2011-10-17 xie Yi,Hua Shan Hospital 1
Leukemia (白血病 )
谢毅（ Xie yi）
Dep.Hematology,Huashan Hospital
2011-10-17 xie Yi,Hua Shan Hospital 2
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)
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Heamatopoietic stem cell
reproduction 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,
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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
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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
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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,
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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,……
leu
ke
mi
a
the tradition classification (FAB)of leukemia
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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
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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
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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
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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
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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
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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
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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
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Epidemiology,mortality
?2.51/105
?Area
city > the countryside
China<Singapore<Japan<USA<united Kingdom <Sweden(7.5～ 9/105)
?In order of the mortality of malignant tumors
in1～ 14y,leukemia is most high
in15～ 44y,leukemia is third high(<stomach Ca< liver Ca)
in all person,leukemia is sixth or eighth high
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Etiology
?radiation
1,atom bomb （ 长 崎 ） 1Km 1.5km 2km
× 100 × 22 × 2.6
2,high dose X radiation,32P therapy
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Etiology
?chemicals
?benzene
?Therapy-related leukemia 47/440000
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? virus
ATLV, 1981,Japan(鹿儿岛 )
electric microscope,virus C
The serum antibody titer of ATLV
decrease with the distance from 鹿儿岛
Etiology
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?Genetics
twin(same egg ) 0.2~0.25
sibling 10/105
Down‘s syndrome (21+) 40－ 60/105
Fanconi anemia 4/66
Etiology
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?from other blood disorders
?Myeloproliferative Disease
chronic myeloid leukemia(CML)
polycythemia vera(PV)
primary thrombocythemia(PT)
myelofibrosis(MF)
? myelodysplastic syndrome(MDS)
? paroxysmal nocturnal hemoglobinuria(PNH)
? lymphoma or myeloma
Etiology
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Mechanism
Radiation,chemicals,virus,genetics & other blood disorders
Chromosome translocation
Fusion gene formation
Fusion protein（ enzyme …… ）
Malignant biologic behaviors
Malignant blood disorders
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Acute leukemia
Clinical manifestation
1,fever,bleeding,anemia
2,infiltration
3,Abnormal morphology
pictures of blood and bone
marrow
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? normal WBC↓→ immune↓ ( ～ AIDS) → fever
?The place where skin and mucosa meet,respiratory tube,
mouth,perineum,anus
?Inflammatory reaction is weakly
?G－ B(psuedomonas aeruginosa……),interstitial pneumonia
(peumosystis arinii,CMV,herpes virus),candida
?PLT↓ ? bleeding
? skin,mucosa or cranial cavity
?RBC↓ ? anemia
1,fever,bleeding,anemia
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2,infiltration
?Hepatomegaly,splenomegaly,lymphadenopathy,
sternal tenderness
?Special infiltration area
?Chloromas:skin,orbit (granulocytic sarcoma)
?Painless enlargement of testicle( ALL)
? CNS involvement,paraplegia(ALL,M4,M5)
?gingivitis(M4,M5)
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3,Abnormal morphology pictures
of blood and bone marrow
?Blood, WBC from < 1× 109/L(non leukemoid)
to >100× 109/L ( hyperleukocytosis ),blasts are
present,anemia,PLT↓
?BM,proliferative(or hypoplastic),blasts>30%,
Auer‘s rods(+),erythropoiesis ↓,
megakaryocytopoiesis↓
Normal bone marrow cell
leukemia cells ( show Auer’s rods )
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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
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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 ALL t(9;22)
(B) t(8;14)
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Fusion gene molecular
?AML1/ETO
?PML/RAR?
