1、1leukemiaHematological department of Renji Hospital2LeukemiaDefinition:A group of malignant clonal malignant disease of hematopoietic tissue.Blockage of cell differentation in different stages.Accumulation of leukemic cells in bone marrow or other organs.Impaired production of normal blood cells.3Pr
2、ogenitor cellStem cell4Normobalst 原红原红Basophilic normoblast 早幼红早幼红Polychromatic normoblast 中幼红中幼红Ortho-chromatic normoblast 晚幼红晚幼红5Myeloblast 原粒原粒Promyelocyte 早幼粒早幼粒Myelocyte 中幼粒中幼粒Metamyelocyte 晚幼粒晚幼粒band cell 杆状核杆状核Segmented cell 分叶核分叶核6Monoblast 原单原单Promonocyte幼单核幼单核Monocyte 单核单核7Lymphoblast 原淋原淋
3、Prolymphocyte 幼淋幼淋Lymphocyte 成熟淋成熟淋Lymphocyte 成熟淋成熟淋8Megakaryoblast 原巨核原巨核Promegakaryocyte 幼巨核幼巨核Granular megakaryocyte 颗粒巨核颗粒巨核Platelate-forming megakaryocyte产板巨核产板巨核910Category of Leukemia Acute Lymphoblastic Leukemia(ALL)Acute Leukemia Acute Myeloid Leukemia(AML)Chronic Myeloid Leukemia(CML)Chron
4、ic Leukemia Chronic Lymphocytic Leukemia(CLL)11Acute myelogenous leukemia(AML)Acute myelogenous leukemia(AML)is a clonal malignant disease of hematopoietic tissues that is characterized by accumulation of abnormal leukemic blast cells,principally in the marrow and impaired production of normal blood
5、 cells.Thus,the leukemic cell infiltration in marrow is accompanied,nearly invariably,by anemia and thrombocytopenia.The absolute neutrophil count may be low or normal,depending on the total white cell count.Incidence of AMLIncidence Rates by RaceRace/EthnicityMaleFemaleAll Races4.3 per 100,000 men3
6、0 per 100,000 womenWhite4.5 per 100,000 men3.1 per 100,000 womenBlack3.5 per 100,000 men2.8 per 100,000 womenAsian/Pacific Islander3.5 per 100,000 men2.8 per 100,000 womenAmerican Indian/Alaska Nativea2.5 per 100,000 men3.1 per 100,000 womenHispanicb3.5 per 100,000 men2.7 per 100,000 womenAge adjus
7、ted incidence 3.6 per 100,000.Median age at diagnosis:66 years.Lifetime risk of a diagnosis of AML:0.39%of people born now.National Cancer Institute.SEER Stat Sheets:Acute Myeloid Leukemia.http:/seer.cancer.gov/statfacts/html/amyl.html13Age distribution of AML14Age distribution of ALL15Incidence of
8、LeukemiaIn China:Acute Leukemia Chronic LeukemiaAdult:AML ALL Children:ALL AML16Etiology of LeukemiaVirus:HTLV-I,HTLV-II,EBIonizing Radiation:Atomic bomb exposureChemical Agents:Benzene;cytotoxic drugs chloramphenicol(氯霉素氯霉素);phenylbutazone(保泰松保泰松).Hereditary Factors:Down syndrome,21trisomy(三体三体)17A
9、CUTE LEUKEMIA18FAB classification of ALLL1:small lymphoblastic typeL2:large lymphoblastic typeL3:large lymphoblastic type with prominent cytoplasmic vacuolization Acute Lymphocytic leukemia(L1)Acute Lymphocytic leukemia(L1)The blast cells have a high nucleocytoplasmic ratio,lack visible The blast ce
10、lls have a high nucleocytoplasmic ratio,lack visible nucleoli and are relative smallnucleoli and are relative small.19Acute Lymphocytic Leukemia(L2)Acute Lymphocytic Leukemia(L2)The blast cells are mainly large and have one or two prominent The blast cells are mainly large and have one or two promin
11、ent nucleoli,which range in size from small to large.nucleoli,which range in size from small to large.20Acute Lymphocytic LeukemiaAcute Lymphocytic Leukemia (L3)(L3)The blast cells have prominent cytoplasmic basophilia and The blast cells have prominent cytoplasmic basophilia and are heavily vacuola
