xie Yi,Hua Shan Hospital Concept of leukemia Definition It is the results of the tumor proliferation of heamotopoietic stem cells.（造血干细胞）Leukemia is a malignant blood disorder. (not solid tumor) 　　　　　　　　Heamatopoietic stem cell r eproduction HSC lymphoid HSC HSC differentiation early progenitor CFU-GEMM myeloid HSC Heamatopoietic Stem Cell (HSC) is the primary cell of Heamatopoietic system and immune system. Tumor proliferation of HSC 	 Differentiation of HSC is blocked. Leukemia cells are stopped on a differentiation stage of HSC & lack of the normal function . Proliferation is out of control and apoptosis is inhibited. Leukemia cell is cloned and accumulated in a great quantity. infiltration and metastasis malignant blood disorders HSC differentiation is blocked. Normal blood cells are decreased and leukemia cell is increased. The function of Blood and immune system are short of. Fever ，bleeding ，anemia malignant blood disorders Proliferation is out of control ,apoptosis is inhibited and leukemia cell is accumulated in a great quantity. Leukostasis( 白细胞淤滞) Abnormal morphology pictures of blood and bone marrow Liver,spleen,lymph nods, skin , CNS are infiltrated and dysfunctional frequently. According to the acute myeloid leukemia（AML）Differentiation & 	 M0 M1 M2 ……………….. M7 Kind of cell blast crisis of CML ，mast cell leukemia，acute eosinophilic leukemia ，basophilic…………leukemia acute lymphocyte leukemia （ALL）L1，L2，L3 T－ALL、B－ALL chronic leukemia ：CML、P－LL、CLL、HCL、……WHO classification ( 2001) 1, Acute myeloid leukemia(AML) (1), AML with recurrent cytogenetic abnormalities AML with t(8;21)(q22;q22),(AML1/ETO) AML with t(15;17)(q22;q12),(PML/RAR ) AML with inv(16)(p13;q22) or t(16;16)(p13;q22) ,CBF /MYH11 AML with 11q23 ( MLL) abnormalities WHO classification ( 2001) (2), AML with multilineage dysplasia With prior myelodysplastic syndrome Without prior myelodysplastic syndrome (3),AML and myelodysplastic syndrome, therapy related Alkylating agent related Topoisomerase ll inhibitor-related WHO classification ( 2001) (4) AML not otherwise categorized AML minimally differentiation AML without maturation AML with maturation Acute myelomonocytic leukemia Acute monoblastic and monocytic leukemia Acute erythroid leukemia Acute megakaryoblastic leukemia Acute basophilic leukemia Acute panmyelosis with myelofibrosis Myeloid sarcoma (5) Acute leukemia of ambiguous lineage WHO classification ( 2001) 2, chronic myeloid leukemia (1), chronic myeloproliferative disease chronic myelogenous leukemia Chronic neutrophilic leukemia Chronic eosinophilic leukemia/hypereosinophilic syndrome (2), myelodysplastic/myeloproliferative disease Chronic myelomonocytic leukemia Atypical chronic myeloid leukemia Juvenile myelomonocytic leukemia WHO classification ( 2001) 3, B-cell neoplasms (1), Precursor B-cell neoplasm Precursor B lymphoblastic leukemia (2), Mature B-cell neoplasm Chronic lymphocytic leukemia/Small lymphocytic lymphoma (CLL/SLL) B-cell prolymphocytic leukemia Hairy cell leukemia Burkitt lymphoma/leukemia WHO classification ( 2001) 4, T-cell and NK-cell neoplasms (1), Precursor T-cell neoplasm Precursor T