? CBF?/MYH11
?MLL abnormalites
?BCR/ABL
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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,
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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
There 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
6MP 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
VP16
Cell cycle and chemotherapy
end cell
apoptosis
Go (source of relapse)
sensitive insensitive
G1
S
G2
M
The drug typing
CCSA CCNSA
Antimetabolic drugs alkylating drugs
S,6MP,6TG mustine,CTX,BU
Ara-C,CC,MTX CB1348,ＣＣＮＵ
HU,VP16 anthracycline antibiotics
M,VCR,VDS,VM26 bleomycin A5(平阳霉素 )
G1,L-ASP,prednisone harringtonine(三尖杉 )
G2,VP16
CCSA CCNSA
effect
dosage dosage
the effect is increased by time the effect increased by dosage
The drug ‘s effect
The toxicity of the drugs
烷化剂 抗代谢类 VCR 三尖杉 激素 蒽环类
BM抑制 ＋＋＋ ＋＋＋ － ＋＋ － ＋＋＋
脱发 ＋＋ ＋ ＋＋＋
口腔溃疡 ＋＋＋
胃肠反应 ＋＋＋ ＋ ＋ ＋＋＋
周围 N炎 ＋＋＋
心毒 ＋＋ ＋＋＋
免疫抑制 ＋＋＋ ＋＋＋ ＋＋ ＋＋ ＋＋ ＋＋
诱变畸变 √ √ √ √ √ √
出血性膀胱炎 ＋＋＋
肝毒 ＋ ＋ ＋＋＋
principle,early,combine，
full,interval,by stages
?full
?the drug should work in all period of cell cycle
?the dosage should be full
?The regimen would be used repeatedly
,
Killing the cells in all period of cell cycle repeatedly could make G
0→ cycle &
control the source of relapse（ MRD)
principle,early,combine，
full,interval,by stages
Interval for 3~4 weeks before next therapy
Leukemia cell normal cell
When get disease the greater part of cells hyperplasia is inhibited
is not in G0 period
easily killed by chemotherapy in G0 period or not?
doubling time long short
Recover in interval not easy to recover easy to recover
principle,early,combine，
full,interval,by stages
remission consolidation maintenance
induction
1011～ 1012 106～ 8 104（ MRD）
prevent CNS leukemia
6 cycles 3～ 5years
Reduce MRD step by step
Keep the DFS for long time
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（ 1） remission induction
?Regimen for ALL
VP VCR 1～ 2mg
(classical) NS 20cc V qw
Prednisone 20~30mg/d p.o
? use it till CR
?would be more effective,but relapse easily
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Induction remission Regimen for ALL
?1) VDLP
VCR 1～ 2mg＋ NS20cc V qw(1,8,15,21d)
DNR 30～ 40mg V gtt qd 1～ 3d,15～ 17d
Pred 40mg～ 60mg p.o 1～ 14d
L-ASP 10,000u V gtt 19－ 28d
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2) VP16 0.2 V gtt qd × 3d
Ara-C 0.1～ 0.15 V gtt qd× 7d
3) MTX 2～ 3g V gtt 24h
after 12h,leucovorin 6～ 9mg m q8h
× 2d
? hydrotherapy & alkalize
? leukemia in CNS could be treated
Induction remission Regimen for ALL
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Induction remission Regimen for ANLL
?HOAP(classical)
VCR 1～ 2mg V
harringtonine 1～ 4mg V gtt qd× 5－ 7d
Ara－ C 50－ 100mg V gtt Bid× 5－ 7d
Prednisone 30－ 60mg p.o qd× 5－ 7d
interval 14d
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Induction remission Regimen for ANLL
?HA
harringtonine 2-4mg V gtt× 7
Ara-C 0.1～ 0.2 V gtt× 7
?HD Ara-C
Ara-C 2.0 V gtt q12h× 3
?DA
DNR 30 ~ 40mg V gtt× 3
Ara-C 0.1～ 0.2 V gtt× 7
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Induction remission Regimen for ANLL
?PML(M3),retinoid acid(ATRA)60－ 80mg p.o
?Use chemotherapy in consolidation stage
?When relapse,As2O3 5mg V gtt× 28d
?Hypoplastic leukemia
? Ara-C 12.5mg M qd× 21d
? harringtonine 1mg M qd× 21d
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CR
? there are not anemia fever hemorrhage
and infiltration
?Hb >100g/L WBC <10× 109/L
PLT >100× 109/L
?BM,blasts<5%
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（ 2） The regimen
in consolidation remission stage
?Using a induction remission regimen for
six cyclesz
