1、白白 血血 病病 LeukemiaSIR RUN RUN SHAW HOSPITALHUANG JINWENRudolf Virchow,who named“leukemia”in 1845Alfred Velpeau who first discrepted“leukemia”in 1827 白血病的分类AcuteChronicMyeloid originLymphoid originAcute Myeloid Leukemia(AML)Acute Lymphoblastic Leukemia(ALL)Chronic Myelogenous Leukemia(CML)Chronic Lymp
2、hocytic Leukemia(CLL)白血病各亚型分布图(2001)ALL11%CLL26%AML31%CML15%others17%Total Reported Cases=31,500Sources from Leukemia,Lyphoma,Myeloma Facts 2001CLL=Chronic LymphocyticALL=Acute LymphocyticCML=Chronic MylogenousAML=Acute MylogenousAcute Myeloid Leukemia概述 Concepts,biology Epidemiology Clinical and la
3、boratory manifestations Diagnosis Management and prognosis造血干细胞分化及白血病起源示意图NeutrophilsEosinophilsBasophilsMonocytesPlateletsRed cellsMyeloidprogenitorLymphoidprogenitorT-lymphocytesPlasmacellsnavedifferentiation blockenhancedproliferationAcuteLeukemia+Gain of function mutations of tyrosine kinaseseg.
4、FLT3,c-KIT，N-and K-RAS mutations BCR-ABL TEL-PDGFbRLoss of function of transcription factors needed for differentiation eg.AML1-ETO CBFb-SMMHC PML-RARa白血病起源学的两种模式FAB(1976)分类 M0-Undifferentiated AML M1-AML without maturation M2-AML with maturation M3-Acute Promyelocytic Leukemia M4-Acute Meylomonocyt
5、ic Leukemia M5-Acute Monocytic Leukemia M6-Erythroleukemia(DiGuglielmos)M7-Megakaryoblastic LeukemiaWHO 分类 AML with recurrent cytogenic translocations AML with multi-lineage dysplasia AML and myelodysplasia,therapy related AML,not otherwise categorizedFAB 与 WHO 分类的异同点 FAB criteria Morphology Cytoche
6、mistry WHO criteria Morphology Immunophenotyping Genetic features Karyotyping Molecular testing Clinical features and history 临床表现 Symptoms due to:marrow failure tissue infiltration leukostasis constitutional symptoms others(DIC)usually short duration of symptoms骨髓功能衰减 Neutropenia:infections,sepsis
7、Anemia:fatigue,pallor Thrombocytopenia:bleeding组织或器官浸润 Enlargement of liver,spleen,lymph nodes Gum hypertrophy Bone pain other organs:CNS,skin,testis,etc。并发症并发症 Hyperleukocytosis and Leukostasis CNS Leukemia Ocular involvement Tumor lysis syndrome/Hyperuricemia Infections/Necrotizing enterocolitis P
8、regnancy过去史过去史 A prior hematologic disorder or a malignancy.Cardiac disease,renal function,etc.Transfusion history or pregnancies.Possible drug allergies.Infection histories.Menses in premenopausal women.体格检查体格检查 Fever Skin Eyes Oropharynx Organomegaly Sternal tenderness牙龈增生ABC髓样肉瘤NEJM 1998诊 断实验室检查实
9、验室检查CBC with WBC differential.Coagulation studies.Aminotransferases,alkaline phosphatase,bilirubin,LDH,etc Creatinine,electrolytes,uric acid,glucoseCalcium,phosphorus外周血涂片外周血涂片骨髓抽吸及活检示意图骨髓抽吸及活检示意图骨髓抽吸及活检并发症 Bleeding Local infection Neuropathy,osteomyelitis,needle breakage Cardiac tamponade,pulmonary
10、 emboli,pulmonary infection,bone erosion/thining正常骨髓象白血病骨髓象Acute Promyelocytic LeukemiaAcute myeloid leukemia with maturationAuer rods in AMLFAB诊断及其分类流程 组化 急淋 AML 急单POX -分化差的原始细胞 -+-+分化好的原始细胞分化好的原始细胞 +PAS +成块或颗粒状 -或+，弥漫 -或+呈弥漫性 性淡红色 或颗粒状NSE -+不被NaF抑制 +能被 NaF 抑制NAP 增加 减少或-正常或增加白血病细胞组织化学染色WHO诊断及其分类流程
