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Dr.

SUHAEMI, SpPD, FINASIM

LEUKEMIA
8 Parameter Cell Counter

 WBC: White Blood  MCH: Mean Cell


Cells Hemoglobin
 RBC: Red Blood Cells  MCHC: Mean Cell
 HgB: Hemoglobin Hemoglobin
 Hct: Hematocrit
Concentration
 RDWt: Red Blood Cell
 MCV: Mean Cell
Distribution Width
Volume

Biomedica Diagnostics Inc. / D. Jette / March 2003 2


Normal Values

 Hematocrit = 40 to 54 %
 Hemoglobin = 13.5 to 18 g/dL
 Red Cells = 4.6 to 6.3 x 106 cells / L
 White Cells = 4.5 to 11 x 103 cells / L
 Platelets = 150 to 450 x 103 cells / L

Biomedica Diagnostics Inc. / D. Jette / March 2003 3


PENDAHULUAN

 Leukemia merupakan penyakit keganasan sel


darah yang berasal dari sumsum tulang ditandai
oleh proliferasi sel sel darah putih, dengan
manifestasi adanya sel sel abnormal dalam
darah tepi.
 Leukosit dalam darah berpoliferasi secara tidak
teratur dan tidak terkendali dan fungsinyapun
menjadi tidak normal
 Oleh karena proses tsb fungsi-fungsi lain dari sel
darah normal juga terganggu hingga
menimbulkan gejala leukemia yang dikenal
dalam klinik
What Is Leukemia?

 Cancer of the white blood cells


 Acute or Chronic
 Affects ability to produce normal blood cells
 Bone marrow makes abnormally large
number of immature white blood cells called
blasts
Leukemia

 Hallmark: proliferation of malignant cells in


the bone marrow
 Divided into:
 acute v. chronic
 lymphoblastic v. myeloid (non-lymphoblastic)
 Each type of leukemia has a different
presentation, natural history, prognosis, and
treatment.
Classification of leukaemias

Acute Chronic

Myeloid Acute Myeloid


Leukaemia (AML) Chronic Myeloid Leukaemia (CML)
origin

Lymphoid Acute Lymphoblastic Chronic Lymphocytic Leukaemia


Leukaemia (ALL) (CLL)
origin
Leukemia

 Acute leukemias: rapid onset, rapid death if


treatment is not successful

 Chronic leukemias: natural history measured


in years, even without initial treatment
FAB (1976) Classification

 M0 -- Undifferentiated AML
 M1 -- AML without maturation
 M2 -- AML with maturation
 M3 -- Acute Promyelocytic Leukemia
 M4 -- Acute Meylomonocytic Leukemia
 M5 -- Acute Monocytic Leukemia
 M6 -- Erythroleukemia (DiGuglielmo’s)
 M7 -- Megakaryoblastic Leukemia
M1 and M2
M4 M3

M5
Acute Leukemia
 Presenting features:
 Anemia
 Fatigue, dyspnea, angina pectoris
 Neutropenia - the leukocyte count may be high or
low, but neutropenia is characteristic
 Unexplained fever, serious infections
 Thrombocytopenia
 Bruising, petechiae
 Less common: lymphadenopathy, splenomegaly, skin
infiltration, chloromas (tumors composed of
malignant marrow cells)
Acute Leukemia

 Diagnosis: >20% blasts in the bone marrow


 Categorized by
 H&E staining
 Cytochemical stains (myeloperoxidase, NSE)
 Flow cytometry
 Cytogenetics
Acute Leukemia

No evidence of maturation within


blood or marrow
What is AML?

 The term Myelogenous  Results from acquired


denotes what type of genetic damage to the
cell is being affected: DNA of the bone
Monocytes and marrow
Neutrophils  Immature cells
 Acute refers to rapid produced are known as
progression forming “blast cells”
immature cells
SIMPLIFIED SCHEMA OF
HEMATOPOETIC CANCERS
WBC
Acute and chronic
Myeloid ‘Leukemias’
RBC

Myeloid Platelets

Hematopoetic
Stem Cell
B Cells
Lymphomas
Lymphoid
Hodgkins (30%)
T cells
Non Hodgkins (70%)
Haematopoiesis

PLURIPOTENT MIXED COMMITTED RECOGNIZABLE MATURE


STEM CELL PROGENITOR PROGENITOR BONE MARROW BLOOD
CELL CELL PRECURSOR CELL CELL

BFU-E/CFU-E pronormoblast red cell


myeloblast neutrophil
CFU-GM
monoblast monocyte
CFU-Eos eosinophil
myeloid CFU-Baso basophil
progenitor
cell CFU-Meg megakaryocyte platelet
pluripotent
stem cell pre-T lymphoblast T-cell
pre-B lymphoblast B-cell
lymphoid & plasma cell
progenitor
cell
ALL
naïve