?Using different induction remission
regimen alternately for six cycles
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（ 3） maintenance remission
regimen
? treatment with extended interval using
the different induction remission regimen
alternately for 3~5Y
?in interval time the patients with ALL will take
CTX,6-MP,6-TG & MTX,P.O
?Not maintain therapy unless leukemia
relapse Protect the capacity of body
immunity,improve quality of life
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supportive care
? conponent transfusion therapy
?RBC,rhEPO
?platelet
?antibiotics（ 倒阶梯）,IVIG,rhG-CSF
?Vein high nutrition
? protect heart,liver & kidney
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others
?Therapeutic Leukapheresis
?To treat the Leukostasis (WBC>105)
?To prevent tumor lysis syndrome
?immunotherapy
?monoantibody to CD33 +drug
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others
?Hemapoietic stem cell transplantation
?Could be curable
?Expensive and high risk
?Acute myelomonocytic leukemia with DIC
?Use the low molecular heparin to improve prognosis
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CNS leukemia
?Incidence of ALL 10－ 40%,ANLL 2－ 4%
?Could be found in youth age,
who suffered from infiltration,
easily onset in remission stage always
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The clinical manifestation &
diagnosis of CNS leukemia
?Clinical examination
? Intracranial hypertension
?The signs of meninges stimulated
? the signs of nerves injure
?CSF examination
? presure>200mmH20,sugar ?,protein（ >40mg/dl),WBC>10/mm3
? could find leukemia cells
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The treatment of CNS leukemia
?High dose MTX injection
?MTX 5－ 10mg sheath enjection Biw－ qw
(dilution with injection water 3ml,
add,dexamethasome 5mg)
?2.4Gy 60Co radiation to head
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The prevention of CNS leukemia
?After CR
?MTX 5－ 10mg sheath rejection qw× 6
?Incidence of CNS leukemia?,<5%
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Chronic Myelogenous Leukemia (CML)
? a Clonal proliferative disorder of pluripotent
stem cell
?Consistently associated with the Ph chromosome and BCR-ABL
fusion gene
?About 15~25% of all cases of leukemia
?25~60 years,slightly more in men than women
9
ABL q34
q11
BCR
22
q34
Ph
q11
t (9;22) (q34;q11)
MECHANISM —Ph CHROMOSONE
BCR
2 ABL BCR-ABL
Fusion gene
8.5Kb mRNA(b3a2 or b2a2)
210Kd protein(P210)
7.5kb mRNA (b1a2) → 190Kd(p190) → Ph(+)ALL
1 2 3
1
MECHANISM—Ph CHROMOSONE
CML
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CML development
?Initial indolent chronic phase(CML-
CP,3~4 years)is followed by
accelerated phase(CML-AP)and blast
phase(CML-BP,as acute leukemia)
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Clinical manifestation
?Weight loss,fatigue,excessive sweating
?sternal tenderness,splenomegaly
?WBC?
?>200× 109/L,Leukostasis(白细胞淤滞 )
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?WBC 10～ 1000× 109/L
Granulocytes at all stages of development are
present in blood（ 幼粒细胞血症）
or PLT >1000× 109/L or anemia
?NAP(neutrophil alkaline phosphatase activity)＝ 0
?BM proliferate ?,Granulopoiesis is dominent,
blast<10%,B & E?
?ph1(+) 90%; pcr,BCR/ABL fusion gene(+)
Clinical manifestation
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CML, diagnosis
?Symptoms are vague and nonspecific
?Splenomagly,90%;sternal tenderness
? WBC 10～ 1000× 109/L
? Granulocytes at all stages of development are present in
blood,NAP＝ 0
?BM proliferate ?,Granulopoiesis is dominent
?blast<10%,B & E? and Erythropoiesis ?
?megakaryocytopeoiesis ? and reticulin fibrosis ?