12、tedare heavily vacuolated2122FAB classification of AMLM0:Acute Myelocytic leukemia with minimally differentiationM1:Acute Myeloblastic Leukemia(without maturation)M2:Acute Myeloblastic Leukemia(with maturation,M2a,M2b)M3:Acute Promyelocytic Leukemia(M3a,M3b)M4:Acute Myelomonocytic Leukemia(M4a,M4b,M
13、4c,M4EO)M5:Acute Monocytic Leukemia(M5a,M5b)M6:Acute ErythroleukemiaM7:Acute Megakaryoblastic Leukemia23FAB M0 type.Blast cells with no evident features of differentiation and with negative reactions for Sudan black B and myeloperoxidase.On immunophenotypic analysis,all B and T markers were negative
14、 but there was expression of CD13,CD33.and CD34.FAB M1 type.Blast cells are small to medium in size with a high nucleocytoplasmic ratio and one of them contains an Auer rod.Sudan black B and peroxidase reactions were positive.Peripheral blood film.Auer rod24FAB M2 type.There is differentiation to pr
15、omyelocytes and there is one neutrophil and a blast cell containing an Auer rod.Bone marrow film.FAB M3 type.Blast cells are in a minority,the dominant cell being a hypergranular promyelocytes,some with bundles of Auer rods.Bone marrow filmAuer rods25FAB M4 category.There are some blasts showing gra
16、nulocytic differentiation and others showing monocytic differentiation.Granulocytic differentiation is more obvious in the bone marrow(left)and monocytic in the peripheral blood(right).Bone marrow and periphera lfilm.FAB M4 category,with eosinophilic differentiation.This category of AML is often ref
17、erred to as M4EO AML.There are mature eosinophils and eosinophil precursors.The latter have large pro-eosinophilic granules,which have basophilic staining characteristics.Bone marrow film.leftright26FAB M5a category.The blasts are large with abundant cytoplasm.They show little signs of differentiati
18、on,but one cell has an indented nucleus.Nucleoli are large and prominent.Sometimes there are fine azurophilic(嗜苯胺蓝颗粒嗜苯胺蓝颗粒)granules.Bone marrow film.FAB M5b category.Monocytic differentiation is apparent.Bone marrow film.27FAB M6 showing erythropoiesis that is dysplastic and grossly megaloblastic(巨幼
19、红细胞巨幼红细胞);there is an excess of proerythroblasts but also of immature granulocytes,including blast cells.Bone marrow film.FAB M7 category.Bonemarrow trephine biopsy shows blast cells(left)and increased reticulin deposition(right).2829Flow chart showing how the WHO hierarchical classification is appl
20、ied.30AML的WHO分型 伴有再现性遗传学异常的伴有再现性遗传学异常的AMLw伴有伴有t(8;21)(q22;q22)(AML1/ETO)的的AMLw伴有伴有inv(16)(p13q22)或或t(16;16)(p13;q22)(CBF/MYH11)和异常骨髓嗜酸细胞的和异常骨髓嗜酸细胞的AMLw伴有伴有t(15;17)(q22;q12)(PML/RAR)的的APLw伴有伴有11q23(MLL)异常的异常的AML伴有多系病态造血的伴有多系病态造血的AMLw由由MDS或或MDS/MPD发展而来的发展而来的AMLw无先前的无先前的MDS或或MDS/MPD病史但二系或三系病态造血细胞病史但二系或
21、三系病态造血细胞50%治疗相关性治疗相关性AML和和MDS t-AML和和t-MDSw烷化剂或放疗所致的烷化剂或放疗所致的AML/MDSwDNA柘扑异构酶抑制剂所致的柘扑异构酶抑制剂所致的AML/MDS 一些可能为一些可能为ALL无法按上述分型的白血病无法按上述分型的白血病NOC-AMLw急性微分化白血病急性微分化白血病w急性未分化白血病急性未分化白血病w急性部分分化的白血病急性部分分化的白血病w急性粒单细胞白血病急性粒单细胞白血病w急性单核细胞白血病急性单核细胞白血病w急性红血病急性红白血病和纯红血病急性红血病急性红白血病和纯红血病w急性巨核细胞白血病急性巨核细胞白血病w急性嗜碱细胞白血病急
22、性嗜碱细胞白血病w急性全髓细胞增生伴骨髓纤维化急性全髓细胞增生伴骨髓纤维化w髓系肉瘤髓系肉瘤315-year 12%5-year 40%5-year 61%32Clinical Features Anemia-pallor,weakness Fever-mainly due to infection(G-bacilli)Bleeding-skin,nasal,gum,intracranial(颅内)Infiltration-organs and tissues33Causes of AnemiaDecreased production of erythrocytesShortened red
