1、Leukemia Peng Zhigang Dep.Hematology， Guangxi Medical University 目的和要求 掌握白血病的临床表现和实验室检查之特掌握白血病的临床表现和实验室检查之特 点，诊断依据。点，诊断依据。 熟悉白血病的治疗原则及方法。熟悉白血病的治疗原则及方法。 了解近代对本病病因及发病机理的认识和了解近代对本病病因及发病机理的认识和 概念，发病情况，分类，预后。概念，发病情况，分类，预后。 Concept of leukemia Definition Leukemia is a malignant Clonal heamotopoietic stem
2、cells disorder Proliferation is out of control apoptosis is inhibited. Differentiation of HSC is blocked. Extramedullary involvement and metastasis Hematopoiesis PLURIPOTENT STEM CELL COMMITTED PROGENITOR CELL RECOGNIZABLE BONE MARROW PRECURSOR CELL MATURE BLOOD CELL myeloblast monoblast pronormobla
3、st red cell neutrophil monocyte basophil platelet CFU-Baso CFU-Eos CFU-GM BFU-E/CFU-E eosinophil pre-T pre-B myeloid progenitor cell lymphoid progenitor cell lymphoblast lymphoblast T-cell B-cell AML, adult ;CML, 2050 years old; CLL ,5070 years old Etiology Most cases arise with no clear cause some
4、accepted risk factors for leukemogenesis Etiology Biologic factors: virus: HTLV-1 can result in Acute T lymphomaic leukemia. Immunology defect Etiology Physical factors radiation exposure: ionic radiation,x-ray 1、atom bomb 2、high dose X radiotherapy、 32P therapy Etiology Chemical factors Chemical ex
5、posure : benzene petroleum Pesticide Other environmental exposures hair dyes smoking Prior chemotherapy alkylating agents Etiology Genetic disorders : familial leukemia 7/1000 Down syndrome Bloom syndrome Fanconis anemia ataxia-telangiectasia Wiskott-Aldrich syndrome In identical twins from other bl
6、ood disorders Myeloproliferative Disease(MPD) chronic myeloid leukemia(CML) polycythemia vera(PV) primary thrombocythemia(PT) myelofibrosis(MF) myelodysplastic syndrome(MDS) Etiology Principles of leukemogenesis a multistep process The mutation of gene(ras ,myc) result in the proliferation of the le
7、ukemic clone Some genetic changes result in differentiation blocked at an early stage Acute Leukemias Classification (FAB system) AML（M1） AML(M2) APL（M3） AML（M4） AML（M4EO） AML（M5） AML（M6)） AML（M7） ALL: FAB Classification L1 - Small cells; subtype represents 25- 30% of adult cases L2 - Large and irre
8、gular nuclear shape, subtype represents 70% of cases (most common) L3 very Large ;subtype represents 1-2% of adult cases ALL（L1） ALL（L2） ALL（L3） Classification （二二）WHO Classification MICM分型分型 morphology: 形态学形态学FAB分型分型 immunology: 免疫学用免疫学用CD 抗原单克隆抗体分型抗原单克隆抗体分型 cytogenetics: 细胞遗传学染色体分型细胞遗传学染色体分型 molec
9、ular biology: 分子生物学基因分型分子生物学基因分型 Clinical Features decrease in normal hematopoiesis accumulation of blast cells in other sites:infiltration Clinical Features Anemia (RBC) pallor, weakness, fatigue, dyspnea, tachycardia Clinical Features bleeding PLT skin,purpura, mucosal bleeding, epistaxis, menorrh
10、agia life-threatening: brain bleeding associated with DIC(M3) Clinical Features Infections: neutrophil immune URI, gingivitis, pharyngitis,bronchitis pneumonitis, septicemia pathogens: gram-negative;fungus Clinical Features decrease in normal hematopoiesis accumulation of blast cells in other sites:
11、infiltration Clinical Features enlargement of liver, spleen, lymph nodes, especially ALL Clinical Features bone pain, sternum tenderness chloroma/granulocytic sarcoma, Spinal column or orbit: exophthalmos, diplopia, blindness Clinical Features gum hypertrophy Skin: rashes, palpable, hard, indigo nod