B-lymphocytes

Plasma
Lymphoid cells
progenitor T-lymphocytes

AML
Hematopoietic Myeloid Neutrophils
stem cell progenitor

Eosinophils

Basophils

Monocytes

Platelets

Red cells
Where AML Originates
Genetic Associations

 Research states that AML is caused by genetic


aberrations such as translocations between
chromosomes that alter the function of
transcriptory regulatory factors
 These translocations are a direct result of
chimeric fusion proteins which are caused by the
abnormal cells and its inability to allow further
growth, proliferation, maturation and
differentiation.
 Class 1 and 2: mutations responsible for the
development of the neoplastic process of
myeloproliferation and de-differentiation
Genetic Associations
Continued
 Class 1: mutations that give rise to proliferation
and/or differentiation and are made from
tyrosine kinases (TK); they have no affect on
differentiation
 Class 2: mutations that interfere with terminal
differentiation and apoptosis thereby providing
survival advantage for the mutated cells;
associated with Core Binding Factors (CBFs)
Two-hit model of
leukemogenesis
Loss of function of Gain of function mutations of
transcription factors tyrosine kinases
needed for differentiation
eg. FLT3, c-KIT mutations
eg. AML1-ETO N- and K-RAS mutations
CBFb-SMMHC BCR-ABL
PML-RARa TEL-PDGFbR

differentiation enhanced Acute


block + proliferation Leukemia
Tyrosine Kinases

 Tyrosine kinases are also


known as oncogenes
 Oncogenes are present in
the mutated neutrophils
and moncytes
 AML activates them
causing uncontrollable
proliferation, apoptosis,
decreased adhesion, and
inhibits differentiation
Causes of acute leukemias

 idiopathic (most)
 underlying hematologic disorders
 chemicals, drugs
 ionizing radiation
 viruses (HTLV I)
 hereditary/genetic conditions
AML and its Impact on the
Immune System
 AML affects the innate immune system
 Secondary Immune System kicks in
 The proliferation of immature neutrophils
and moncytes takes place
 Unable to leave the bone marrow to go into
blood stream and tissues to fight off
infections
Main Types

 Acute Lymphocytic Leukemia (ALL)


 Acute Mylogenous Leukemia (AML)
 Chronic Lymphocytic Leukemia (CLL)
 Chronic Mylogenous Leukemia (CML)
Symptoms

 When there are excessive white blood cells --


> Infections
 When there are few red blood cells: Paleness
--> Anemia
 When there are few platelets --> Excessive
bleeding
Tests For Diagnosis

 Finger prick
 Blood sample
 Blood dye
 Bone marrow sample
 Spinal Tap/Lumbar Puncture
Lab Studies

 Flow cytometry:
CD3 (T-lineage ALL)
CD19 (B-lineage ALL)
 Cytogenetics:
t(22;9)
t(4;11)
t(2;8)
t(8;14))
Lab Studies

 Coagulogramm:
elevated prothrombin time
decreased fibrinogen levels
presence of fibrin split products
 Chemistry profile:
elevated lactic dehydrogenase level
elevated uric acid level
liver function tests
BUN/creatinine determinations
Cytogenetics

 Technique
 Needs dividing cells, so marrow usually better
 Complemented and extended by FISH and
rtPCR
 FISH: “Fluorescence In Situ Hybridization”
 Typically in metaphase cells, peripheral blood works
fine- so ideal when marrow unavailable
 rtPCR- for 15;17
 rtPCR for BCR:ABL in ALL
Cytogenetics

 “Good” (that’s a laugh…)


 15;17
 8;21
 M2, “AML with differentiation”, often with CD19
 Core binding factor
 INV16
 M4eo, basophilic eosinophils in marrow
 Watch for CNS disease
 Core binding factor
 These abnormalities typically “trump” bad risk
cytogenetics.
Cytogenetics

 Intermediate
 Normal
 One or two abnormalities
Cytogenetics

 Bad…
 Chromosome 7
 Chromosome 5
 Complex (3 or more)
 11q23
 Any trisomy?
Management:

 A-Supportive measure:
-isolation in positive laminer flux room
-insertion of central line
-family and patient support by permanent social worker
-AlKaline diuresis to prevent tumor lysis syndrome
-oropharynx/GIT decontamination to prevent fungal
infection
-IV antibiotics for infection
-Blood transfusion if anemia and thrombocytopenia.
Therapeutic option

 B-Curative intent:
only allogenic bone marrow transplant .

