5Lesson 5 - Leukemia
Transcript of 5Lesson 5 - Leukemia
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LeukemiaLeukemia
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General introductionGeneral introduction
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DefinitionClassification
Etiology
Incidence and prevalence
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DefinitionDefinition
A heterogeneous group of neoplasms arising
from the malignant transformation of
hematopoietic cells.Leukemia cells proliferate primarily in the bone
marrow and lymphoid tissues where they
interfere with normal hematopoiesis and immunity
They emigrate into the peripheral blood and
infilitrate other tissues
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EtiologyEtiology
The cause is not known in most patients 1. Virus : a unique human retrovirus
1) Human T-cell leukemiavirus I
(HTLV-I ): adult T-cell leukemia (ATL)
2) Human T-cell leukemiavirus II
(HTLV-II) : chronic T-cell leukemia( CTL)
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EtiologyEtiology 2. Environmental factors 1) Ionizing radiation: causes leukemia in
experimental animal
2) Chemicals: benzene and other aromatic hydrocarbons associated with
AML; treatment with alkylating agents and
other chemotherapeutic drugs lead to anincreased incidence of AML
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EtiologyEtiology
3. Genetic factors
Down syndrome
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ClassificationClassification
AcuteAcute myelogenous leukemia
Acute lymphocytic leukemia ( have a rapid clinical course)
ChronicChronic myelogenous leukemia
Chronic lymphocytic leukemia
(have a more prolonged nature course)
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Incidence and prevalenceIncidence and prevalence
Incidence: 2.76 / 100,000 people / year in China
Sex predilection: somewhat higher in men thanin women
Peak age incidence:AML: at all agesCML: adults
ALL : children and a part of the elderlyCLL : in the elderly
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Acute leukemiaAcute leukemia
Acute myelogenous leukemia
Acute lymphocytic leukemia
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Acute myelogenousAcute myelogenous
leukemialeukemia
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DefinitionDefinition
A clonal malignant disease of hematopoietictissue that is characterized by
(1) the proliferation of abnormal blast cells,principally in the marrow
(2)impaired production of normal blood cells Leukemic cell infiltration in marrow is nearly
invariably accompanied by anemia and
thrombocytopenia.
The absolute neutrophil count may be low ornormal, depending on the total white cell count
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FAB ClassificationFAB Classification
eight subtypes M0
M1 M2 M3 M4
M5 M6 M7
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Morphologic subtypes ofMorphologic subtypes of
AMLAML M0:
Blast cells with no evident features ofdifferentiation and with negative reactions forSudan black B and myeloperoxidase.
On immunophenotypic analysis, all B and Tmarkers were negative but there was expression of
CD13 and CD33. Without immunophenotypingsuch cases cannot be distinguished from L2 acutelymphoblastic leukaemia.
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Morphologic subtypes ofMorphologic subtypes of
AMLAMLM1:AML without maturation , 20% of AMLMorphology :myeloblasts 90% of NECReactivity with special stains: Peroxidase(POX)/sudan black: +/
at least 3% positive
Nonspecific esterase: +/ Periodic acid schiff (PAS):
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Morphologic subtypes ofMorphologic subtypes of
AMLAMLM2:AML with maturation , 30% of AML
Morphology : blasts with promyelocytic
granules, myeloblasts between 30-89% ofNEC,other stages of granulocytes 10%,monocytes 20% auer rods may bepersent
Reactivity with special stains:
POX/sudan black: ++
Nonspecific esterase: +/
PAS: +
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Morphologic subtypes ofMorphologic subtypes of
AMLAMLM3:
Acute promyelocytic leukemia , 5% of AML
Morphology : Hypergranular promyelocytes oftenwith multiple auer rods per cell , abnormal
promyelocytes 30% of NEC,
Reactivity with special stains:
POX/sudan black: +++
Nonspecific esterase: +
PAS: +
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Morphologic subtypes ofMorphologic subtypes of
AMLAMLM4:Acute myelomonocytic leukemia , 30% of
AML Morphology :both granulocytic and monocytic
differentiation in blood and marrow 20% ofpromonocytes and monocytesReactivity with special stains:
POX/sudan black: ++ Nonspecific esterase: +++ PAS: ++/+
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Morphologic subtypes ofMorphologic subtypes of
AMLAML
M5:
Acute monocytic leukemia , 10% of AML
Morphology :Leukemic cells are large and often
