5Lesson 5 - Leukemia

8/14/2019 5Lesson 5 - Leukemia

1/83

LeukemiaLeukemia


2/83

General introductionGeneral introduction


3/83

DefinitionClassification

Etiology

Incidence and prevalence


4/83

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


5/83

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)


6/83

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


7/83

EtiologyEtiology

3. Genetic factors

Down syndrome


8/83

ClassificationClassification

AcuteAcute myelogenous leukemia

Acute lymphocytic leukemia ( have a rapid clinical course)

ChronicChronic myelogenous leukemia

Chronic lymphocytic leukemia

(have a more prolonged nature course)


9/83

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


10/83

Acute leukemiaAcute leukemia

Acute myelogenous leukemia

Acute lymphocytic leukemia


11/83

Acute myelogenousAcute myelogenous

leukemialeukemia


12/83


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


13/83

FAB ClassificationFAB Classification

eight subtypes M0

M1 M2 M3 M4

M5 M6 M7


14/83

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.


15/83


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):


16/83


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: +


17/83


AMLAMLM3:

Acute promyelocytic leukemia , 5% of AML

Morphology : Hypergranular promyelocytes oftenwith multiple auer rods per cell , abnormal

promyelocytes 30% of NEC,


POX/sudan black: +++

Nonspecific esterase: +

PAS: +


18/83


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: ++/+


19/83


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


POX/sudan black: +/

Nonspecific esterase: +++


20/83


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: ++


21/83


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


POX/sudan black:

Nonspecific esterase: +/

PAS: +


22/83

Clinical featuresClinical features

Anemia

Bleeding

Infection

Organ and tissue infiltration


23/83


1.Anemia : the first sign including pallor , fatigue, weakness,

palpitations and dyspnea on exertion


24/83


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.


25/83


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.


26/83

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


27/83

Laboratory featuresLaboratory features

Blood cell findings

Marrow findings


28/83

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


29/83

Marrow findingsMarrow findings

Morphology

Cytogenetic features


30/83

MorphologyMorphology

30 (20)to 95 % of marrow cells are

blasts at the time of diagnosis or

relapse


31/83

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


32/83

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


33/83

TherapyTherapy

Temporary

Supportive care

Chemotherapy


34/83

Temporary careTemporary care

Hyerleukocytosis

usually WBC 200 109/L

headache confusion and dyspnea

Emergent leukapheresis


35/83

Supportive careSupportive care

Antibiotic therapy

The use of Growth factors that stimulate

granulopoiesisComponent transfusion therapy


36/83

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


37/83

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


38/83

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


39/83

ChemotherapyChemotherapy

Remissioninduction therapy

Remissionmaintenance therapy


40/83

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


41/83


Current standard induction treatment :

1. Daunorubicin plus cytosine

arabinoside ( DA )

2. Homoharringtonine plus cytosine

arabinoside ( HA )

The remission rates: 50%~90%.


42/83

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


43/83

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)


44/83

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


45/83

Acute lymphocytic leukemiaAcute lymphocytic leukemia


46/83


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


47/83

IncidenceIncidence

ALL has its greatest incidence under 10

years of age and a modest secondary

increase in frequency beginning at about50 years of age


48/83

ClassificationClassification

Morphology Classification : L1, L2, L3

Immunophenotype: T-cell, B-cell

Cytogenetic characteristics


49/83

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


50/83


51/83


52/83


53/83

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)


54/83

ImmunophenotypeImmunophenotype

B-cell ALL : HLA-DR , CD19 , CD20

CD10

T-cell ALL : CD7, CD5, CD2

AML: CD13, CD33

C i h i i


55/83

Cytogenetic characteristicsCytogenetic characteristics

Four major groups:1. Normal karyotype

2. Pseudodiploid

3.Hyperdiploid group I or hyperdiploid

group II

4.Chromosomal translocation


56/83


Anemia : pallor , fatigue, weakness, palpitatioms and dyspnea on exertion

BleedingInfection

Pain

Lymphadenopathy and hepatosplenomegalyInfiltration into other tissues such as skin,

nervous tissue and bone


57/83

Laboratory featuresLaboratory features

Blood cell findings

The total leukocyte count

Anemia

Thrombocytopenia

Borrow

Histochemical analysis


58/83

TherapyTherapy


59/83

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


60/83


Current standard induction treatment :

1. Vincristine , Daunorubicin , L-

Asparaginase plus Prednisone (VDLP )

2. Vincristine , Daunorubicin ,

Cyclophosphamide plus Prednisone

(VDCP)


61/83

Consolidation therapyConsolidation therapy

High-dose methotrexate


62/83

Prophylactic treatment ofProphylactic treatment of

central nervous systemcentral nervous systemIntrathecal injection

methotrexate, hydrocortisone, cytosine

arabinoside


63/83

Maintenance therapyMaintenance therapy

Methotrexate and 6 -mercaptopurine


64/83

Chronic myelogenousChronic myelogenous

leukemia(CML)leukemia(CML)


65/83


A hemopoietic stem cell disease

Characterized by

anemia , extreme blood granulocytosis and

granulocytic immaturity, basophilia

often thrombocytosis and splenomegaly


66/83


Epidemiology

Account for about 20% of all cases of

leukemia

Occur Slight often in men than in

women

Usually occur in adults


67/83


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


68/83

Laboratory findingsLaboratory findings

Blood

Marrow

Cytogenetics

Chemical abnormalities


69/83

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


70/83

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


71/83


72/83

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


73/83


74/83


75/83

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


76/83

Chemical abnormalitiesChemical abnormalities

1. Uric acid is increased;

2. Serum vitamin B12- binding protein

and vitamin B12 is increased


77/83

TherapyTherapy

Chemotherapy

Alpha-interferon

Bone marrow transplantation

Glivec


78/83

ChemotherapyChemotherapy

Decrease the peripheral white blood cell

count and splenomegaly

BusulfanHydroxyurea

Al h i t fAl h i t f


79/83

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


80/83


81/83

Glivec(Imatinib)Glivec(Imatinib)

Tyrosine protein kinase inhibitor

Targeted therapy

C


82/83

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


83/83

Answer the following question:Answer the following question:

What are the clinical features of AML ?

Documents

5Lesson 5 - Leukemia