内科学：Leukemia

1、Leukemia,Introduction,Definition History 1827 Velpeal with his blood like gruel” 1845 Benett ，Edinburg, England. with color and consistency of their blood; Virchow ，Berlin,Germany introduced leukemia from Greek meaning white blood,Introduction,Definition Leukemia is a group of clonal malignant desea

2、ses developed form hematopoietic stem cell or progenitor cell. that lead to Suppression of normal hematopoiesis Infiltrations in outside of bonemarrow,Introduction,Classification Acute Leukemia Acute lymphocytic Leukemia（ALL） Acute myelogenous Leukemia or Acute non-lymphocytic Leukemia（AML，ANLL） Chr

3、onic Leukemia Chronic Granulocytic Leukemia（CGL，CML） Chronic lymphocytic Leukemia（CLL）Leukemia uncommon in clinic,Introduction,Incidence The total morbidity : 2.67/100 thousands higher than the chance to win a lottery(1/400 thousands ) 男：女=1.8：1,Introduction,Prognosis,100%,0,1 2 3 4 5 YEAR,BMT,CHEMO

4、,Etiology and Pathogenesis Virus ATLV HTLV-I HTLV-II HTLV-III Chemical substance Bemzene poisoning Ionizing radiation,Introduction,swell,National Cancer Institute (NCI)researcher Robert Gallo reports isolation of an AIDS virus he calls HTLV-III,Etiology and Pathogenesis Virus ATLV HTLV-I HTLV-II HTL

5、V-III Chemical substance Benzene poisoning Ionizing radiation,Introduction,Introduction,Pathogenesis,Introduction,1)those that confer a proliferative or and survival KIT FLT3 ， NF-1 2) those that impair hematopoietic differentiation and confer properties of self-renewal RUNX1-ETO,CBFB-SMMHC ,TEL-RON

6、X1 fusions mutation,Introduction,Properties of LSC: self-renewal,quiescent,proliferation,multi-potentiality? , differentiation damaged . Immunophenotype of LSC : AML CD34+CD38-CD71-CD90-CD117+ CD123+,HLA-DR-; CML CD34+CD38-,Acute Leukemia,Acute Leukemia,Definition characterized by a huge(massive) ac

7、cumulation of blastcells .the infiltration of these blastcells result in ： 1 ）suppression of normal hematopoiesis lead to anemia,infection,bleeding 2 ）clinic manifestation related to involvement of organs outside BM,Acute Leukemia,Classification： 1976 Morphologic Classifying by International FAB coo

8、perative group ， 1980 MIC ，Morphology, Immunology, Cytogenetics 2001 WHO,Acute Leukemia,FAB classification ALL： L1: lymphoblast cells are small, usually 12 um in diameter .with scanty cytoplasm and inconspicuous(indistinctive) nucleoli .more common in children (approximately 85% of children cases of

9、 AL).Prognosis is better .,Acute Leukemia,ALL L2: lymphoblasts are larger in size (12um),have more prominent nucleoli and abundant cytoplasm .more common in adult ,worse in prognosis,Acute Leukemia,ALL L3: identical morphologically to Burkitts lymphoma.have manifest deeply blue(basophilia) cytoplasm

10、 and prominent vacuolation,Acute Leukemia,AML,M0 Acute myeloblastic leukemia,minimal differentiated M1 Acute myeloblastic leukemia,without maturation M2 Acute myeloblastic leukemia,with maturation M3 Acute promyelocytic leukemia,hypergranular M3v Acute promyelocytic leukemia,variant,microgranular M4

11、 Acute myelomonocytic leukemia M4e0 Acute myelomonocytic leukemia with eosinophilia M5a Acute monoblastic leukemia,poorly differentiated M5b Acute monoblastic leukemia, differentiated M6 Acute erythroleukemia M7 Acute megakaryoblastic leukemia,Acute Leukemia,M0 minimal differentiated CD33,CD13+,Acut

12、e Leukemia,M1 myeloblast90%,Acute Leukemia,M2 myeloblast 3089%,Acute Leukemia,M3 Acute promyelocytic leukemia,Acute Leukemia,M3 Acute promyelocytic leukemia microgranlular,Acute Leukemia,M4 Blast 30% Monocyte20% CD14+,Acute Leukemia,M5 Monoblast+ Promonocyte 30% CD14+,Acute Leukemia,M6 Acute erythro

