Leukemia

General introduction

Definition Classification Etiology Incidence

and prevalence

Definition

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

Etiology
 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)

Etiology
 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 an increased incidence of AML

Etiology
 3. 

Genetic factors Down syndrome

Classification
Acute
 Acute

myelogenous leukemia  Acute lymphocytic leukemia  ( have a rapid clinical course)

Chronic
 Chronic

myelogenous leukemia  Chronic lymphocytic leukemia  (have a more prolonged nature course)

Incidence and prevalence
Incidence: 2.76 / 100,000 people / year in China Sex predilection: somewhat higher in men than in women Peak age incidence: AML: at all ages CML: adults ALL : children and a part of the elderly CLL : in the elderly

Acute
 Acute

leukemia

myelogenous leukemia  Acute lymphocytic leukemia

Acute myelogenous leukemia

Definition
A

clonal malignant disease of hematopoietic tissue 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 or normal, depending on the total white cell count

FAB Classification
 eight
       

subtypes

M0 M1 M2 M3 M4 M5 M6 M7

Morphologic subtypes of AML

M0:

 Blast

cells with no evident features of differentiation and with negative reactions for Sudan black B and myeloperoxidase.  On immunophenotypic analysis, all B and T markers were negative but there was expression of CD13 and CD33. Without immunophenotyping such cases cannot be distinguished from L2 acute lymphoblastic leukaemia.

Morphologic subtypes of AML
 M1:  AML

without maturation , 20% of AML  Morphology :myeloblasts > 90% of NEC  Reactivity with special stains:  Peroxidase(POX)/sudan black: +/– at least > 3% positive  Nonspecific esterase: +/–  Periodic acid schiff (PAS): –

 M2:

Morphologic subtypes of AML

 AML

with maturation , 30% of AML Morphology : blasts with promyelocytic granules, myeloblasts between 30-89% of NEC,other stages of granulocytes > 10%, monocytes < 20% auer rods may be persent  Reactivity with special stains: POX/sudan black: ++  Nonspecific esterase: +/–  PAS: +

Morphologic subtypes of AML
 M3:  Acute

promyelocytic leukemia , 5% of AML Morphology : Hypergranular promyelocytes often with multiple auer rods per cell , abnormal promyelocytes > 30% of NEC,  Reactivity with special stains: POX/sudan black: +++  Nonspecific esterase: +  PAS: +

Morphologic subtypes of AML
 M4:  Acute

AML  Morphology :both granulocytic and monocytic differentiation in blood and marrow ,> 20% of promonocytes and monocytes  Reactivity with special stains:  POX/sudan black: ++  Nonspecific esterase: +++  PAS: ++/+

myelomonocytic leukemia , 30% of

Morphologic subtypes of AML
 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 are rare, nucleus is often convoluted and contain one to four large nucleoli, all monocytes > 80%, monoblasts > 80% is the M5a, < 80% is the M5b  Reactivity with special stains:  POX/sudan black: +/–  Nonspecific esterase: +++

Morphologic subtypes of AML
 M6:  Acute

erythroleukemia , 5% of AML  Morphology :erythroblasts are in abundance initially in marrow and often in blood,erythrocytes > 50% in BM  Reactivity with special stains:  POX/sudan black: –  Nonspecific esterase: –  PAS: ++

 M7:

Morphologic subtypes of AML

 Acute

megakaryocytic leukemia , 5% of AML  Morphology : Large and small megakaryoblasts with high nucleus/cytoplasm ratio, pale agranular cytoplasm . undifferentiated blasts react with antiplatelet antibodies and contain platelet peroxidase  Reactivity with special stains:  POX/sudan black: –  Nonspecific esterase: +/ –  PAS: +

Clinical features
 Anemia  Bleeding  Infection  Organ

and tissue infiltration

Clinical features
1.Anemia

: the first sign including pallor , fatigue, weakness, palpitations and dyspnea on exertion

Clinical features
 2.