bizarre; nuclear cytoplasmic ratio 1:1 or less.Cytoplasm contains fine granules. Auer rods arerare, nucleus is often convoluted and contain oneto four large nucleoli, all monocytes 80%,
monoblasts 80% is the M5a, 80% is theM5b
Reactivity with special stains:
POX/sudan black: +/
Nonspecific esterase: +++
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Morphologic subtypes ofMorphologic subtypes of
AMLAMLM6:
Acute erythroleukemia , 5% of AML
Morphology :erythroblasts are in abundanceinitially in marrow and often in blood,erythrocytes
50% in BM
Reactivity with special stains: POX/sudan black:
Nonspecific esterase:
PAS: ++
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Morphologic subtypes ofMorphologic subtypes of
AMLAMLM7:Acute megakaryocytic leukemia , 5% of AML
Morphology : Large and small megakaryoblastswith high nucleus/cytoplasm ratio, pale agranularcytoplasm . undifferentiated blasts react withantiplatelet antibodies and contain platelet
peroxidase
Reactivity with special stains:
POX/sudan black:
Nonspecific esterase: +/
PAS: +
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Clinical featuresClinical features
Anemia
Bleeding
Infection
Organ and tissue infiltration
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Clinical featuresClinical features
1.Anemia : the first sign including pallor , fatigue, weakness,
palpitations and dyspnea on exertion
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Clinical featuresClinical features
2. Bleeding : related to thrombocytopenia
petechiae and easy bruisability are common;
hemorrhage becomes increasing common whenthe PLT count is less than 20,000/ul.
Spontaneous bleeding involing the central nervous
system,lungs,or other viscera may also occur.
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Clinical featuresClinical features
3.Infection: a frequent complication of AML
common sites: skin, gingival,lungs,and urinary
tract.Septicemia often occurs without an apparent
source.
Fever is present in many patients at the time of
diagnosis.
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Clinical featuresClinical features 4.Organ and tissue infiltration
Lymphadenopathy and hepatosplenomegaly
extramedullary tissues infiltration
Any systems DIC
stomatitis and gum hypertrophy
persistent penis erection (caused by high
WBC)
Bone and joint infiltration
pain
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Laboratory featuresLaboratory features
Blood cell findings
Marrow findings
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Blood cell findingsBlood cell findings
1.Anemia
Mildly shortened red cell life-span
2.Thrombocytopenia, rare the -cytosis
3. The increased total leukocyte count
Myeloblasts almost always presenting
in the blood
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Marrow findingsMarrow findings
Morphology
Cytogenetic features
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MorphologyMorphology
30 (20)to 95 % of marrow cells are
blasts at the time of diagnosis or
relapse
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Myeloblasts are distinguished fromlymphoblasts by any of three pathognomonicfeatures:
1. Reactivity with the specific histochemical
stains
2. Auer rods in the cells
3. Reactivity with the specific monoclonal antibodies against epitopes present on
myeloblast ( MPO antibody,CD13,CD33)
MorphologyMorphology
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Cytogenetic featuresCytogenetic features
Aneuploidy
Pseudodiploidy
Trisomy 8, 21; monosomy 7, 21
t(15,17)q(22,21),the PML-RARa fusion
gene for M3
Loss of an X or Y chromosome
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TherapyTherapy
Temporary
Supportive care
Chemotherapy
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Temporary careTemporary care
Hyerleukocytosis
usually WBC 200 109/L
headache confusion and dyspnea
Emergent leukapheresis
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Supportive careSupportive care
Antibiotic therapy
The use of Growth factors that stimulate
granulopoiesisComponent transfusion therapy
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Antibiotic therapyAntibiotic therapy
Pancytopenia after treatment is a sign of
effective drug action
The patient usually becomes febrile(>38o
C),oftensevere, and cultures of stool, urine,blood, throat,
and , if available, sputum should be obtained
Empirical antibiotic therapy should be started
immediately after cultures are obtained
G th f t th t ti l tGrowth factors that stimulate
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Growth factors that stimulateGrowth factors that stimulate
granulopoiesisgranulopoiesis
Cytokine therapy is an adjunctive treatment forAML
Granulocyte-monocyte colony-stimulating factor
(GM- CSF ) has been used in thechemotherapy of AML
It increases blast cell proliferation in a proportionof patients, and this can render the cells more
sensitive to simultaneous or subsequentlyadministered chemotherapy