23、blood cell survival timeHemorrahage Post-chemotherapy34Causes of infectionReduced normal granulocytes in numberImpaired function of granulocytesWeakened cellular immunity Post-chemotherapy effects35Causes of BleedingQuantity and quality of platelet Perivascular infiltration of leukemic cells Coagula
24、tion abnormalities(凝血异常)DIC:release of tissue factor-like procoagulants(促凝物质)from granules within the leukemic cells36Leukemia infiltration Lymphadenopathy,Hepatomegaly,Splenomegaly:especially in ALL Bone(sternum tenderness，胸骨压痛胸骨压痛)and Joint Chloroma（绿色瘤绿色瘤）:AML Oral Cavity and Skin:gum infiltratio
25、n frequently seen in M4,M5 Central Nerve System Leukemia(CNS-L):mainly in ALLTesticular(睾丸睾丸)Leukemia:mainly in ALL37gum infiltrationskin bleeding and infiltration38Lab Findings:Peripheral BloodWBC-5.0 to 50.0 x109/L 100 x109/L Leukemic cells often can be seen Aleukemic type:WBC decreased without le
26、ukemic cellsAnemia-RBC count and Hb decreasePlatelet Count-decreased Acute Leukemia-Peripheral BloodAcute Leukemia-Peripheral Blood 3940Lab Findings:Peripheral BloodSubtype according to peripheral bloodLeukemic type:WBC increased with leukemic cellsSubleukemic type:WBC normal range with leukemic cel
27、lsAleukemic type:WBC decreased without leukemic cells41Lab Findings:Bone Marrow General Aspects:HyperplasiaLeukemic cells excessively proliferationInhibiting other cell linesLeukemic cells 20%Bone MarrowBone MarrowAcute leukemia Acute leukemia Normal Normal 4243Bone marrow AML44Bone marrow of APL45R
28、enji hospital Renji hospital Clinical and molecular characteristics of APL 46Bone marrow of acute monocytic leukemia 47Bone marrow of ALL48Cytochemistry of leukemic cellsALLAMLAMoLPOX-+-+PAS+clump or granular-/+diffused-/+diffusedNSENAP -/+Not inhibit by NaF/-+Inhibited by NaFN/Cytochemical stainCyt
29、ochemical stainPOX NSEPAS4950POX of APLSE of APL51Immunologic Markers Lineage Antigen B-cell CD19,CD20,CD21,CD22,HLA-DR T-cell CD1,CD2,CD3,CD4,CD5,CD7,CD8 Myeloid CD13,CD14,CD15,CD33,CD4152Immunologic Markers M1 M2 M3 M4 M5 M6 M7CD13 +-CD33 +-CD14 -+-CD41 -+53Immunologic Markers Lineage Antigen Eryt
30、hroid Glycophorin A Megakaryocytic CD41,CD42b,CD61 54Cytogenetics and Molecular BiologyAML M3 t(15;17)(q22;q21)PML/RAR RAR/PMLM4EO ivn(16)(q22)CBFB/MYH11M2 t(8;21)(q22;q22)AML1/ETOM5 t/del(11)(q23)MLL/ENL 55PMLRAR PML-RAR RAR -PML15171517Cytogenetics and Molecular Biology of APL56RISK STATUS BASED O
31、N CYTOGENETICS AND MOLECULAR MUTATIONS57Distribution of common cytogenetic abnormalities in patients aged less than or more than 60.58The DFS and OS of cytogenetic changes in AMLBetter-riskIntermediate-riskPoor-riskBetter-risk1Intermediate-riskPoor-risk59Cytogenetics and Molecular BiologyALL t(9;22)
32、q34;q11)BCR/ABLALL-L2 t(1;19);t(4;11)ALL-L3 t(8;14)(q24;q32)MYC/IgH 60Renato Bassan et al,2004,Oncology Hematology61MICM CategorywM-morphologywI -immunologywC-cytogeneticswM-molecular biology62Lab Findings:Others Hyperuricemia(高尿酸血症高尿酸血症)-tumor cell lysisLactate Dehydrogenase(LDH)increaseActivity o
33、f lysozyme(溶菌酶溶菌酶)increase,common in M4 or M5DIC:more common in AML than ALL,especially in M3(APL)Lab findingsCellular morphologyBlood routinebiochemistryimmunologyGene mutations：C-KIT、FLT3-ITD、NPM1、CEBPACytogeneticMolecular features(PML/RAR、AML1/ETO、CBFb/MYH11、MLL)2Lab findings64Diagnosic criteriaC
