内科学：白血病

1、Leukemia,目的和要求,掌握白血病的临床表现和实验室检查之特点，诊断依据。 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概念，发病情况，分类，预后。,Concept of leukemia,Definition,Leukemia is a malignant Clonal heamotopoietic stem cells disorder Proliferation is out of control apoptosis is inhibited. Differentiation of HSC is blocked. Extramedullary involvem

2、ent and metastasis,Hematopoiesis,PLURIPOTENT STEM CELL,COMMITTED PROGENITOR CELL,RECOGNIZABLE BONE MARROW PRECURSOR CELL,MATURE BLOOD CELL,myeloblast monoblast,pronormoblast,red cell,neutrophil monocyte,basophil,platelet,eosinophil,pre-T,pre-B,myeloid progenitor cell,lymphoid progenitor cell,lymphob

3、last,lymphoblast,T-cell,B-cell, AML, adult ;CML, 2050 years old; CLL ,5070 years old,Etiology,Most cases arise with no clear cause some accepted risk factors for leukemogenesis,Etiology,Biologic factors: virus: HTLV-1 can result in Acute T lymphomaic leukemia. Immunology defect,Etiology,Physical fac

4、tors radiation exposure: ionic radiation,x-ray 1、atom bomb 2、high dose X radiotherapy、 32P therapy,Etiology,Chemical factors Chemical exposure : benzene petroleum Pesticide Other environmental exposures hair dyes smoking Prior chemotherapy alkylating agents,Etiology,Genetic disorders : familial leuk

5、emia 7/1000 Down syndrome Bloom syndrome Fanconis anemia ataxia-telangiectasia Wiskott-Aldrich syndrome In identical twins,from other blood disorders Myeloproliferative Disease(MPD) chronic myeloid leukemia(CML) polycythemia vera(PV) primary thrombocythemia(PT) myelofibrosis(MF) myelodysplastic synd

6、rome(MDS),Etiology,Principles of leukemogenesis,a multistep process The mutation of gene(ras ,myc) result in the proliferation of the leukemic 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）,AM

7、L（M4EO）,AML（M5）,AML（M6)）,AML（M7）,ALL: FAB Classification,L1 - Small cells; subtype represents 25-30% of adult cases L2 - Large and irregular 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）WH

8、O Classification MICM分型 morphology: 形态学FAB分型 immunology: 免疫学用CD 抗原单克隆抗体分型 cytogenetics: 细胞遗传学染色体分型 molecular biology: 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

9、, tachycardia,Clinical Features,bleeding PLT skin,purpura, mucosal bleeding, epistaxis, menorrhagia life-threatening: brain bleeding associated with DIC(M3),Clinical Features,Infections: neutrophil immune URI, gingivitis, pharyngitis,bronchitis pneumonitis, septicemia pathogens: gram-negative;fungus

10、,Clinical Features,decrease in normal hematopoiesis accumulation of blast cells in other sites: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,

11、 diplopia, blindness,Clinical Features,gum hypertrophy Skin: rashes, palpable, hard, indigo node,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,Blo

12、od ： WBC usually elevated, but can be normal or low,WBC10109/L ( hyperleukocytosis ) blasts are 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 s

13、tudies,Bone marrow aspiration Proliferative(most case);hypoplastic(10%) WHO:blasts20% Auers rods(+) 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 常见AL的细胞化学鉴别 急淋白血病(ALL) 急粒白血病 急性单核细胞白血病 过氧化物酶(POX)（） 分化差的原始细胞 （）（） （）（） 分

14、化好的原始细胞 （）（+） 糖原PAS反应 （）成块 （）或（）， （）或（）呈弥漫 或颗粒状 弥漫性淡红色 性淡红色或颗粒状 非特异性脂酶 (NSE) （）（）（） （）NaF抑制50% NaF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,Immunophenotyping

15、 Cytogenetics,表6-9-2 白血病免疫学积分系统（EGILL，1998）,IMMUNO-PHENOTYPING,mab M1 M2M3M4M5M6M7 CD13+- CD33+- CD14-+- CD41-+ Ret-+- Lectoferrin -+-+- CD19CD7HLA-DRCD3MPO T- + - + - B+ - + - -,Immunophenotyping,According to Immunophenotype of leukemia, AL is divided into four typess: 1 acute undifferentiated leuk

16、emia （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,表6-9-4 ALL常见染色体和分子学异常的检出率,Common Cytogenetic Abnormalities in AML and ALL,Laboratory studies,Chemistry : LDH and, UA DIC: APTT,PT, fibrinogen ,Laboratory studies,Chemistry

17、 CSF of GNS-L : 1, spinal fluid pressure （200mmH2O） 2,WBC （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

