogenetic abnormalities --presumptive MDSPersistent cytopenia(s) + No dysplasia +No specific cytogenetic abnormalities =ICUS,Monday, August 09, 2010,The significance of the Auer rod,Virt

16、ually diagnostic of AML for several decade Evidence of a high-grade MDS (RAEBT) in the FAB classification(1982), irrespective of the blast percentage in the PB or BMEvidence of RAEB-2 regardless of the blast percentag

17、e in the 2001 WHO classification The concept is retained in the present classificationCases of MDS with <5% blasts in the BM and < 1 % in the PB may rarely have Auer rods.Associated with an adverse prognosis,Dif

18、ferential diagnostic considerations,dysplasia is not in itself definitive evidence of a clonal disordermyelodysplasia due to a clonal disorderthe result of some other factorsEssential element deflcienciesexposure to

19、 heavy metals,particularly arsenic and several commonly used drugs and biologic agents磺胺甲基異惡唑-marked neutrophil nuclear hypolobationCongenital haematological disorders such as congenital dyserythropoietic anemia,組織病理學(xué)及

20、免疫組織化學(xué)Histopathology and immunohistochemistry,骨髓涂片混血時(shí)可與AML鑒別與低增生AML鑒別與AA鑒別發(fā)現(xiàn)CD34+祖細(xì)胞多灶性聚集發(fā)現(xiàn)CD34+祖細(xì)胞異常定位，ALIP發(fā)現(xiàn)巨核細(xì)胞異常形態(tài)及聚集顯示骨髓纖維化顯示血管新生診斷低增生MDS顯示細(xì)胞遺傳學(xué)標(biāo)記診斷共發(fā)骨髓細(xì)胞腫瘤(如肥大細(xì)胞增多癥、淋巴瘤等),MDS中推薦的免疫組化標(biāo)記物,流式細(xì)胞術(shù)在MDS中的應(yīng)用,MDS

21、中重現(xiàn)的異常免疫表型,流式細(xì)胞術(shù)在MDS中的應(yīng)用,MDS中重現(xiàn)的異常免疫表型（續(xù)）,流式細(xì)胞術(shù)在MDS中的應(yīng)用,Determining the size and immunophenotype of the blast populationGenerally good correlation betweenPercentage of blasts as determinedBy morphologic examination of

22、 routine smearBy imprintBy immunohistologic preparationsPercentage of CD34+ cells determined by flow cytometry (FC)FC percentages of CD34+ cells cannot replace differential counts on smearsMF, haemodilute,流式細(xì)胞術(shù)在MDS中

23、的應(yīng)用,Abnormal phenotypes of CD34+ cellsEvidence of dysplasiaEmerging pathological population of CD34 or CD117 cells In low-grade MDS Suggest evolution of the disease,流式細(xì)胞術(shù)在MDS中的應(yīng)用,Assessing the maturation pattern of th

24、e myeloid cell populationflow cytometry results correlate well with morphology and cytogenetics in MDSsingle aberrant features by FC are not significantborderline dysplasia by morphology no cytogenetic abnormalities

25、Only if there are three or more aberrant features in erythropoietic,granulocytic or monocytic maturationFC results are highly suggesitve for MDS,MDS染色體核型分析,傳統(tǒng)核型分析：G帶、Q帶、R帶。熒光原位雜交（FISH）：探針應(yīng)包括5q31, CEP7, 7q31, CEP8, 20q,

26、 CEPY, p53?？寺。簝蓚€(gè)骨髓細(xì)胞獲得相同的染色體物質(zhì)或具有同樣結(jié)構(gòu)的變異，或者三個(gè)骨髓細(xì)胞丟失同樣的染色體。亞克隆：一個(gè)克隆中的至少兩個(gè)或三個(gè)細(xì)胞出現(xiàn)新的染色體變異。復(fù)雜染色體核型：至少在兩個(gè)細(xì)胞中出現(xiàn)三個(gè)或三個(gè)以上不同的染色體變異。復(fù)雜核型同樣具有亞克隆，復(fù)雜核型組的MDS患者可能由不同復(fù)雜程度的亞群構(gòu)成，可能具有不同的預(yù)后。當(dāng)懷疑MDS進(jìn)展時(shí)，核型分析有助于發(fā)現(xiàn)克隆進(jìn)展的細(xì)胞遺傳學(xué)證據(jù)。,Genetics of M