34、linical manifestationPeripheral blood changesAnemiaThrombocytopeniaLeukemic cellsBone marrow examination leukemic cells 20%65Differential diagnosisMyelodysplastic syndromes(MDS)Leukemoid reactionAplastic anemia66James w,et al.Blood,2002,100(7):229267ManagementGeneral management:Supportive cares trea
35、ting of ongoing infections and preventing Chemotherapy,usually combined remedyProphylactic and treatment of extramedullary leukemiaImmunotherapyBMT68ChemotherapyGOALS:Achieve Complete Remmission(CR);Prolong Disease Free Survival(DFS);Cure the disease69Principles of ChemotherapySelection of drugs and
36、 protocolsDrugs focusing on different cell cyclesDrugs working corporatelyNo sever overlap of toxicity70Anti-Leukemia Drugs:Killers:making the leukemic cells dead-most of the drugs we use Inducer of differentiation:leading the blasts to mature ones-ATRAPromotor of Apotosis:leading leukemic cells to“
37、natural death”-As2O371Strategy of ChemotherapyTherapeutic period and intermittent periodvRemission Induction TherapyvPost-Remission Therapy72TreatmentInductionConsolidationmaintenance73Treatment strategy74ALL:Remission Induction DVP Regimen:wDaunomycin(D)45 mg/m2/d,D 1-3(15-17)or Idarubicin(ID)8-12
38、mg/m2/d,D 1-3(15-17)wVincristine(V)1.4 mg/m2/d,D1,8,15,22wPrednisone(P)40 mg/m2/d,D1-28CR rate:adult-8090%NCCN Guideline for AML76AML:Remission induction DA Regimen:Daunomycin(D)60-90mg/m2/d,D1-3 or Idarubicin(ID)8-12 mg/m2/d,D 1-3 Ara-C (A)150 mg/m2/d,D1-7HA Regimen:Harringtonin(H)3-4 mg/d,D1-3Ara-
39、C (A)150 mg/m2/d,D1-7CR rate:65-85%Postremission therapyAccording to cytogenetics and molecular abnormalitieswBetter risk or intermediate-risk(no donor)HD-AraC 2.0g/m2,q12h,d1,d2,d3wIntermediate-risk:Allo-PBSCTwPoor-risk:Allo-PBCST78Acute promyelocytic leukemia(APL)DiagnosiswBM:cellular morphologywC
40、ytogenetics:t(15;17)wMolecular feature:PML-RARwOthers:t(11;17)PLZFRAR,NuMA RARt(5 ;17)NPM RARAML-M3aCytogenetics and molecular features of APLcytogeneticsIncidence in APLFusion geneClinical featurest(15;17)(q22;q21)95%PML-RARaATRA sensitiveRARa-PMLArsenic sensitivet(11;17)(q23;q21)0.8%PLZF-RARaATRA
41、no sensitiveRARa-PLZFArsenic resistancet(11;17)(q13;q21)rareNuMA-RARaATRA sensitivet(5;17)(q35;q21)10X109/L(high risk)ATRA:25mg/m2/d,d1-CRIDA:8mg/m2/d,d2,4,6,8;or DNR:45-60mg/m2/d,d1-3Ara-CATO 0.16mg/kg/d,d1-CRWBC10 x109/LShortness of breathHypoxemia(低氧血症低氧血症)Pleural(胸膜胸膜)or pericardial(心包心包)effusio
42、nsTreatmentClose monitoring of pulmonary status(肺功能状态肺功能状态)If the patient develops pulmonary infiltrates or hypoxemia,dexamethasone:10mg BID for 3-5daysInterrupt ATRA therapy until hypoxemia resolves91Criterias for Complete RemissionNo symptoms and signs of leukemia;Hb 100g/L(male)or 90g/L(female an
43、d children),neutrophil count 1.5x109/L,platelet 100 x109/L;No leukemic cell in peripheral blood;BM:normal plasia,blast+procyte 5%,and normal growth of red cell line and megakaryocyte.92Prophylaxis and treatment of CNS leukemiaMTX 10mg+DX 2.5mg inject intrathecal.twice weekly x 5 doses60Co cranial ir
44、radiation 2400 rads/20days93Bone Marrow TransplantationAlloBMT/AlloPBSCTDifficult to find a donor Rejection(GVHD)expensiveAutoBMT/AutoPBSCT High incidence of relapse94ConclutionClinical manifestationLab findings:Peripheral blood Bone marrow;Cytochemistry,MorphologyImmunologyCytogeneticsFAB classification:ALL,ANLLManagementThank you!95