Bleeding : related to thrombocytopenia  petechiae and easy bruisability are common;  hemorrhage becomes increasing common when the PLT count is less than 20,000/ul.  Spontaneous bleeding involing the central nervous system,lungs,or other viscera may also occur.

Clinical 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.

Clinical 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

Laboratory features
 Blood

cell findings  Marrow findings

Blood 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

Marrow findings
Morphology  Cytogenetic features

Morphology
 30

(20)to 95 % of marrow cells are blasts at the time of diagnosis or relapse

Morphology
 Myeloblasts

are distinguished from lymphoblasts by any of three pathognomonic features:  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)

Cytogenetic 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

Therapy
 Temporary  Supportive

care  Chemotherapy

Temporary care
 Hyerleukocytosis 

usually WBC > 200 ×109/L headache confusion and dyspnea Emergent leukapheresis

Supportive care
 Antibiotic

therapy  The use of Growth factors that stimulate granulopoiesis  Component transfusion therapy

Antibiotic therapy
 Pancytopenia

after treatment is a sign of effective drug action  The patient usually becomes febrile(>38oC),often severe, 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

Growth factors that stimulate granulopoiesis
 Cytokine

AML  Granulocyte-monocyte colony-stimulating factor (GM- CSF ) has been used in the chemotherapy of AML  It increases blast cell proliferation in a proportion of patients, and this can render the cells more sensitive to simultaneous or subsequently administered chemotherapy  This cytokine shortens the duration of neutropenia by about 3 to 5 days in treated patients

therapy is an adjunctive treatment for

Component transfusion therapy
 Red

cell transfusion: be used to keep Hb>80g/L or higher  Platelet transfusion: be used for hemorrhagic manifestations 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

Chemotherapy
 Remission–induction

therapy  Remission–maintenance therapy

Remission–induction therapy
 Tenet

:  1. two competing populations of cells in marrow: a normal, polyclonal population and a leukemic, monoclonal population  2. Profound suppression of the leukemic cells;Restoration of polyclonal hemopoiesis

Remission–induction therapy
 Current

standard induction treatment :  1. Daunorubicin plus cytosine  arabinoside ( DA )  2. Homoharringtonine plus cytosine  arabinoside ( HA )  The remission rates: 50%~90%.

The therapy promyelocytic
 All-trans

for Acute leukemia

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 suppress the malignant clone, restoring polyclonal hemopoiesis  Arsenical(As2O3)
 The

intensive chemotherapy should be used after remission–induction therapy with all-trans retinoic acid  Most dangerous and Best Prognosis

Remission–maintenance therapy
 Early

intensive consolidation therapy after remission results in a somewhat longer remission duration and , more significantly, a subset of patients who have a prolonged remission ( > 2 years)

Features influencing outcome of therapy in AML
 The

age of the patient at the time of diagnosis has the greatest impact on the probability of remission and on the duration of survival  The cytogenetic pattern of leukemic blast cells influences outcome , but the relationship is complex

Acute lymphocytic

leukemia

Definition
A

malignant disorder resulting from a clonal proliferation and accumulation of progenitors that exhibit cell markers associated with the earliest stages of lymphoid maturation  The leukemia originates in the marrow, and  Exhibit features of either B-cell or T-cell

Incidence
 ALL

has its greatest incidence under 10 years of age and a modest secondary increase in frequency beginning at about 50 years of age

Classification
 Morphology

Classification : L1, L2, L3  Immunophenotype: T-cell, B-cell  Cytogenetic characteristics

Features of the FAB classification

           

L1 Cell features Size small ; uniform Cytoplasm scanty ; Nucleus ; regular shape ;

L2 large ; nonuniform variable irregular shape ; prominent nucleoli 14 60

L3 large; uniform moderately vacuoles regular shape prominent nucleoli 1 9

inconspicuous nucleoli Age distribution(%) Childern 85 Adults 31

Immunophenotype
 Characterization

of leukemia blast cells by immunophenotyping is usually done with a flow cytometer and specific monoclonal antibodies that identify antigens with a specific cluster designation(CD)