12、e Clinical Features CNS-L: often occurred in ALL, headache,dizziness,vomiting, neck rigidity Clinical Features testis often occurred in ALL, Testicular painless enlargement any organ Laboratory studies Blood ： WBC usually elevated, but can be normal or low,WBC10109 /L ( hyperleukocytosis ) blasts ar
13、e present anemia (normocytic) ,immature RBC may be present PLTthrombocytopenia Laboratory studies Bone marrow aspiration necessary for diagnosis useful for determining type useful for prognosis Laboratory studies Bone marrow aspiration Proliferative(most case);hypoplastic(10%) WHO:blasts20% Auers ro
14、ds(+) in AML erythropoiesis megakaryocytopoiesis leukemia cells ( show Auers rods ) Laboratory studies Cytochemistry: 主要用于协助形态鉴别各类白血病主要用于协助形态鉴别各类白血病 常见常见AL的细胞化学鉴别的细胞化学鉴别 急淋白血病急淋白血病(ALL) 急粒白血病急粒白血病 急性单核细胞白血病急性单核细胞白血病 过氧化物酶过氧化物酶(POX)（） 分化差的原始细胞分化差的原始细胞 （）（） （）（）（）（） 分化好的原始细胞分化好的原始细胞 （）（+） 糖原糖原PAS反应反应
15、（）成块成块 （）或或（）， （）或或（）呈弥漫呈弥漫 或颗粒状或颗粒状 弥漫性淡红色弥漫性淡红色 性淡红色或颗粒状性淡红色或颗粒状 非特异性脂酶非特异性脂酶 (NSE) （）（）（） （）NaF抑制抑制50% NaF抑制抑制50% Laboratory studies cytochemical stains Peroxidase stain: AML Nonspecific esterase and inhibited by sodium fluorid: M4, M5 Periodic acid-Schiff (PAS) stain: ALL Laboratory studies Immu
16、nophenotyping Cytogenetics 表6-9-2 白血病免疫学积分系统（EGILL，1998） 分值分值 B B系系 T T系系 髓系髓系 2 2 CyCD79aCyCD79a CyCD22CyCD22 CyIgMCyIgM CD3CD3 TCRa/BTCRa/B TCRr/BTCRr/B CyMPOCyMPO 1 1 CD19CD19 CD20CD20 CD10CD10 CD2CD2 CD5CD5 CD8CD8 CD117CD117 CD13CD13 CD33CD33 CD65CD65 0.50.5 TdTTdT CD24CD24 TdTTdT CD7CD7 CD1aCD1
17、a CD14CD14 CD15CD15 CD64CD64 IMMUNO-PHENOTYPING mab M1 M2 M3 M4 M5 M6 M7 CD13 + + + + + - - CD33 + + + + + - - CD14 - - + + - - CD41 - - - - - - + Ret - - - - - + - Lectoferrin - + - + - - - CD19 CD7 HLA-DR CD3 MPO T - + - + - B + - + - - Immunophenotyping According to Immunophenotype of leukemia, A
18、L is divided into four typess: 1 acute undifferentiated leukemia （AUL） 2 Acute mixed lineage leukemia 3 (1) M+ ALL;(2) L+AML 4 A single phenotype: (1) ALL;(2) AML 表6-9-3 AML常见的染色体和分子学异常的意义 预后等级预后等级 细胞遗传学（染色体）细胞遗传学（染色体） 分子生物学异常分子生物学异常 良好良好 t(15;17)t(15;17)（q22;q12q22;q12）APL(APL(PML/RARa) ) t(8;21)t(
19、8;21)（q22;q22q22;q22）AMLM2a(AMLM2a(AML1/ETO) ) inv(16)inv(16)（p13q22p13q22）/t(16;16 )/t(16;16 )（p13;q22p13;q22） AMLM4Eo(AMLM4Eo(CBFB/MYH11) ) 正常核型伴有孤立的正常核型伴有孤立的NPM1NPM1突突 变变 中等中等 正常核型、孤立的正常核型、孤立的+8+8、 孤立的孤立的t(9;11)t(9;11)（p22p22；q23q23）、）、 其他异常其他异常 t(8;21)t(8;21)或或 inv(16) inv(16) 伴有伴有 c c- -kitkit突
20、变突变 不良不良 复杂核型复杂核型(3(3种种) )，- -5 5、- -7 7、5q5q- -、7q7q- -、 11q2311q23异常，除外异常，除外t(9;11)t(9;11)、 inv(3)inv(3)、 t(3;3)t(3;3)、 t(6;9)t(6;9)、 t(9;22)t(9;22)、 正常核型伴有单独的正常核型伴有单独的FLT3FLT3- - ITDITD 表6-9-4 ALL常见染色体和分子学异常的检出率 染色体核型染色体核型 基因基因 发生率（成人）发生率（成人） 发生率（儿童）发生率（儿童） 超二倍体超二倍体 亚二倍体亚二倍体 - - - - 7% 7% 2%2% 25
21、%25% 1%1% t(9;22)t(9;22)（q22;q22q22;q22）：）：Ph+Ph+ t(12;21)t(12;21)（p13;q22p13;q22） t(v;11t(v;11q23q23) ) t(1;19)t(1;19) BCRBCR- -ABLABL TELTEL- -AML1AML1 MLLMLL E2AE2A- -PBX1PBX1 25%25% 2%2% 10%10% 3%3% 3% 3% 22%22% 8%8% 5%5% t(5;14)t(5;14)（q31;q32q31;q32） t(8;14) t(2;8) t(8;22)t(8;14) t(2;8) t(8;22
22、) t(1;14)t(1;14)（p32;q11p32;q11） t(10;14)t(10;14)（q24;q11q24;q11） t(5;14)t(5;14)（q35;q32q35;q32） IL3IL3- -IGH IGH c c- -mycmyc TAL1TAL1 HOX11HOX11 HOX11L2HOX11L2 1% 4% 12% 8% 1% 1% 2% 7% 1%1% 3%3% Chromosome translocation Fusion gene M2 t(8;21) AML1/ETO M3 t(15;17) PML/RAR M4 inv(16), t(16;16) CBF/M