18、 syndromes (MDS) Pancytopenia Dysheamtopoiesis(2 lines) in bone marrow Blast 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 c

19、ause Plt is normal No Auer rod in blast, marrow granulocyte 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 hyperleukocyto

20、sis: leukapheresis hydroxyurea hydrated chemotherapy,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 :

21、 (Hyperkalemia ;hyperphosphatemia;hyperuriemia; hypocalcemia 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 M

22、etabolic management,Treatment : Chemotherapy,aims of treatment eliminate abnormal clone allow repopulation of marrow with normal hemopoietic cells,Therapeutic principle of AL,early Combine CCSA+CCNSA full Interval 2-3w Repeat individualization,Chemotherapy,Two phases Remission induction treatment (i

23、nduction chemotherapy) Treatment After Remission 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 ar

24、e no extramedullary infiltration.,Consolidation 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.,

25、Maintenance chemotherapy,Maintenance chemotherapy 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,VP (classical) VCR 2mg+ NS 20cc V qw Prednisone 2030mg/d p .o CR50% but relapse easily

26、 2. VDLP VCR 12mgNS20cc V qw(1,8,15,21d) 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,CN

27、S-L prophylaxis and treatment(ALL),Prophylaxis 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% mitoxantro

28、ne + cytarabine(MA),Treatment of APL,ATRA 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 twic

29、e a day on days 1, 3, and 5 of each cycle, 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 consolidat

30、ion chemotherapy with high-dose araC for 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: usua

31、lly 2 courses of idarubicin and araC. 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 d

32、isoder Onset slowly,splenomegaly -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, a

33、norexia, abdominal discomfort, weight 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,Labor

34、atory features,Blood The WBC above 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

35、features,Bone marrow: The marrow is 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- presenc

36、e of the Ph chromosome t（9；22）（q34；q11）； 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 b

37、ecame 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 Blasts in blood or bone marrow-10-19% Basophilia 20% Plt 1000 109/L Additional chromo

38、somal aberrations Reticulin fibrosis,Blast phase (blast crisis) of CML,Criteria of blast phase Blasts 20% Blasts+promylocte in Bone marrow 50% Blasts+promylocte in peripheral blood 30% extramedullary tumors,Diagnosis,Clinical features :splenomegaly the peripheral blood film shows leucocytes with man

39、y immature forms Marrow examination shows increased cellularity.NAP(-) Cytogenetic shows the presence of the Ph chromosome and bcr/abl,Differential diagnosis,Diseases of splenomegaly The clinical characteristics of the primary disease Without the typical change of CML in Bone marrow ang blood Ph and

40、 bcr/abl（ ）,Differential diagnosis,Leukemoid reaction complicated by severe infection, malignant tumor,hemolysis Blood: Plt ,Hb,E,B is normal, poisoning particles and vacuoles in granulocyte cytoplasm NAP+ Ph and bcr/abl（） WBC back to normal， after the primary disease control,Differential diagnosis,

41、Myelofibrosis Blood:WBC CML( 30109/L), Tears form RBC , immature granulocyte and erylocytes Bone marrow biopsy is collagen fiber hyperplasia significantly NAP+ Ph and bcr/abl（） JAK2（+）,Differential diagnosis,Diseases of splenomegaly Leukemoid reaction Myelofibrosis,鉴别诊断,一、其他原因引起脾大的疾病 1、如血吸虫病、慢性疟疾、肝硬

42、化、脾亢等。各病均有原发病的临床特点。 2、血象及骨髓象无CML的典型改变。 3、Ph染色体及BCR/ABL融合基因阴性。,鉴别诊断,二、类白血病反应 1、常并发于严重感染、恶性肿瘤等基础疾病，并有相应原发病的临床表现。 2、血象：粒细胞胞浆中常有中毒颗粒和空泡，BPC和Hb大多正常，E和B不增多。 3、NAP反应强阳性。 4、Ph染色体和BCR/ABL融合基因阴性。 5、原发病控制后，白细胞恢复正常。,鉴别诊断,三、原发性骨髓纤维化 1、WBC少于CML（30109/L），幼粒幼红细胞血症，泪滴状红细胞易见。 2、骨髓常“干抽”，骨髓活检可见胶原纤维显著增生。 3、NAP呈阳性反应。 4、Ph染色体和BCR/ABL融合基因阴性。 5、部分患者JAK2V617阳性。,Treatment of CP,Eliminate of hyperleukocytosis: leukapheresis hydroxyurea hydrated chemotherapy,Treatment of CP,Moleculor targeting treatment Imatinib mesylate (STI571) is the first choice It acts by specifically inhibiting the