27、DS,Clonal cytogenetic abnormalities in -50% of MDSIsolated del(5q)primarily in womenmegakaryocytes with non-Iobated or hypolobated nuclei,refractory macrocytic anaemianormal or increased platelet counta favourable

28、clinical course17p-pseudo Pelger-Huet anomaly and small vacuolated neutrophilsTP53 mutationunfavourable clinical coursemost common in therapy-related MDS,Genetics of MDS,Some clonal cytogenetic abnormalities are not

29、 definitive evidence for MDS in the absence of morphological criteria -Y, +8, del(20q),Genetics of MDS,isolated del(20q)morphologic abnormalities of erythroid cells and megakaryocytesinv(3)(q21q26.2) or t(3:3)(q21:q2

30、6.2)increased abnormal megakaryocytes,Genetics of MDSRecurring chromosomal abnormalities,Genetics of MDSRecurring chromosomal abnormalities,Prognosis and predictive factorsof MDS,Prognosis of morphologic subtypesThe

31、 low-risk groups RCUD and RARSThe intermediate-risk groupsRCMD with or without ring sideroblasts and RAEB-1the high-risk groupRAEB-2,Prognosis and predictive factorsof MDS,Prognosis of cytogeneticsGoodnormal, -Y,

32、 del(5q), del(20q)PoorComplex karyotypes (≥3 abnormalities) -7/del(7q)]IntermediateOther abnormalities,lnternational Prognostic Scoring System (IPSS) for MDS,*This group is recognized as AML in the WHO classificatio

33、n.#Cytopenias:Haemoglobin < 100g/L;ANC<1.8xl09/L;Platelets < 100xl09/L,Prognosis and predictive factorsof MDS,* In the absence of therapy,2008 WHO MDS分型,2008 WHO MDS分型,2008 WHO MDS分型,說明,RCUD中可有2系血細(xì)胞減少，全血細(xì)胞

34、減少者應(yīng)診斷為MDS-U骨髓中原始細(xì)胞<5%,外周血原始細(xì)胞2%－4%,應(yīng)診斷RAEB-1其他標(biāo)準(zhǔn)符合RCMD或RCUD，但外周血原始細(xì)胞1%,應(yīng)診斷MDS-U骨髓Auer小體陽性，外周血原始細(xì)胞<5%,骨髓原始細(xì)胞<10%, 應(yīng)診斷RAEB-2,低增生性MDS (Hypoplastic MDS),10% MDS難以與AA鑒別AA治療方案（如ATG）對(duì)部分患者有效注意與中毒性骨髓病(toxic myelop

35、athy)及自身免疫性疾病鑒別,MDS with myelofibrosis,約10%的MDS伴明顯的骨髓纖維化大多數(shù)患者原始細(xì)胞增多且進(jìn)展迅速(aggressive)僅憑骨髓涂片易誤診為低危組MDS原始細(xì)胞檢測(cè)需結(jié)合骨髓活檢病理及免疫組織化學(xué),MDS最低診斷標(biāo)準(zhǔn),意義未明的特發(fā)性血細(xì)胞減少（ICUS）,分子分型及點(diǎn)突變分析在MDS的應(yīng)用,分子分型 有助于明確是否存在克隆型疾病與輔助診斷標(biāo)準(zhǔn)中的其他實(shí)驗(yàn)一起判斷“高度懷疑MDS

