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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 leukemia
 Acute 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): –
Morphologic subtypes of
AML
 M2:
 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 myelomonocytic leukemia , 30% of
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: ++/+
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: ++
Morphologic subtypes of
AML
 M7:
 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

 Antibiotictherapy
 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 therapy is an adjunctive treatment for
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
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–inductiontherapy
 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 for Acute
promyelocytic leukemia
 All-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 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 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

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 ALL :
HLA-DR , CD19 , CD20
 CD10
 T-cell ALL : CD7, CD5, CD2
 AML: CD13, CD33
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
 Intrathecalinjection
 methotrexate, hydrocortisone, cytosine
arabinoside
Maintenance therapy
 Methotrexate 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 well-
being, decreased tolerance to exertion,
anorexia, abdominal discomfort, early
satiety , weight loss , excessive sweating
Symptoms
 Pallor, splenomegaly, sternal tenderness
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
 % 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
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
Answer the following question:
 What are the clinical features of AML ?