?ph1(+),bcr-abl (+)
CML by stages
Chronic phase accelerative phas blast phase
Asymptomatic,anemia,hemorrhage,like as acute
splenomegaly splenomegaly leukemia
eosinophilia basophilic cell
basophlia >20%
blast blast blast
< 10% 10~20% >20%
PLT<100× 109/L
> 1000× 109/L
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CML:differentiation diagnosis
1,leukemoid reaction,
?infection,cancer etc
? WBC ?,there isn’t splenomegaly
?NAP ?, absence of Blast,ph1,bcr～ abl
?2,myelofibrosis,
?WBC ? & Splenomegaly
?teardrop poikilocytes,nucleared red cell in blood
? BM:aspiration is often unsuccessful; NAP ?, absence of
Blast,ph1 and bcr～ abl; biopsy,collagen fibrosis
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CML:differentiation diagnosis
3,acute leukemia
? ph1 in 2% AML
? ph1 in 5~25% ALL
4,acute abdomen
?Absence of splenomegaly and the fricative in left
hypochondrial region
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CML, treatment
1,keep WBC 4.0～ 10.0× 109/L
?(1) Hydroxyurea (羟基脲 ) 0.5～ 2.0 tid
Busulfan (马利兰 )1～ 10mg qd
当归芦荟丸 → 青黛 → 靛玉红 → 甲异靛
?(2)Interferon α-2b 500万 u H qd
Ara-C 25mg H qd 14~21天
?(3) Grivec (Greevec,格列卫,STI 571 ) 400~600mg/d
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CML’s THERAPY
2,WBC>200× 109/L,Leukostasis
?therapeutic luekopheresis
3,Blast Phase
?Like as acute leukemia,difficultly
4,Allo-BMT,Allo- PBSCT,CBT)
?curabale
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Chronic lymphocytic leukemia(CLL)
?CLL is neoplastic disease
?The apoptosis of lymphocyte is inhibited
?Accumulation of small mature appearing CD5+ B
lymphocytes in blood, marrow and lymphoid tissues
? immunodeficiency
? incidence 20/ 105 in western country,2/
105 in China
?90%>50y male,female=2:1
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CLL:diagnosis
?25% patients are asymptomatic
?Maybe nontender lymphadenopathy,
splenomegaly and hepatomegaly
?Unexplained absolute lymphcytosis
?WBC 10~200,lymphocytes> 50%,> 5× 109/L
(5000/mm3 ),>4 weeks
?BM lymphocytes >40%
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CLL:diagnosis
?Lymphocyte surface immunologic marker can
determine monoclonality
? immunophenotyping
?B,surface or cytoplasmic immunoglobuline, ? or ? light chains,
CD5+, CD19+, CD20+
? T (fewer), CD2+,CD3+,CD8+,CD5 –
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CLL,Rai staging diagnosis
median survival
0 |L| >15× 109/L >150 month
I 0＋ lymphadenopathy 105
II I＋ spleno-hepatomegaly 71
III I＋ Hb <110g/L 19
IV I+Plt <100× 109/L 19
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CLL:differentiation diagnosis
?With reactive lymphocytosis
?Mononucleosis syndrome,
?Epstein Barr virus
?Cytomegalovirus
?HIV
?With other lymphoproliferative disorders
?Prolymphocytic leukemia,hairy cell leukemia,
lymphoma,Waldenstr?m macroglobulinemia,
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CLL,therapy
?O observe,if WBC?,Lymphapheresis
?I / II Chlorambucil(CB1348),CB1348＋ prednisone
?III / IV
COP / Fludarabine（氟达拉宾）
Cladribin （ 2-CdA,2-氯脱氧腺苷）
Pentostatin（ Deoxycoformycin，脱氧助间霉素）
? mabthera (CD20 mab,美罗华 ),FCR regimen
? radiotherapy
Leukemia (白血病 )
谢毅（ Xie yi）
Dep.Hematology,Huashan Hospital
2011-10-17 xie Yi,Hua Shan Hospital 2
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)
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Heamatopoietic stem cell
reproduction 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,
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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
2011-10-17 xie Yi,Hua Shan Hospital 6
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
2011-10-17 xie Yi,Hua Shan Hospital 7
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,
2011-10-17 xie Yi,Hua Shan Hospital 8
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,……
leu
ke
mi
a
the tradition classification (FAB)of leukemia
2011-10-17 xie Yi,Hua Shan Hospital 9
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
2011-10-17 xie Yi,Hua Shan Hospital 10
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
2011-10-17 xie Yi,Hua Shan Hospital 11
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
2011-10-17 xie Yi,Hua Shan Hospital 12
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
2011-10-17 xie Yi,Hua Shan Hospital 13
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
2011-10-17 xie Yi,Hua Shan Hospital 14
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
2011-10-17 xie Yi,Hua Shan Hospital 15
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
