mds的診斷與治療

1、中國醫(yī)學科學院血液學研究所血液病醫(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準,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(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,高質量的制片和染色新鮮標本(抗凝標本不應超過2小時) 計數(shù)500個細胞 粒紅比≤1:1時計數(shù)500個非紅

7、系細胞，不包括淋巴細胞、漿細胞、肥大細胞原始細胞比例應為非紅系比例環(huán)形鐵粒幼細胞比例 >15%時，即認為是紅系發(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,組織病理學及

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

21、中重現(xiàn)的異常免疫表型,流式細胞術在MDS中的應用,MDS中重現(xiàn)的異常免疫表型（續(xù)）,流式細胞術在MDS中的應用,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,流式細胞術在MDS中

23、的應用,Abnormal phenotypes of CD34+ cellsEvidence of dysplasiaEmerging pathological population of CD34 or CD117 cells In low-grade MDS Suggest evolution of the disease,流式細胞術在MDS中的應用,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）：探針應包括5q31, CEP7, 7q31, CEP8, 20q,

26、 CEPY, p53。克?。簝蓚€骨髓細胞獲得相同的染色體物質或具有同樣結構的變異，或者三個骨髓細胞丟失同樣的染色體。亞克?。阂粋€克隆中的至少兩個或三個細胞出現(xiàn)新的染色體變異。復雜染色體核型：至少在兩個細胞中出現(xiàn)三個或三個以上不同的染色體變異。復雜核型同樣具有亞克隆，復雜核型組的MDS患者可能由不同復雜程度的亞群構成，可能具有不同的預后。當懷疑MDS進展時，核型分析有助于發(fā)現(xiàn)克隆進展的細胞遺傳學證據(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系血細胞減少，全血細胞

34、減少者應診斷為MDS-U骨髓中原始細胞<5%,外周血原始細胞2%－4%,應診斷RAEB-1其他標準符合RCMD或RCUD，但外周血原始細胞1%,應診斷MDS-U骨髓Auer小體陽性，外周血原始細胞<5%,骨髓原始細胞<10%, 應診斷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)患者原始細胞增多且進展迅速(aggressive)僅憑骨髓涂片易誤診為低危組MDS原始細胞檢測需結合骨髓活檢病理及免疫組織化學,MDS最低診斷標準,意義未明的特發(fā)性血細胞減少（ICUS）,分子分型及點突變分析在MDS的應用,分子分型 有助于明確是否存在克隆型疾病與輔助診斷標準中的其他實驗一起判斷“高度懷疑MDS

36、”將來有助于預測對治療的反應 點突變分析MDS懷疑伴有系統(tǒng)性肥大細胞增多癥時，檢測KIT基因 D816V點突變MDS伴有顯著血小板增多時，檢測Jak-2基因V671F點突變,MDS的危險積分系統(tǒng),目前：國際預后積分系統(tǒng)（IPSS ）有提議將LDH水平納入IPSS即將：WHO修正的預后積分系統(tǒng)（WPSS） 將輸血依賴作為一個重要指標,MDS的非強烈治療及療效反應標準,非強烈治療 適合低

37、危MDS及不適合強烈治療的高危MDS者治療目標：維持生活質量（QOL）及防治輸血相關的發(fā)病及死亡 祛鐵治療：適應于長期輸血的MDS患者 EPO或EPO+G-CSF：作為低?；蜉斞蕾嚨珒仍碋PO水平不高且輸血頻率低的INT-1患者標準治療方案 G-CSF/GM-CSF：適用于反復或難治的中性粒細胞減少所致感染的患者 TPO/IL-11：不作為MDS標準治療方案,MDS的非強烈治療及療效反應標準,建議修訂的IWG改變M

38、DS自然病程療效判定標準,MDS的非強烈治療及療效反應標準,建議修訂的IWG改變MDS自然病程療效判定標準（續(xù)）,MDS的非強烈治療及療效反應標準,建議修訂的IWG血液學改善療效判定標準,MDS的強烈治療,選擇強烈治療需考慮以下幾點：造血干細胞移植（SCT）僅適用于少數(shù)患者，其具有相對高風險的移植相關發(fā)病率及死亡率強烈多藥化療能恢復部分患者的多克隆造血，但只有少數(shù)患者能獲得長期無病生存，大多數(shù)患者會在一段時間內復發(fā)即使是高危組M

39、DS的自然病程也不盡相同，生存期從幾個月到數(shù)年不等合并疾病、年齡及其他個體因素可能會影響SCT和強烈化療的結果。高危組MDS移植后復發(fā)率仍達10~40%,MDS患者是否需要治愈性的治療手段？,MDS的強烈治療,大部分化療方案類似于AML患者大約50%能達到CR達到CR的年輕患者，可考慮SCT作為鞏固治療,MDS的強烈治療,待解決的問題：SCT合適時機合適的預處理方案自體SCTSCT后復發(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未來的標準治療方案姑息治療白細胞增高時，應用羥基脲,2024/3/10,Thank You !,Erythroid karyorrhexis in m