23、YH11 M5 t(4;11),11q23 MLL abnormalites ALL(15% ) L 3 t(9;22) t(8;14) BCR/ABL MYC, IgH rearrangement Common Cytogenetic Abnormalities in AML and ALL Laboratory studies Chemistry : LDH and, UA DIC: APTT,PT, fibrinogen Laboratory studies Chemistry CSF of GNS-L : 1, spinal fluid pressure （200mmH2O） 2,WB
24、C （0.01109/L） 3,Protein （450mg/L） 4,blasts present in the spinal fluid, Diagnosis Clinical features BM aspiration (FAB): morphology, cytochemical staining, immunophenotyping, cytogenetics, molecular biology Differential Diagnosis Myelodysplastic syndromes (MDS) Pancytopenia Dysheamtopoiesis(2 lines)
25、 in bone marrow Blast 20%20% Differential Diagnosis Infections: infectious mononucleosis Shorter, more can be self-healing Heteromorphous lymphocyte Blast cell Differential Diagnosis Bone marrow recovering from acute agranulocytosis Have obvious cause Plt is normal No Auer rod in blast, marrow granu
26、locyte mature returned to normal In the short term Differential Diagnosis Megaloblastic anemia(M6) The blast cells in bone marrow is not increased PAS（）in erythroblasts Folic acid, Vit12 treatment is effective Treatment Eliminate of hyperleukocytosis: leukapheresis hydroxyurea hydrated chemotherapy
27、Leukostasis accumulation of blasts in microcirculation with impaired perfusion lungs: hypoxemia, dyspnea, pulmonary infiltrates CNS: stroke, dizziness, stupor, intracerebral hemorrhage only seen with WBC 50 x 109/L Avoid of tumor lysis syndromes : (Hyperkalemia ;hyperphosphatemia;hyper uriemia; hypo
28、calcemia combination of hydration, allopurinol, and alkalinization of urine with sodium bicarbonate Treatment Supportive care Replacement of blood products : packed red blood cells, platelets, fresh frozen plasma Antibiotics Use of growth factors Metabolic management Treatment : Chemotherapy aims of
29、 treatment eliminate abnormal clone allow repopulation of marrow with normal hemopoietic cells Therapeutic principle of AL early Combine CCSA+CCNSACCSA+CCNSA full Interval 2-3w Repeat individualization Chemotherapy Two phases Remission induction treatment (induction chemotherapy) Treatment After Rem
30、ission Consolidation therapy Maintenance chemotherapy Induction chemotherapy Aims CR Complete remission : no signs or symptoms of the disease normal peripheral blood cell count normocellular marrow with less than 5% blasts in the marrow In addition, there are no extramedullary infiltration. Consolid
31、ation therapy Consolidation therapy is treatment to clear residual leukemia when patients are in morphologic remission. Molecular markers of residual disease can often be detected after induction chemotherapy, which indicates the need for further treatment. Maintenance chemotherapy Maintenance chemo
32、therapy is used primarily in ALL and APL , since lowdose antileukemic agents administered over 18-24 months can prevent relapse. Treatment of ALL Regimen induced remission 1. VP (classical) VCR 2mg+ NS 20cc V qw Prednisone 2030mg/d p .o CR50% but relapse easily 2. VDLP VCR 12mgNS20cc V qw(1,8,15,21d
33、) DNR 3040mg V gtt qd 13d, 1517d Pred 40mg60mg p.o 114d L-ASP 10,000u V gtt 1928d CR 8090% VDLCP: T ALL + CTX; Ph+ALL: +TKI Consolidation therapy of ALL The consolidation with alternating cycles of high-dose Ara-C (HDAC) and etoposide with high-dose MTX HSCT CNS-L prophylaxis and treatment(ALL) Prop