Immunophenotype
 B-cell

HLA-DR , CD19 , CD20  CD10  T-cell ALL : CD7, CD5, CD2  AML: CD13, CD33

ALL :

Cytogenetic characteristics
 Four

major groups:  1. Normal karyotype  2. Pseudodiploid  3.Hyperdiploid group I or hyperdiploid  group II  4.Chromosomal translocation

Clinical features
 Anemia

: pallor , fatigue, weakness, palpitatioms and dyspnea on exertion  Bleeding  Infection  Pain  Lymphadenopathy and hepatosplenomegaly  Infiltration into other tissues such as skin, nervous tissue and bone

Laboratory features
 Blood

cell findings  The total leukocyte count  Anemia  Thrombocytopenia  Borrow  Histochemical analysis

Therapy

Four component to ALL treatment protocol
 1.

phase of remission induction  2. Followed by prophylactic treatment of  central nervous system sanctuary area  3. A consolidation or intensification phase  after remission  4.Maintenance or continuation therapy for  a total treatment period of 2 to 3 years

Remission–induction therapy
 Current

standard induction treatment :  1. Vincristine , Daunorubicin , L Asparaginase plus Prednisone (VDLP )
 2.

Vincristine , Daunorubicin ,  Cyclophosphamide plus Prednisone  (VDCP)

Consolidation therapy
 High-dose

methotrexate

Prophylactic treatment of central nervous system
 Intrathecal

injection  methotrexate, hydrocortisone, cytosine arabinoside

Maintenance
 Methotrexate

therapy

and 6 -mercaptopurine

Chronic myelogenous leukemia(CML)

Definition
A

hemopoietic stem cell disease  Characterized by  anemia , extreme blood granulocytosis and granulocytic immaturity, basophilia  often thrombocytosis and splenomegaly

Clinical features
Epidemiology

Account for about 20% of all cases of leukemia Occur Slight often in men than in women  Usually occur in adults

Clinical features
Signs
 Easy

fatigability, loss of sense of wellbeing, decreased tolerance to exertion, anorexia, abdominal discomfort, early satiety , weight loss , excessive sweating splenomegaly, sternal tenderness

Symptoms
 Pallor,

Laboratory findings
 Blood  Marrow  Cytogenetics  Chemical

abnormalities

blood
 The

total leukocyte count is elevated and rises progressively in untreated patients  Granulocytes at all stages of development are present in the Blood  The platelet count is elevated  Neutrophil alkaline phosphatase activity is low or absent in over 90% of patients  Eosinophil and basophil counts are increased in the blood

Blood white cell differential count at the time of diagnosis in CML

           

Myeloblasts Promyelocytes Myelocytes Metamyelocytes Band forms Segmented forms Basophils Eosinophils Nucleated red cells Monocytes Lymphocytes

% of total leukocytes (mean values) 3 4 12 7 14 38 3 2 0.5 8 8

Marrow
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

Cytogenetics
 Ph

chromosome, t(9;22)(q34;q11);  Present in all blood cell lineages;  Have the classic Ph chromosome in about 90% of patients in CML

Chemical abnormalities
 1.

Uric acid is increased;  2. Serum vitamin B12- binding protein  and vitamin B12 is increased

Therapy
 Chemotherapy  Alpha-interferon  Bone

marrow transplantation  Glivec

Chemotherapy
 Decrease

the peripheral white blood cell count and splenomegaly  Busulfan  Hydroxyurea

Alpha-interferon
 Mechanism

: decrease the number of Ph+ cells in the bone marrow and enrich the normal clone 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

Bone marrow transplantation
 The

only potentially curative means of treating CML

Glivec(Imatinib)
 Tyrosine

protein kinase inhibitor  Targeted therapy

Course
 1.Chronic

phase: present in most patient lasting from 3 to 5 years but may be shorter 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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are the clinical features of AML ?

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