2011-10-17 xie Yi,Hua Shan Hospital 16
Epidemiology,mortality
?2.51/105
?Area
city > the countryside
China<Singapore<Japan<USA<united Kingdom <Sweden(7.5～ 9/105)
?In order of the mortality of malignant tumors
in1～ 14y,leukemia is most high
in15～ 44y,leukemia is third high(<stomach Ca< liver Ca)
in all person,leukemia is sixth or eighth high
2011-10-17 xie Yi,Hua Shan Hospital 17
Etiology
?radiation
1,atom bomb （ 长 崎 ） 1Km 1.5km 2km
× 100 × 22 × 2.6
2,high dose X radiation,32P therapy
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Etiology
?chemicals
?benzene
?Therapy-related leukemia 47/440000
2011-10-17 xie Yi,Hua Shan Hospital 19
? virus
ATLV, 1981,Japan(鹿儿岛 )
electric microscope,virus C
The serum antibody titer of ATLV
decrease with the distance from 鹿儿岛
Etiology
2011-10-17 xie Yi,Hua Shan Hospital 20
?Genetics
twin(same egg ) 0.2~0.25
sibling 10/105
Down‘s syndrome (21+) 40－ 60/105
Fanconi anemia 4/66
Etiology
2011-10-17 xie Yi,Hua Shan Hospital 21
?from other blood disorders
?Myeloproliferative Disease
chronic myeloid leukemia(CML)
polycythemia vera(PV)
primary thrombocythemia(PT)
myelofibrosis(MF)
? myelodysplastic syndrome(MDS)
? paroxysmal nocturnal hemoglobinuria(PNH)
? lymphoma or myeloma
Etiology
2011-10-17 xie Yi,Hua Shan Hospital 22
Mechanism
Radiation,chemicals,virus,genetics & other blood disorders
Chromosome translocation
Fusion gene formation
Fusion protein（ enzyme …… ）
Malignant biologic behaviors
Malignant blood disorders
2011-10-17 xie Yi,Hua Shan Hospital 23
Acute leukemia
Clinical manifestation
1,fever,bleeding,anemia
2,infiltration
3,Abnormal morphology
pictures of blood and bone
marrow
2011-10-17 xie Yi,Hua Shan Hospital 24
? normal WBC↓→ immune↓ ( ～ AIDS) → fever
?The place where skin and mucosa meet,respiratory tube,
mouth,perineum,anus
?Inflammatory reaction is weakly
?G－ B(psuedomonas aeruginosa……),interstitial pneumonia
(peumosystis arinii,CMV,herpes virus),candida
?PLT↓ ? bleeding
? skin,mucosa or cranial cavity
?RBC↓ ? anemia
1,fever,bleeding,anemia
2011-10-17 xie Yi,Hua Shan Hospital 25
2,infiltration
?Hepatomegaly,splenomegaly,lymphadenopathy,
sternal tenderness
?Special infiltration area
?Chloromas:skin,orbit (granulocytic sarcoma)
?Painless enlargement of testicle( ALL)
? CNS involvement,paraplegia(ALL,M4,M5)
?gingivitis(M4,M5)
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3,Abnormal morphology pictures
of blood and bone marrow
?Blood, WBC from < 1× 109/L(non leukemoid)
to >100× 109/L ( hyperleukocytosis ),blasts are
present,anemia,PLT↓
?BM,proliferative(or hypoplastic),blasts>30%,
Auer‘s rods(+),erythropoiesis ↓,
megakaryocytopoiesis↓
Normal bone marrow cell
leukemia cells ( show Auer’s rods )
2011-10-17 xie Yi,Hua Shan Hospital 29
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
2011-10-17 xie Yi,Hua Shan Hospital 30
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 ALL t(9;22)
(B) t(8;14)
2011-10-17 xie Yi,Hua Shan Hospital 34
Fusion gene molecular
?AML1/ETO
?PML/RAR?
? CBF?/MYH11
?MLL abnormalites
?BCR/ABL
2011-10-17 xie Yi,Hua Shan Hospital 35
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,
2011-10-17 xie Yi,Hua Shan Hospital 36
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
There 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
6MP 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
VP16
Cell cycle and chemotherapy
end cell
apoptosis
Go (source of relapse)
sensitive insensitive
G1
S
G2
M
The drug typing
CCSA CCNSA
Antimetabolic drugs alkylating drugs
S,6MP,6TG mustine,CTX,BU
Ara-C,CC,MTX CB1348,ＣＣＮＵ
HU,VP16 anthracycline antibiotics
M,VCR,VDS,VM26 bleomycin A5(平阳霉素 )
G1,L-ASP,prednisone harringtonine(三尖杉 )
G2,VP16
CCSA CCNSA
effect
dosage dosage
the effect is increased by time the effect increased by dosage
The drug ‘s effect
The toxicity of the drugs
烷化剂 抗代谢类 VCR 三尖杉 激素 蒽环类
BM抑制 ＋＋＋ ＋＋＋ － ＋＋ － ＋＋＋
脱发 ＋＋ ＋ ＋＋＋
口腔溃疡 ＋＋＋
胃肠反应 ＋＋＋ ＋ ＋ ＋＋＋
周围 N炎 ＋＋＋
心毒 ＋＋ ＋＋＋
免疫抑制 ＋＋＋ ＋＋＋ ＋＋ ＋＋ ＋＋ ＋＋
诱变畸变 √ √ √ √ √ √
出血性膀胱炎 ＋＋＋
肝毒 ＋ ＋ ＋＋＋
principle,early,combine，
full,interval,by stages
?full
?the drug should work in all period of cell cycle
?the dosage should be full
?The regimen would be used repeatedly
,
Killing the cells in all period of cell cycle repeatedly could make G
0→ cycle &
control the source of relapse（ MRD)
principle,early,combine，
full,interval,by stages
Interval for 3~4 weeks before next therapy
Leukemia cell normal cell
When get disease the greater part of cells hyperplasia is inhibited
is not in G0 period
easily killed by chemotherapy in G0 period or not?