34、hylaxis IT MTX 10mg+NS5ml+Dex5mg 2/w,3w Treatment IT MTX 10mg+NS5ml+Dex5mg 2/w, CSF is normaml IT Ara-C 50mg cranial irradiation. Induction therapy of AML(no APL) regimens idarubicin+ cytarabine(IA) daunorubicin + cytarabine (DA) CR50- 80% HA CR60-65% mitoxantrone + cytarabine(MA) Treatment of APL A
35、TRA or Arsenic Trioxide is the first choice retinoic acid syndromeis characterized by fever, weight gain, pleural and pericardial effusions, and respiratory distress. Consolidation therapy of AML(no APL) good-risk AML, ie, t(8;21) ,16(inv16), araC at 3 g/m2 twice a day on days 1, 3, and 5 of each cy
36、cle, repeated monthly for 4 consolidation cycles. Transplantation should be reserved for patients who relapse. Consolidation therapy of AML(no APL) intermediate-risk controversial. Some refer patients in first remission for transplantation others give consolidation chemotherapy with high-dose araC f
37、or 4 courses and reserve transplantation for patients who relapse. Consolidation therapy of AML(no APL) high-risk They are rarely cured with chemotherapy They should be offered allo- transplantation in first remission. Treatment of APL consolidation therapy: usually 2 courses of idarubicin and araC.
38、 Arsenic Trioxide Maintenance therapy with ATRA, 6- MP, and methotrexate Treatment of relapse and refractory AML HSCT Clinical trial Treatment of Aged AL Reduce dose chemotherapy Chronic myelogenous leukaemia Chronic Myelogenous Leukemia (CML) -myeloproliferative disoder -Onset slowly,splenomegaly -
39、peripheral blood show increased granulocytic cells with their immature precursors -Ph and/or bcr/abl positive Chronic phase Clinical features 30 percent of patient are asymptomatic at the time of diagnosis Symptoms are gradual in onset: easy fatigability, malaise, anorexia, abdominal discomfort, wei
40、ght loss, excessive sweating Clinical features Less frequent symptoms: Night sweats, gouty arthitis, Physical signs: Pallor,hepatomegaly splenomegaly, sternal pain Clinical features symptoms of leukostasis tinnitus, stupor,headche Respiratory distress priapism Laboratory features Blood The WBC above
41、 500-100109/L , granulocytes at all stages of development are present B, E is increased Neutrophils alkaline phosphatase (NAP)activity is low or absent (90%) Laboratory features Plt is normal or increased Hb is decreased Nucleated red cells in blood film Laboratory features Bone marrow: The marrow i
42、s hypercellular (granulocytic hyperplasia) Erythroid cells Megakaryocyte cell in normal or Laboratory features Chemistry profile Hyperuricemia Serum vitamin B12-binding proteine and serum vitamin B12 levels are increased Laboratory features Cytogenetic test- presence of the Ph chromosome t（9；22）（）（q
43、34q34；q11q11）；）； Molecular test presence of the BCR- ABL fusion gene Etiology of CML -Philadelphia chromosome, Ph 1 ( 95%) -Non-Philadelphia chromosome ( 5%) p190 p210 chimeric protein p239 Tyrosine kinase activity Pathogenesis Accelerated phase of CML Most patients eventually became resistant to therapy and the disease enters a more agressive phase refractory splenomegaly or refractory leucocytosis Symptoms are gradual in onset again Accelerated phase of CML Criteria of accelerated phase 1. Blas