This cytokine shortens the duration of neutropenia by about 3 to 5 days in treated patients
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Component transfusion therapyComponent transfusion therapy
Red cell transfusion: be used to keep Hb>80g/Lor higher
Platelet transfusion: be used for hemorrhagicmanifestations related to thromocytopenia
Granulocyte transfusion: just in few hospitals
1. Not be used prophylactically for neutropenia
2. Be used in patients with high fever,rigors,and bacteremia unresponsive to antibiotics,
patients with fungal infections, or patients
in septic shock
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ChemotherapyChemotherapy
Remissioninduction therapy
Remissionmaintenance therapy
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RemissionRemissioninduction therapyinduction therapy
Tenet :
1. two competing populations of cells in
marrow: a normal, polyclonal populationand a leukemic, monoclonal population
2. Profound suppression of the leukemic
cells;Restoration of polyclonalhemopoiesis
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RemissionRemissioninduction therapyinduction therapy
Current standard induction treatment :
1. Daunorubicin plus cytosine
arabinoside ( DA )
2. Homoharringtonine plus cytosine
arabinoside ( HA )
The remission rates: 50%~90%.
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The therapy for AcuteThe therapy for Acute
promyelocytic leukemiapromyelocytic leukemiaAll-trans retinoic acid (ATRA) has been used
to initiate the therapy for acute promyelocytic
leukemia. The effect of ATRA is to induce
maturation of the leukemic cells and to suppressthe malignant clone, restoring polyclonal
hemopoiesis
Arsenical(As2O3)
The intensive chemotherapy should be used
after remissioninduction therapy with all-trans
retinoic acid
Most dangerous and Best Prognosis
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RemissionRemissionmaintenancemaintenance
therapytherapyEarly intensive consolidation therapy
after remission results in a somewhat
longer remission duration and , moresignificantly, a subset of patients who
have a prolonged remission ( > 2 years)
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Features influencing outcome ofFeatures influencing outcome of
therapy in AMLtherapy in AML
The age of the patient at the time of
diagnosis has the greatest impact on the
probability of remission and on theduration of survival
The cytogenetic pattern of leukemic blast
cells influences outcome , but therelationship is complex
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Acute lymphocytic leukemiaAcute lymphocytic leukemia
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DefinitionDefinition
A malignant disorder resulting from a
clonal proliferation and accumulation
of progenitors that exhibit cellmarkers associated with the earliest
stages of lymphoid maturation
The leukemia originates in the marrow, andExhibit features of either B-cell or T-cell
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IncidenceIncidence
ALL has its greatest incidence under 10
years of age and a modest secondary
increase in frequency beginning at about50 years of age
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ClassificationClassification
Morphology Classification : L1, L2, L3
Immunophenotype: T-cell, B-cell
Cytogenetic characteristics
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Features of the FAB classificationFeatures of the FAB classification
L1 L2 L3
Cell features Size small ; large ; large;
uniform nonuniform uniform
Cytoplasm scanty ; variable moderately
vacuoles Nucleus regular shape ; irregular shape ; regular shape
;
inconspicuous prominent prominent
nucleoli nucleoli nucleoli Age distribution(%)
Childern 85 14 1
Adults 31 60 9
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ImmunophenotypeImmunophenotype
Characterization of leukemia blast cells by
immunophenotyping is usually done with a
flow cytometer and specific monoclonalantibodies that identify antigens with a
specific cluster designation(CD)
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ImmunophenotypeImmunophenotype
B-cell ALL : HLA-DR , CD19 , CD20
CD10
T-cell ALL : CD7, CD5, CD2
AML: CD13, CD33
C i h i i
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Cytogenetic characteristicsCytogenetic characteristics
Four major groups:1. Normal karyotype
2. Pseudodiploid
3.Hyperdiploid group I or hyperdiploid
group II
4.Chromosomal translocation
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Clinical featuresClinical features
Anemia : pallor , fatigue, weakness, palpitatioms and dyspnea on exertion
BleedingInfection
Pain
Lymphadenopathy and hepatosplenomegalyInfiltration into other tissues such as skin,
nervous tissue and bone
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Laboratory featuresLaboratory features
Blood cell findings
The total leukocyte count
Anemia
Thrombocytopenia
Borrow
Histochemical analysis