11、Morphology/Enzyme cytochemical stains Immunophenotyping/flow cytometry Cytogenetic analysis Molecular genetic analysis or Fluorescence in situ hybrization(FISH)类型类型 染色体改变染色体改变 基因改变基因改变M2 t(8;21)(q22;q22)AML1/ETOM3 t(15;17)(q22;q21)PML/RARa a,RARa a/PMLM4Eo inv/del(16)(q22)CBFB/MYH11M5 t/del(11)(q23)
12、MLL/ENLAMLAML常见的染色体和基因特异改变常见的染色体和基因特异改变t(8:21)RUNX1-RUNX1T1(previously AML1-ETO)WHO：Aml诊断标准Blast 20%of ANC of the BM aspirate，or Blasts 20%of peripheral blood t(8;21),inv(16),or t(15;17)，or Myeloid sarcoma.Myeloid origin demonstrated by either Auer rods,cytochemical,or immunophenotypingClinical feat
13、ures WHO：AML 分类 AML with recurrent cytogenetic translocations AML with t(8;21)APL with t(15;17)AML with inv(16)or t(16;16)AML with 11q23 MLL abnormalities AML with multilineage dysplasia With prior MDS,Without prior MDS AML with myelodysplastic syndrome,therapy related Alkylating agent related,Epipo
14、dophyllotoxin related,Other types AML not otherwise categorized AML minimally differentiated AML without maturation AML with maturation Acute myelomonocytic leukemia Acute monocytic leukemia Acute erythroid leukemia,Acute megakaryocytic leukemia Acute basophilic leukemia,Acute panmyelosis with myelo
15、fibrosis其它检查及操作其它检查及操作 CXR(chest x-ray)EKG(electrocardiogram)EF(cardiac ejection fraction)Lumbar puncture HBV，Herpes simplex and CMV serology Insertion of Hickman central catheter or PICC line.Consultation prior to chemotherapy HLA typing of the patient and siblings Dental consultation核磁共振核磁共振治疗原则 C
16、ombination chemotherapy#first goal is complete remission#further Treatments to prevent relapse Complications Supportive medical care#transfusions,antibiotics,nutrition Psychosocial support#patient and familyAML诱导缓解方案 Drugs Dosing Comments Cytarabine plusdaunorubicin Cytarabine:100 to 300 mg/m2 daily
17、 as a continuous infusion for 7 days;Daunorubicin:60-90 mg/m2 intravenous push on each of the first 3 days of treatmentStandard 7+3 induction regimen resulting in approximately 60 to 80 percent remission rate and acceptable toxicity in patients under 60 years old HDAC plusdaunorubicinCytarabine:1 to
18、 3 g/m2 twice daily for a total of 12 doses;Daunorubicin:45 mg/m2 intravenous push for 3 days following cytarabineYields a 90 percent remission rate;however,substantial toxicity precludes postremission therapy in a high proportion of patientsCytarabine plus idarubicinCytarabine:100-200 mg/m2 daily a
19、s a continuous infusion for 7 days;Idarubicin:12-13 mg/m2 IV push on each of first 3 days of treatmentHas produced a greater remission rate(88 versus 70 percent)than cytarabine/daunorubicin in younger patients;appears superior to daunorubicin in patients with hyperleukocytosis;overall survival not c
20、learly superior to standard regimen造血干细胞移植术 permits“rescue”from otherwise excessively toxic treatment additional advantage of graft-vs-leukemia effect in allogeneic transplants trade-off for allogeneic transplantation:greater anti-leukemic effect but more toxic完全缓解定义完全缓解定义 ANC 1.0X103/dL,Plt 100X103