doubling time long short
Recover in interval not easy to recover easy to recover
principle,early,combine，
full,interval,by stages
remission consolidation maintenance
induction
1011～ 1012 106～ 8 104（ MRD）
prevent CNS leukemia
6 cycles 3～ 5years
Reduce MRD step by step
Keep the DFS for long time
2011-10-17 xie Yi,Hua Shan Hospital 47
（ 1） remission induction
?Regimen for ALL
VP VCR 1～ 2mg
(classical) NS 20cc V qw
Prednisone 20~30mg/d p.o
? use it till CR
?would be more effective,but relapse easily
2011-10-17 xie Yi,Hua Shan Hospital 48
Induction remission Regimen for ALL
?1) VDLP
VCR 1～ 2mg＋ NS20cc V qw(1,8,15,21d)
DNR 30～ 40mg V gtt qd 1～ 3d,15～ 17d
Pred 40mg～ 60mg p.o 1～ 14d
L-ASP 10,000u V gtt 19－ 28d
2011-10-17 xie Yi,Hua Shan Hospital 49
2) VP16 0.2 V gtt qd × 3d
Ara-C 0.1～ 0.15 V gtt qd× 7d
3) MTX 2～ 3g V gtt 24h
after 12h,leucovorin 6～ 9mg m q8h
× 2d
? hydrotherapy & alkalize
? leukemia in CNS could be treated
Induction remission Regimen for ALL
2011-10-17 xie Yi,Hua Shan Hospital 50
Induction remission Regimen for ANLL
?HOAP(classical)
VCR 1～ 2mg V
harringtonine 1～ 4mg V gtt qd× 5－ 7d
Ara－ C 50－ 100mg V gtt Bid× 5－ 7d
Prednisone 30－ 60mg p.o qd× 5－ 7d
interval 14d
2011-10-17 xie Yi,Hua Shan Hospital 51
Induction remission Regimen for ANLL
?HA
harringtonine 2-4mg V gtt× 7
Ara-C 0.1～ 0.2 V gtt× 7
?HD Ara-C
Ara-C 2.0 V gtt q12h× 3
?DA
DNR 30 ~ 40mg V gtt× 3
Ara-C 0.1～ 0.2 V gtt× 7
2011-10-17 xie Yi,Hua Shan Hospital 52
Induction remission Regimen for ANLL
?PML(M3),retinoid acid(ATRA)60－ 80mg p.o
?Use chemotherapy in consolidation stage
?When relapse,As2O3 5mg V gtt× 28d
?Hypoplastic leukemia
? Ara-C 12.5mg M qd× 21d
? harringtonine 1mg M qd× 21d
2011-10-17 xie Yi,Hua Shan Hospital 53
CR
? there are not anemia fever hemorrhage
and infiltration
?Hb >100g/L WBC <10× 109/L
PLT >100× 109/L
?BM,blasts<5%
2011-10-17 xie Yi,Hua Shan Hospital 54
（ 2） The regimen
in consolidation remission stage
?Using a induction remission regimen for
six cyclesz
?Using different induction remission
regimen alternately for six cycles
2011-10-17 xie Yi,Hua Shan Hospital 55
（ 3） maintenance remission
regimen
? treatment with extended interval using
the different induction remission regimen
alternately for 3~5Y
?in interval time the patients with ALL will take
CTX,6-MP,6-TG & MTX,P.O
?Not maintain therapy unless leukemia
relapse Protect the capacity of body
immunity,improve quality of life
2011-10-17 xie Yi,Hua Shan Hospital 56
supportive care
? conponent transfusion therapy
?RBC,rhEPO
?platelet
?antibiotics（ 倒阶梯）,IVIG,rhG-CSF
?Vein high nutrition
? protect heart,liver & kidney
2011-10-17 xie Yi,Hua Shan Hospital 57
others
?Therapeutic Leukapheresis
?To treat the Leukostasis (WBC>105)