lymphoblastic leukemia (2), Mature T-cell and NK-cell neoplasms T-cell prolymphocytic leukemia T-cell large granular lymphocytic leukemia Aggressive NK leukemia/lymphoma Adult T-cell leukemia/lymphoma Epidemiology : incidence 3/105 ，increase with years ? acute>chronic , AML>ALL Special distribution: Sex man：female ＝2：1 Age ALL, adolescent 80％<20y; AML, adult CML, 20~50 years old; CLL ,50~70 years old Area adult T lymphocytic leukemia CML , eastern countries CLL, western countries Epidemiology: mortality 2.51/105 Area city > the countryside China100×109/L ( hyperleukocytosis ) , blasts are present, anemia , PLT↓BM：proliferative ( or hypoplastic )，blasts>30%, Auer‘s rods(+), erythropoiesis ↓，megakaryocytopoiesis ↓Clinic Diagnosis of AL The normal blood cell ↓and luekemia cell ↑are shown by clinical signs, symptoms, laboratory features and special examinations. blast more than 30% in non erythrocytic cells(NEC) of bone marrow smear MICM TYPING DIAGNOSIS MICM Morphology Immunology Cytogenetics Molecular morphology lymphoblast myeloblast monoblast plasma 少，透明中，Auer‘s 多，泡沫样chromatin 粗粒细砂细chromosome 短粗细长粗Accompany 破碎C, 幼淋粒系幼单, 成熟单POX	 －＋/＋＋粗粒－/＋细粒NSE	 －－/+,NaF 不抑制＋, NaF 抑制PAS	 粗粒－结块弥漫一片红钟表面样IMMUNO-PHENOTYPING　　　　　　　　mab	 	M1 	M2	M3	M4	M5	M6	M7 CD13		+	+	+	+	+	-	- CD33		+	+	+	+	+	-	- CD14		-	±	-	+	+	-	- CD41		-	-	-	-	-	-	+ Ret		-	-	-	-	-	+	- Lectoferrin -	+	-	+	-	-	- 			CD19	CD7	HLA-DR	CD2	MPO 	 	T	-	 +	 -	 	 +	 - 	B	+	 -	 +		 -	 - 　　　　Chromosome translocation M1 +8,-5,-7 		 inv(3) M2 t(8;21) t(6;9) M3 t(15;17) M4 inv(16) M5 t(4;11), t(8;16) M6 M7 Fusion gene molecular AML1/ETO PML/RAR CBF /MYH11 MLL abnormalites BCR/ABL MICM TYPING DIAGNOSIS We could use traditional typing diagnosis as what FAB asked. If the situation permit, we could use FCM, chromosome, PCR or FISH in a WHO typing diagnosis way. Differential Diagnosis Myelodysplastic syndrome (MDS) refractory anemia or pancytopenia , BM: dysplasia , blasts<30% Leukemoid reaction mature leukocytes proliferative would play a main role , NAP↑, if progenitor increase, only shortly on time CML: mature progenitors ↑E↑、B↑，NAP=0, ph'(＋)，bcr-abl(+) Stomatitis，Infectious mononucleosis ，ITP, AA ，agranulocytopenia T here is no blasts in bone marrow principle: early ，combine，full ，interval，by stages why early ? The over hyperplasia & infiltration could bring the difficulty on therapy Tumor lysis Leukemia cell enter into the area protected by the barrier between blood and brain Could make anti-infection , support and chemotherapy to be done at same time if it were necessary principle: early ，combine，full ，interval，by stages use Combination regimen of these drugs which have different action, typing and toxicity to increase curative effect and decrease toxicity Different Action of Drugs 嘌呤碱嘧啶碱6 MP 6TG MTX	 氮杂胞苷核苷酸MTX HU 脱氧核苷酸VM26			 Ara-C,CC 蒽环类抗生素DNA 破坏烷化剂，CCNU AMSA RNA DNA L－ASP VCR ,VM26 protein 子细胞DNA 蒽环类：阿霉素，表阿霉素，柔红，阿克拉，米妥蒽醌烷化剂：CTX，氮芥，BU，CB1348，CCNU，BCNU Cell cycle and chemotherapy 			 end cell 							 apoptosis 		 Go (source of relapse ) sensitive insensitive The drug typing CCSA				CCNSA Antimetabolic drugs 	alkylating drugs S, 6MP, 6TG		 mustine ，CTX，BU