21、/dL,and independence from RBC transfusion.A normal maturation of all cellular components in bone marrow Blast cells 5%in the bone marrow Non clusters or collections of blast cells in BM biopsy.Extramedullary leukemia must be absent.The absence of a previously detected clonal cytogenetic abnormality,
22、etc.影响影响AMLAML预后的因素预后的因素Favorable FactorsUnfavorable factorsAge60Karnovsky score 60 percentKarnovsky score 60 percentCD34-negative phenotypeCD34-positive phenotypeMDR 1-negative phenotypeMDR 1-positive phenotypeHypocellular LeukemiaPrior myelodysplastic syndrome,myeloproliferative or hematologic dis
23、order,chemotherapy,or radiation therapyNormal karyotype inv(16)t(8;21)t(15;17)Trisomy 8 Complex karyotypic abnormalities，t(6;9)Absence of changes in chromosomes 5 or 7Changes in chromosomes 5 or 7(eg,trisomy,deletions,etc)FLT3 gene mutations absentFLT3 gene mutations present细胞遗传学分类Cytogenetic risk g
24、roup#Induction successOverall survivalFavorablet(8;21)inv(16)or t(16;16)t(8;21)inv(16)or t(16;16)del(9q)*AdverseComplex karyotype (ie,3 abnormalities)inv(3)or t(3;3)abn(12p)Complex karyotype (ie,3 abnormalities)inv(3)or t(3;3)t(6;9)t(6;11)-7 +8(sole abnormality)+8 with 1 other abnormality*t(11;19)(q
25、23;p13.1)#Patients with t(15;17)and t(9;22)were excluded from this analysis.The intermediate risk group included:normal karyotype;-Y;del(5q);loss of 7q;t(9;11);+11;del(11q);abn(12p);+13;del(20q);and+21.细胞遗传学分类与总体生存率细胞遗传学分类与总体生存率年龄对AML生存及化疗疗效的影响OS according to age irrespective of management Blood 200
26、9;113:4179.Copyright 2009 American Society of Hematology patients with de novo AML,fit for intensive treatment 细胞核型及治疗选择KaryotypeKaryotypeCompleteCompleteremission remission raterateRemission Remission durationdurationTreatment approachTreatment approacht(8;21)(q22,q22)HighLongStandard induction wit
27、h an anthracycline.Intensive consolidation chemotherapy with three repetitive courses of HDACinv(16)(p13q22)or t(16;16)(p13;q22)HighIntermediate to longStandard induction with an anthracycline.Intensive consolidation chemotherapy with three repetitive courses of HDACt(15;17)(q22;q11-12)HighIntermedi
28、ate to longAll-trans retinoic acid together with an anthracycline.Arsenic trioxide to treat relapse.t(9;11)(p22;q23)HighIntermediateStandard induction and intensive consolidation with HiDAC.Reserve HCT for second remission for most t(9;11)patients.del(5q),+13,+8,-7,inv3,del(12p),t(9;22),other t(11q2
29、3),orcomplex bnormalitiesLowShortNew induction regiments,including use of New induction regiments,including use of growth factors during or after growth factors during or after chemotherapy,or modulators of drug chemotherapy,or modulators of drug resistance.Perform HCT in first CR.resistance.Perform
30、 HCT in first CR.Acute Lymphoblastic Leukemia白血病，还是淋巴瘤 Lymphoma(LBL)diagnosed,with a mass lesion,or/and 25 percent bone marrow blasts.WHO 分类 Precursor B Cell(Acute)Lymphoblastic Leukemia Precursor T Cell(Acute)Lymphoblastic Leukemia ALLALL骨髓象骨髓象L1：原始和幼淋细胞以小细胞原始和幼淋细胞以小细胞 为主为主L2：原始和幼淋细胞以大细胞为主原始和幼淋细胞以大
31、细胞为主L3：原始和幼淋细胞以大细胞为主，原始和幼淋细胞以大细胞为主，大小较一致，细胞内有明显空大小较一致，细胞内有明显空 泡，胞浆嗜碱性，染色深泡，胞浆嗜碱性，染色深.ALL与AML的鉴别诊断 MPO(myeloperoxidase)neg.TdT pos.ALL与AML基因谱的表达B细胞分化抗原的表达 Early precursor B(pro-B-ALL)：membrane CD19+,CD79a+,and cytoplasmic CD22+Common ALL：CD10+Late pre-B ALL：CD20+,cytoplasmic mu heavy chain.Early or p
