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1、Chronic leukemia,Category of Chronic leukemia,Chronic Myelocytic Leukemia(CML) Chronic Leukemia Chronic Lymphocytic Leukemia(CLL),Chronic Myelocytic leukemia,CML,Chronic myelogenous leukemia (CML) is a pluripotential stem cell disease characterized by anemia, extreme blood granulocytosis and granulo
2、cytic immaturity, basophilia, often thrombocytosis, and splenomegaly. One important landmark in the study of CML was the discovery of the Philadelphia (Ph) chromosome in 1960. Another was the characterization in the 1980s of the BCRABL chimeric gene and associated oncoprotein.,N Engl J Med. 2004 ;35
3、1:657-67, Weissmans lab,Hematopoietic stem cells,Chronic Myelocytic leukemia,Clonal stem cell disorder Overproduction granulocytic cells Marked splenomegaly Very high WBC,Incidence,11.5/100,000 Peak age: 50 years old Male: female 3:2,Incidence,Review of CML,CML pathophysiology t(9;22)(q34;q11) BCR-A
4、BL oncoprotein, p210 increased tyrosine kinase activity(酪氨酸激酶),Ph chromosome,BCR-ABL (激活的酪氨酸激酶),BCR,ABL,Philadephia （Ph）CML,Clinical Features,Symptoms Fatigue Anorexia Weight loss Fever Abdominal pain,Clinical Features,Signs Splenomegaly Hepatomegaly Lymphadenopathy Sternal tenderness Purpura,Lab Fi
5、ndings,Peripheral Blood WBC elevated, 20 x109/L Basophil and Eosinophil increased Anemia: mild Platelet: normal or elevated Immature granulocytes in different stage Blast cell :13%,Chronic Leukemia-Peripheral blood,Lab Findings,Bone Marrow Hyperplasia Immature granulocytes of different stages Blasts
6、 10% NAP slight positive or negative Basophil and Eosinophil elevated,Bone Marrow Chronic Leukemia Normal,Cytogenetics and Molecular Biology,Ph1 chromosome- t(9;22)-95% of CML bcr/abl fusion gene P210 protein(tyrosine kinase) Important role in pathogenesis of CML Target of treatment,The Philadelphia
7、 Chromosome,BCR-ABL,CML BCR/ABL,Clinical manifestations: splenomegaly Peripheral blood Bone marrow examination Ph Chromosome positive BCR/ABL fusion gene,Diagnosis,Reactive CML Leukocytosis infection + + or - splenomegaly - or + + NAP + - Ph1 - + Basophilia N leukocyte more mature immature,Different
8、ial Diagnosis,Stages of CML,Chronic Phase Accelerated Phase Acute Transformation (Blastic Phase),Accelerated phase,Symptoms and signs: Fever,night sweating, weight loss Rapidly enlarged spleen Bone pain Aggravating anemia and bleeding Poor response to treatment,Accelerated phase,Laboratory Findings:
9、 Blast in peipheral or bone marrow 10% Peripheral basophil20% Platelet count decrease or increase Cytogenetic evolution Difficult to control WBC Marrow reticulin or collagen fibrosis,Blastic Phase,Terminal stage of CML Similar to acute leukemia in clinic, including extramedullary infiltration Most c
10、ases transform into AML,Blastic Phase,Laboratory Findings: Peripheral: blast+promyelocyte30% BM: myeloblast+promyelocyte30% BM: blast+procyte20% Cytogenetic clonal evolution Extramedullary blastic chloroma,Treatment Options in CML,Hydroxyurea, Busulfan SCT ( DLI) IFN- ( ara-C) Imatinib New agents se
11、ncond TKI Others,Treatment of CML,Hydroxyurea: Inhibit ribonucleotide reductase Dose: 0.53 g/ day Side effects: nausea, skin rash Busulfan: 46 mg/ day Side effects: sever and prolonged marrow aplasia, pulmonary fibrosis, hypoadrenalism,Treatment of CML,Small dose Ara-C: 1530mg/m2.d Interferon-: 25 m
12、illion /m2 .d x 612 months Antiproliferative agent Early chronic phase,Treatment of CML,Allogeneic transplantation Allo-BMT Allo-PBSCT HLA-matched sibling Age: 50 years Long-term disease-free survival: 50%,Treatment of CML,Imatinib (Gleevec,伊马替尼): target to bcr/abl protrein If blastic phase happens
13、treat as acute leukemia,Treatment of CML,Gleevec (Imatinib, signal transduction inhibitor) Inhibition of binding site for ATP to the Abl kinase Inhibit BCR-ABL tyrosine kinase activity Specificity for Abl, PDGF-R, c-kit tyrosine kinase,Y = Tyrosine P = Phosphate,Structure and Mechanism of Action of
14、Imatinib Mesylate (Gleevec),Class: Phenylaminopyrimidines, 589.7 mw,Imatinib mesylate,Treatment of CML,Gleevec study in newly-diagnosed CML Doses: 400mg/d 3 months: cytogenetic response 76% vs IFN 3% to 24%; complete 36% vs IFN 2% to 5% 6 months: CCR 50%,Treatment of CML,Gleevec side-effects Myelosu
15、ppression (骨髓抑制) Nausea, vomiting, diarrhea Edema Rashes, muscle cramps(痛性痉挛), bone and joint aches Rare seizures(癫痫) or liver dysfunction,Resistance to Imatinib Through Mutations,Imatinib,Bcr-Abl,Mutation Bcr-Abl,非依赖性机制,Amplification/overexpression 扩增/过度表达,Abl kinases mutation激酶结构域突变,Bcr-Abl-Independent 非依赖性,Bcr-Abl-Dependent 依赖性,von Bubnoff et al. Leukemia. 2003;17:829.,Mechanisms of Resistance to Imatinib,伊马替尼 (STI571),达沙替尼 (BMS-354825),300x,结合活化构像多靶点 (SRC),Dasatinib is second generation tyrosine kinase inhibitor,N,N,N,H,N,C,H,3,N,H,N,O,N,C,H,3,