13、leukemia immature erythrocyte50% blast 30%,Acute Leukemia,M7 megablast30% CD41+,CD61+, CD42+,Acute Leukemia,干细胞 （M0） M1 M4 M5 M6 M7 myeloblast monoblast erythroblast MK blasts M2 M3 promyelocte PROmonocyte 早幼红,Acute Leukemia,FAB classification is simple and convenient ,but have some shortage : （1）It

14、 cannot avoid misdiagnosis since it rely on the experience in morphology of observer （2）It cannot identify the the further cell line the leukemic cells origined from. （3）It cannot distinguish M0、L2、M7、biphenotypic leukemias, mixed lineage leukemias,Acute Leukemia,WHO 2001 ACUTE MYELOID LEUKAEMIAS Ac

15、ute myeloid leukaemias with recurrent cytogenetic abnormalities A M L with t(8;21)(q22;q22), ( A M L 1 / E TO ) 9 8 9 6 / 3 A M L with inv(16)(p13q22) or t(16;16)(p13;q22), (CBF /MYH11) 9871/3 Acute promyelocytic leukaemia ( A M L with t(15;17)(q22;q12), ( P M L / R A R ) and variants) 9866/3 AML wi

16、th 11q23 (MLL) abnormalitie,Acute Leukemia,Acute myeloid leukaemia with multilineage dysplasia 9895/3 with prior myelodysplastic syndrome without prior myelodysplastic syndrome Acute myeloid leukaemia and myelodysplastic syndrome, therapy related 9920/3 Alkylating agent related Topoisomerase II inhi

17、bitor-related,Acute Leukemia,Acute myeloid leukaemia not otherwise categorised Acute myeloid leukaemia, minimally differentiated 9872/3 Acute myeloid leukaemia without maturation 9873/3 Acute myeloid leukaemia with maturation 9874/3 Acute myelomonocytic leukaemia 9867/3 Acute monoblastic and monocyt

18、ic leukaemia 9891/3 Acute erythroid leukaemia 9840/3 Acute megakaryoblastic leukaemia 9910/3 Acute basophilic leukaemia 9870/3 Acute panmyelosis with myelofibrosis 9931/3 Myeloid sarcoma 9930/3 Acute leukaemia of ambiguous lineage,Acute Leukemia,Clinic Manifestation manifestation related to pancytop

19、enia （1）Infection 1）general feature： 2）infection site ： 3）Infective pathogens ：,associated with granulocytopenia and defect in immune system. 1）general feature：fever T38.5C；the local imflammation is mild； progress rapidly，and easy to spread；increased opportunistic organisms infection. 2）infection si

20、te ：respiratory tract （nasal cavity,oral cavity,throat,lung），digestive tract（esophagus,GI, anal areas），skin etc. oral candidiasis pneumonia ;dysphagia(difficult to swallow ) ;esophageal candidiasis, perirectal abscesses 3）Infective pathogens ：Gram-negative and positive bacteria are major pathogens o

21、f infection including E.coli, Pseuduomonas-aeruginosa, klebsiella pneumoniae，Staphylococcus aureus， pneumonococcus。Fungus（candida,aspergillus,cryptococcus） infections take more than 1020%. Viraus,mycoplasma can also be pathogens of infection.,Acute Leukemia,（2）Anemia early of onset develope progress

22、ively,Acute Leukemia,（3）Bleeding mainly caused by thrombocytopenia ,but also related to dysfunction of blood vessel that associated with infections and anemia.,petechial,ecchymosis,Acute Leukemia,manifestations caused by involvement of organs outside BM 1）Peripheral WBC： 2）Enlargement of liver,splee

23、n,and lymphonode: 3）Infiltration of oral mucous and gum : 4）Infiltration of skin:,sweet,Evection nodule,Acute Leukemia,5）CNS-L common in ALL(50%),only 57% in AML Many are asymptomatic. present with intracranial hypertension颅内高压、stiff-neck颈强直、papilledema视乳头水肿、nervous lesion第VI对cranial nerve lesion. C

24、NS-L can be diagnosed by determine of cerebrospinal fluid cytology. 6）Involvement of other organs: Bone pain is common. eyes, lung, pleura, heart, pericardium, kidney can also be involvement.,Acute Leukemia,Leukostasis The high number (50000/mm3 specially M5)of circulating bastcells increase blood v

25、iscosity and is associated with small vessel leukoblastic emboli ,resulting in leukostasis.,Acute Leukemia,manifestatoins related to metabolic abnormality： hyperuricemia hypercalcinemia 其他： tumor lysis syndrome is characterized by the rapid development of hyperuricemia, hyperkalemia ,hyperphosphatem