32、ro-T：CD2,CD7,CD38 and cytoplasmic CD3(30 percent)Common thymocyte：CD1a,sCD3,CD4/CD8 double positive(50 percent)Late thymocyte：CD4 or CD8 single positive(20 percent)T细胞分化抗原的表达细胞遗传学及基因学 The t(9;22)and t(v;11q23)are often associated with a pro-B immunophenotype and a poor prognosis t(12;21)and hyperdip
33、loidy are associated with a good prognosis.TCR beta or gamma&IgH may not be lineage-specific临床表现 What are different manifestations of ALL from AML What are different complications between ALL and AML成人成人PhPh+ALLALL 的治疗的治疗 Induction Chemo:A BCR-ABL tyrosine kinase inhibitor(TKI)plus combination chemo
34、 reg.Consolidation Chemo:Allo-trans.or TKI+Chemo,Maintenance Tx TKI Follow up:Conventional chemo regimens Allo hematopoietic stem cell transplantation成人成人PhPh ALLALL 的治疗的治疗ALL 常规化疗方案 General considerations:DAU,CTX,Pred,L-asp+CNS prophylaxis Cancer and Leukemia Group B(CALGB study 8811 or 9111)ALL re
35、gimen Larson RA et al,Blood.1995;85(8):2025-37 Standard or augmented Berlin-Frankfurt-Munster(BFM)has been used by the Children Cancer Group for children and adolescents Stock W et al,Blood.2008;112(5):1646-54 Hyperfractionated CTX,VCR,DOX,and DXM(Hyper-CVAD)alternating with high-dose MTX and ARA-C
36、Kantarjian HM et al,J Clin Oncol.2000;18(3):547-61 French GRAALL-2003 regimen for younger adults Huguet F et al,J Clin Oncol.2009;27(6):911-8CR1后异基因移植生存率汇总表*patients who receive post-remission therapy may expect five-year survival rates of 40 to 60 percent Chronic Myelogenous LeukemiaCML vs AML的外周血象
37、Myeloid cell CML AML normalblasts q qpromyelocytes qmyelocytes qmetamyelocytes qbands qneutrophils q#q临床表现 A triphasic or biphasic clinical course Asymptomatic,suspected from routine blood tests Symptomatic,fatigue,malaise,weight loss,excessive sweating,abdominal fullness,bleeding episodes,Abdominal
38、 pain/discomfort Acute gouty arthritis,splenomagely,low sternum tenderness,etc.白细胞淤滞 Accumulation of blasts in microcirculation with impaired perfusion Lungs:hypoxemia,pulmonary infiltrates CNS:stroke only seen with WBC 50 x 109/LCMLCML骨髓象和外周血象骨髓象和外周血象费城染色体费城染色体FISH：t(9;21)positive nucleiCMLCML诊断要点诊
39、断要点 Neutrophilic leukocytosis with circulating immature cells of the granulocyte series NAP Splenomegaly,Basophilia Ph+chromosome,BCR-ABL fusion mRNA,or bcr-abl protein CMLCML加速期诊断标准加速期诊断标准CMLCML急变期诊断标准急变期诊断标准 Blasts 20 percent in peripheral blood or in bone marrow Large foci or clusters of blasts o
40、n the bone marrow biopsy Extramedullary blastic infiltratesCMLCML急变骨髓象急变骨髓象慢性期骨髓细胞形态慢性期骨髓细胞形态急变期骨髓细胞形态急变期骨髓细胞形态CML 慢性期治疗建议 Tyrosine kinase inhibitor(TKI)(Grade 1A).Allogeneic hematopoietic cell transplantation(HCT)may be a reasonable alternative in rare circumstances The second generation TKIs improved clinical benefit over imatinib Imatinib is not tolerated or the goal not been achieved or lost,therapy should be altered Overall survival of CMLOverall survival of CMLChelsea I can see your halo,I pray you wont fade away.THANKS