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TherapyTherapy
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Four component to ALL treatmentFour component to ALL treatment
protocolprotocol
1. phase of remission induction
2. Followed by prophylactic treatment of
central nervous system sanctuary area3. A consolidation or intensification phase
after remission
4.Maintenance or continuation therapy for a total treatment period of 2 to 3
years
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RemissionRemissioninduction therapyinduction therapy
Current standard induction treatment :
1. Vincristine , Daunorubicin , L-
Asparaginase plus Prednisone (VDLP )
2. Vincristine , Daunorubicin ,
Cyclophosphamide plus Prednisone
(VDCP)
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Consolidation therapyConsolidation therapy
High-dose methotrexate
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Prophylactic treatment ofProphylactic treatment of
central nervous systemcentral nervous systemIntrathecal injection
methotrexate, hydrocortisone, cytosine
arabinoside
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Maintenance therapyMaintenance therapy
Methotrexate and 6 -mercaptopurine
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Chronic myelogenousChronic myelogenous
leukemia(CML)leukemia(CML)
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DefinitionDefinition
A hemopoietic stem cell disease
Characterized by
anemia , extreme blood granulocytosis and
granulocytic immaturity, basophilia
often thrombocytosis and splenomegaly
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Clinical featuresClinical features
Epidemiology
Account for about 20% of all cases of
leukemia
Occur Slight often in men than in
women
Usually occur in adults
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Clinical featuresClinical features
Signs
Easy fatigability, loss of sense of well-
being, decreased tolerance to exertion,anorexia, abdominal discomfort, early
satiety , weight loss , excessive sweating
SymptomsPallor, splenomegaly, sternal tenderness
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Laboratory findingsLaboratory findings
Blood
Marrow
Cytogenetics
Chemical abnormalities
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bloodblood
The total leukocyte count is elevated andrises progressively in untreated patients
Granulocytes at all stages of developmentare present in the Blood
The platelet count is elevated
Neutrophil alkaline phosphatase activityis low or absent in over 90% of patients
Eosinophil and basophil counts areincreased in the blood
Blood white cell differential countBlood white cell differential count
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at the time of diagnosis in CMLat the time of diagnosis in CML % of total leukocytes (mean values) Myeloblasts 3
Promyelocytes 4
Myelocytes 12
Metamyelocytes 7 Band forms 14
Segmented forms 38
Basophils 3 Eosinophils 2
Nucleated red cells 0.5
Monocytes 8
Lymphocytes 8
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MarrowMarrow
The markedly hypercellular marrow
Hemopoietic tissue takes up 75% to 90% of the
marrow volume Granulopoiesis is dominant
Erythropoiesis is usually decreased
Thrombocytosis
Eosinophilia
basophilia
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CytogeneticsCytogenetics
Ph chromosome, t(9;22)(q34;q11);
Present in all blood cell lineages;
Have the classic Ph chromosome inabout 90% of patients in CML
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Chemical abnormalitiesChemical abnormalities
1. Uric acid is increased;
2. Serum vitamin B12- binding protein
and vitamin B12 is increased
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TherapyTherapy
Chemotherapy
Alpha-interferon
Bone marrow transplantation
Glivec
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ChemotherapyChemotherapy
Decrease the peripheral white blood cell
count and splenomegaly
BusulfanHydroxyurea
Al h i t fAl h i t f
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Alpha-interferonAlpha-interferonMechanism : decrease the number of Ph+ cells
in the bone marrow and enrich the normalclone of cells
Usage:
alone or combined with cytosine arabinoside
given subcutaneously or intravenously
Long-term treatment
Side effects : fever, malaise, anorexia, weight
loss, and other flu-like symptoms
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Glivec(Imatinib)Glivec(Imatinib)
Tyrosine protein kinase inhibitor
Targeted therapy
C
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CourseCourse
1.Chronic phase: present in most patientlasting from 3 to 5 years but may beshorter or longer
2. Accelerated phase:last short time
3. Blast crisis phase:
Represent a genuine acute leukemia
The treatment is difficult
End in death between 3 to 6 months
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Answer the following question:Answer the following question:
What are the clinical features of AML ?