26、ia and hypocalcemia etc.,Acute Leukemia,Laboratory Findings Blood Routine Examination 1） WBC count 2）leukemic cells can be found in 90% patients,Acute Leukemia,Bone Marrow Aspiration 1）Cellularity . found in 90% patients . 2）Leukemic cells 30% nonerythroid cells 3） Auer rods (spindle-shaped)can only

27、 be found in AML,Auer rods,Acute Leukemia,Cytochemical Stain,Lymphoblast myeloblast monoblast,peroxydase - + + + nonspecific esterase - + + PAS(periodic aicd-Schiff) ： + - +,Acute Leukemia,peroxydase Stain,Acute Leukemia,Immunophenotypic Markers in AL,CD3 CD7 CD10 CD19 CD34 CD13 CD14 CD33 CD41,61 Gl

28、y A CD2 CD20 CD22 CD15,B-CELL - - + + + - - - - - - T-CELL + + + - - + - - - - - - M0 - - - - + + + M14 - - - - - + + + - - - M6 - - - - - - - = - - + M7 - - - - + - - - + + -,Immunophenotypic classification of ALL,Acute Leukemia,Cytogenetics,类型 染色体 基因,M3 t（15；17） PML-RARa CML t（9；22） ALL t（9；22） AB

29、L-BCR M2 t (8; 21) AML1-ETO M4EO inv/del(16) CBFB-MYH11 L3 t (8 ;14) MYC IgH M5 t/del(11) MLL-ENL,Risk groups in AML according to Cytogenetics,Impact of karyotype on outcome in younger adults with AML. Overall survival is shown for adults with AML (median age 43 years, range 1659) treated in success

30、ive Medical Research Council/National Cancer Research Institute trials (MRC AML10, AML12, AML15).,Grimwade D , and Hills R K Hematology 2009;2009:385-395,Impact of karyotype on outcome in younger adults with AML. Overall survival is shown for adults with AML (median age 43 years, range 1659) treated

31、 in successive Medical Research Council/National Cancer Research Institute trials (MRC AML10, AML12, AML15).,Grimwade D , and Hills R K Hematology 2009;2009:385-395,2009 by American Society of Hematology,Stratification based on cytogenetic and molecular entities,Acute Leukemia,AML with t（15；17）,Acut

32、e Leukemia,CML t（9；22）,Acute Leukemia,Diagnosis and differential diagnosis Diagnosis approach to diagnosis If abnormality be found in blood routine test, specially pancytopenia and immature cells ,the bonemarrow aspiration and biopsy must be done establish the diagnosis blastcells30%(FAB) ,or 20% (W

33、HO,2003) classification would be correctly,Acute Leukemia,Differential Diagnosis In fact ,blastcells30% never can be seen in any other disease except Acute Leukemia. Aplastic Anemia, Infectious monocytosis , Infectious lymphocytosis etc.,Acute Leukemia,Therapy 1865 Lissauer treated CML with Fowler l

34、iquid with As in it. Farber treated ALL in children with MTX (methotrexate),Acute Leukemia,1956 Thomas, a firstman treated leukemia with bonemarrow transplantation,Acute Leukemia,Therapeutic principle,long term survival,BMT,确诊 Induction therapy CR PBSCT,按难治AL处理treat as refractory leukemia,chemothera

35、y,复发relapse,NR,Acute Leukemia,Support care high WBC WBC10,000/3 oral administration of allopurinol WBC50,000/3 Infection no fever T101OF,broad spectrum antibiotics (eg Imipenen) mus be used. If pneumonia has been confirmed or temperature can not decreased in three days and blood bacterial culture is

36、 negative ,amphotericin B would be used empirically .,Acute Leukemia,Bleeding platelet transfusion: no signs of bleeding but PLT10000/3 signs of bleeding , PLT 50000/ 3,Acute Leukemia,Chemotherapy化学治疗： Chemotherapeutic Protocol in ALL化疗方案： (1).VP and VDP,VDLP (2)High dose Ara-C(HDAC) High dose methotrexate （HDMTX）,Acute Leukemia,Chemotherapeutic protocols in AML,young adult APL non-APL ATRA+ anthracycline DA3+7 AS2O3 inv 16 or t(8;21) 中 差 SCT high-dose allo-SCT,Acute Leukemia,M3(APL) induction remission therapy (1)ALL-Trans- retinoic aci