?To prevent tumor lysis syndrome
?immunotherapy
?monoantibody to CD33 +drug
2011-10-17 xie Yi,Hua Shan Hospital 58
others
?Hemapoietic stem cell transplantation
?Could be curable
?Expensive and high risk
?Acute myelomonocytic leukemia with DIC
?Use the low molecular heparin to improve prognosis
2011-10-17 xie Yi,Hua Shan Hospital 59
CNS leukemia
?Incidence of ALL 10－ 40%,ANLL 2－ 4%
?Could be found in youth age,
who suffered from infiltration,
easily onset in remission stage always
2011-10-17 xie Yi,Hua Shan Hospital 60
The clinical manifestation &
diagnosis of CNS leukemia
?Clinical examination
? Intracranial hypertension
?The signs of meninges stimulated
? the signs of nerves injure
?CSF examination
? presure>200mmH20,sugar ?,protein（ >40mg/dl),WBC>10/mm3
? could find leukemia cells
2011-10-17 xie Yi,Hua Shan Hospital 61
The treatment of CNS leukemia
?High dose MTX injection
?MTX 5－ 10mg sheath enjection Biw－ qw
(dilution with injection water 3ml,
add,dexamethasome 5mg)
?2.4Gy 60Co radiation to head
2011-10-17 xie Yi,Hua Shan Hospital 62
The prevention of CNS leukemia
?After CR
?MTX 5－ 10mg sheath rejection qw× 6
?Incidence of CNS leukemia?,<5%
2011-10-17 xie Yi,Hua Shan Hospital 63
Chronic Myelogenous Leukemia (CML)
? a Clonal proliferative disorder of pluripotent
stem cell
?Consistently associated with the Ph chromosome and BCR-ABL
fusion gene
?About 15~25% of all cases of leukemia
?25~60 years,slightly more in men than women
9
ABL q34
q11
BCR
22
q34
Ph
q11
t (9;22) (q34;q11)
MECHANISM —Ph CHROMOSONE
BCR
2 ABL BCR-ABL
Fusion gene
8.5Kb mRNA(b3a2 or b2a2)
210Kd protein(P210)
7.5kb mRNA (b1a2) → 190Kd(p190) → Ph(+)ALL
1 2 3
1
MECHANISM—Ph CHROMOSONE
CML
2011-10-17 xie Yi,Hua Shan Hospital 66
CML development
?Initial indolent chronic phase(CML-
CP,3~4 years)is followed by
accelerated phase(CML-AP)and blast
phase(CML-BP,as acute leukemia)
2011-10-17 xie Yi,Hua Shan Hospital 67
Clinical manifestation
?Weight loss,fatigue,excessive sweating
?sternal tenderness,splenomegaly
?WBC?
?>200× 109/L,Leukostasis(白细胞淤滞 )
2011-10-17 xie Yi,Hua Shan Hospital 68
?WBC 10～ 1000× 109/L
Granulocytes at all stages of development are
present in blood（ 幼粒细胞血症）
or PLT >1000× 109/L or anemia
?NAP(neutrophil alkaline phosphatase activity)＝ 0
?BM proliferate ?,Granulopoiesis is dominent,
blast<10%,B & E?
?ph1(+) 90%; pcr,BCR/ABL fusion gene(+)
Clinical manifestation
2011-10-17 xie Yi,Hua Shan Hospital 69
CML, diagnosis
?Symptoms are vague and nonspecific
?Splenomagly,90%;sternal tenderness
? WBC 10～ 1000× 109/L
? Granulocytes at all stages of development are present in
blood,NAP＝ 0
?BM proliferate ?,Granulopoiesis is dominent
?blast<10%,B & E? and Erythropoiesis ?
?megakaryocytopeoiesis ? and reticulin fibrosis ?