36、”將來有助于預(yù)測(cè)對(duì)治療的反應(yīng) 點(diǎn)突變分析MDS懷疑伴有系統(tǒng)性肥大細(xì)胞增多癥時(shí)，檢測(cè)KIT基因 D816V點(diǎn)突變MDS伴有顯著血小板增多時(shí)，檢測(cè)Jak-2基因V671F點(diǎn)突變,MDS的危險(xiǎn)積分系統(tǒng),目前：國(guó)際預(yù)后積分系統(tǒng)（IPSS ）有提議將LDH水平納入IPSS即將：WHO修正的預(yù)后積分系統(tǒng)（WPSS） 將輸血依賴作為一個(gè)重要指標(biāo),MDS的非強(qiáng)烈治療及療效反應(yīng)標(biāo)準(zhǔn),非強(qiáng)烈治療 適合低

37、危MDS及不適合強(qiáng)烈治療的高危MDS者治療目標(biāo)：維持生活質(zhì)量（QOL）及防治輸血相關(guān)的發(fā)病及死亡 祛鐵治療：適應(yīng)于長(zhǎng)期輸血的MDS患者 EPO或EPO+G-CSF：作為低危或輸血依賴但內(nèi)源EPO水平不高且輸血頻率低的INT-1患者標(biāo)準(zhǔn)治療方案 G-CSF/GM-CSF：適用于反復(fù)或難治的中性粒細(xì)胞減少所致感染的患者 TPO/IL-11：不作為MDS標(biāo)準(zhǔn)治療方案,MDS的非強(qiáng)烈治療及療效反應(yīng)標(biāo)準(zhǔn),建議修訂的IWG改變M

38、DS自然病程療效判定標(biāo)準(zhǔn),MDS的非強(qiáng)烈治療及療效反應(yīng)標(biāo)準(zhǔn),建議修訂的IWG改變MDS自然病程療效判定標(biāo)準(zhǔn)（續(xù)）,MDS的非強(qiáng)烈治療及療效反應(yīng)標(biāo)準(zhǔn),建議修訂的IWG血液學(xué)改善療效判定標(biāo)準(zhǔn),MDS的強(qiáng)烈治療,選擇強(qiáng)烈治療需考慮以下幾點(diǎn)：造血干細(xì)胞移植（SCT）僅適用于少數(shù)患者，其具有相對(duì)高風(fēng)險(xiǎn)的移植相關(guān)發(fā)病率及死亡率強(qiáng)烈多藥化療能恢復(fù)部分患者的多克隆造血，但只有少數(shù)患者能獲得長(zhǎng)期無病生存，大多數(shù)患者會(huì)在一段時(shí)間內(nèi)復(fù)發(fā)即使是高危組M

39、DS的自然病程也不盡相同，生存期從幾個(gè)月到數(shù)年不等合并疾病、年齡及其他個(gè)體因素可能會(huì)影響SCT和強(qiáng)烈化療的結(jié)果。高危組MDS移植后復(fù)發(fā)率仍達(dá)10~40%,MDS患者是否需要治愈性的治療手段？,MDS的強(qiáng)烈治療,大部分化療方案類似于AML患者大約50%能達(dá)到CR達(dá)到CR的年輕患者，可考慮SCT作為鞏固治療,MDS的強(qiáng)烈治療,待解決的問題：SCT合適時(shí)機(jī)合適的預(yù)處理方案自體SCTSCT后復(fù)發(fā),免疫抑制劑、新的靶向藥

40、物及姑息治療,免疫抑制劑（ATG±CsA）適用于年輕、低危MDS（RA、IPSS中危1組） HLA-DR15、PNH克隆、低增生性MDS的反應(yīng)更好雷利度胺成為MDS伴有5q-治療的一線藥物去甲基化劑（5-氮雜胞苷、地汐他濱）部分中心已考慮將其作為高危組MDS未來的標(biāo)準(zhǔn)治療方案姑息治療白細(xì)胞增高時(shí)，應(yīng)用羥基脲,2024/3/10,Thank You !,Erythroid karyorrhexis in m