?ph1(+),bcr-abl (+)
CML by stages
Chronic phase accelerative phas blast phase
Asymptomatic,anemia,hemorrhage,like as acute
splenomegaly splenomegaly leukemia
eosinophilia basophilic cell
basophlia >20%
blast blast blast
< 10% 10~20% >20%
PLT<100× 109/L
> 1000× 109/L
2011-10-17 xie Yi,Hua Shan Hospital 71
CML:differentiation diagnosis
1,leukemoid reaction,
?infection,cancer etc
? WBC ?,there isn’t splenomegaly
?NAP ?, absence of Blast,ph1,bcr～ abl
?2,myelofibrosis,
?WBC ? & Splenomegaly
?teardrop poikilocytes,nucleared red cell in blood
? BM:aspiration is often unsuccessful; NAP ?, absence of
Blast,ph1 and bcr～ abl; biopsy,collagen fibrosis
2011-10-17 xie Yi,Hua Shan Hospital 72
CML:differentiation diagnosis
3,acute leukemia
? ph1 in 2% AML
? ph1 in 5~25% ALL
4,acute abdomen
?Absence of splenomegaly and the fricative in left
hypochondrial region
2011-10-17 xie Yi,Hua Shan Hospital 73
CML, treatment
1,keep WBC 4.0～ 10.0× 109/L
?(1) Hydroxyurea (羟基脲 ) 0.5～ 2.0 tid
Busulfan (马利兰 )1～ 10mg qd
当归芦荟丸 → 青黛 → 靛玉红 → 甲异靛
?(2)Interferon α-2b 500万 u H qd
Ara-C 25mg H qd 14~21天
?(3) Grivec (Greevec,格列卫,STI 571 ) 400~600mg/d
2011-10-17 xie Yi,Hua Shan Hospital 74
CML’s THERAPY
2,WBC>200× 109/L,Leukostasis
?therapeutic luekopheresis
3,Blast Phase
?Like as acute leukemia,difficultly
4,Allo-BMT,Allo- PBSCT,CBT)
?curabale
2011-10-17 xie Yi,Hua Shan Hospital 75
Chronic lymphocytic leukemia(CLL)
?CLL is neoplastic disease
?The apoptosis of lymphocyte is inhibited
?Accumulation of small mature appearing CD5+ B
lymphocytes in blood, marrow and lymphoid tissues
? immunodeficiency
? incidence 20/ 105 in western country,2/
105 in China
?90%>50y male,female=2:1
2011-10-17 xie Yi,Hua Shan Hospital 76
CLL:diagnosis
?25% patients are asymptomatic
?Maybe nontender lymphadenopathy,
splenomegaly and hepatomegaly
?Unexplained absolute lymphcytosis
?WBC 10~200,lymphocytes> 50%,> 5× 109/L
(5000/mm3 ),>4 weeks
?BM lymphocytes >40%
2011-10-17 xie Yi,Hua Shan Hospital 77
CLL:diagnosis
?Lymphocyte surface immunologic marker can
determine monoclonality
? immunophenotyping
?B,surface or cytoplasmic immunoglobuline, ? or ? light chains,
CD5+, CD19+, CD20+
? T (fewer), CD2+,CD3+,CD8+,CD5 –
2011-10-17 xie Yi,Hua Shan Hospital 78
CLL,Rai staging diagnosis
median survival
0 |L| >15× 109/L >150 month
I 0＋ lymphadenopathy 105
II I＋ spleno-hepatomegaly 71
III I＋ Hb <110g/L 19
IV I+Plt <100× 109/L 19
2011-10-17 xie Yi,Hua Shan Hospital 79
CLL:differentiation diagnosis
?With reactive lymphocytosis
?Mononucleosis syndrome,
?Epstein Barr virus
?Cytomegalovirus
?HIV
?With other lymphoproliferative disorders
?Prolymphocytic leukemia,hairy cell leukemia,
lymphoma,Waldenstr?m macroglobulinemia,
2011-10-17 xie Yi,Hua Shan Hospital 80
CLL,therapy
?O observe,if WBC?,Lymphapheresis
?I / II Chlorambucil(CB1348),CB1348＋ prednisone
?III / IV
COP / Fludarabine（氟达拉宾）
Cladribin （ 2-CdA,2-氯脱氧腺苷）
Pentostatin（ Deoxycoformycin，脱氧助间霉素）
? mabthera (CD20 mab,美罗华 ),FCR regimen
? radiotherapy