 C_Classical approch(curative/palliative)
-induction chemotherapy
-consolidation of remission
-intensification
-maintenance chemotherapy
-CNS prophylaxis
Medical Care

 Induction therapy:
4-drug regimen of vincristine, prednisone,
anthracycline, and cyclophosphamide or L-
asparaginase or a 5-drug regimen of vincristine,
prednisone, anthracycline, cyclophosphamide, and L-
asparaginase given over the course of 4-6 weeks.
 Consolidation therapy:
a standard 4- to 5-drug induction usually include
consolidation therapy with Ara-C in combination with
an anthracycline or epipodophyllotoxin.
 Maintenance
 CNS prophylaxis
AML therapy

 Cytarabine
 Infusional or high-dose
 Anthracycline
 Any will do- dauno, ida, mitoxantrone
 Other active agents
 Etoposide
 Cyclophosphamide
 Hydroxyurea
 6MP/TG
 Topotecan
Supportive Care
 Replacement of blood products: packed red blood
cells, platelets, fresh frozen plasma
 Antibiotics: a third-generation cephalosporin (or
equivalent) with an aminoglycoside. Patients with
persistent fever after 3-5 days of antibacterial
antibiotics have amphotericin added to their regimen.
 The use of prophylactic antibiotics in neutropenic
patients who are not febrile is controversial. A
commonly used regimen includes ciprofloxacin (500
mg orally twice daily, fluconazole (Diflucan) (200 mg
orally daily), and acyclovir (200 mg orally 5 times/d).
Supportive Care

 Growth factors
 Allopurinol 300 mg 1-3 times/d
 Central venous catheter
Prognosis

 Good risk includes (1) no adverse cytogenetics, (2) age


younger than 30 years, (3) WBC count of less than
30,000/mL, and (4) complete remission within 4
weeks.
 Intermediate risk does not meet the criteria for either
good risk or poor risk.
 Poor risk includes (1) adverse cytogenetics [(t9;22),
(4;11)], (2) age older than 60 years, (3) precursor B-cell
WBCs with WBC count greater than 100,000/mL, or (4)
failure to achieve complete remission within 4 weeks.
Prognosis

Genetic abnormalities:
t(9;22) - poor outlook
t(4;11) - younger age, female predominance,
high white cell counts, and L1 morphology
t(8;14) - older age, male predominance, frequent
CNS involvement, and L3 morphology
Both are associated with a poor prognosis.
Prognosis in AML

parameters Favorable unfavorable

Cytogentics T(15;17). Deletion of chromosome5or7.


T(8;21). 11q23
Inv(16). T(6;9)
Abn(3q)complex
rearrangments
BM response to <5% blasts after first course >20% blasts after first course.
remission induction

age <60yrs >60yrs


Differential diagnosis of Acute
leukemias:

 Lymphoma.
 Myelodysplastic syndrome.
 Multiple myeloma.
 Aplastic anemia
 Sever megaloblastic anemia due to B12
defeciency.
 Severe lymphocytosis due to infections.
Myeloid maturation

myeloblast promyelocyte myelocyte metamyelocyte band neutrophil

MATURATION

Adapted and modified from U Va website


Erythrocytes
 Normal range 4.2-
5.5 million per
mm3 in adults.
 Biconcave shape.
 Diameter 7
microns.
 Cells for transport
of O2 and CO2.
 Life span 120
days.
Leukocytes
 Normal range 4 -
11 thousand per
mm3 in adults.
 Five types.
 Size 8-20 microns.
 Involved in
fighting infection,
combatting
allergic reactions,
and immune
responses.
Thrombocytes

 Smallest cells in
the blood.
 Normal range
130,000-400,000.
 Active role in
coagulation and
hemostasis.
Pictures Of Blood
Platelet Platelet
White Cell Red Cell Red Cell Blasts
White Cell

Normal human blood Blood with leukemia


Sources from beyond2000.com
Sources from Arginine.umdnj.edu
Acute Myelogenous Leukemia:
Auer Rod
Blasts

Acute Myelogenous Leukemia with differentiation


Petechiae
Infiltration of
tissues/organs
 enlargement of liver, spleen, lymph nodes
 gum hypertrophy
 bone pain
 other organs: CNS, skin, testis, any organ
Gum hypertrophy
AML – gingival hypertrophy
Gingival Infiltration in
Monocytic (AML M4 eos) Variant of
AML

 Mani, A, Lee, DA. Leukemic Gingival Infiltration. N Engl J Med 2008; 358(3): 274. Copyright ©2008 Massachusetts Medical Society
Chloromas

C
NEJM 1998
Effects On the Body

 Attacks the immune system


 Infections
 Anemia
 Weakness
 No more regular white blood cells, red blood cells,
and platelets
 Blasts clog blood stream and bone marrow
Causes

 High level radiation/toxin exposure


 Viruses
 Genes
 Chemicals
 Mostly unknown
 Can’t be caught
Treatment

 Chemotherapy
 Immunotherapy
 Radiation
 Bone marrow transplant
Research

 New drugs
 Cord blood and planceta
Myeloblasts with auer rods
Lymphoblast
AML
Auer rods in AML
LEUKEMIA LIMFOBLASTIK AKUT

 LLA merupakan leukemia yg paling sering


dijumpai pada anak anak.
 Pada anak kecil ditandai dgn mendadak
panas,pucat dan memar di kulit.
 Sering dijumpai nyeri di tulang beberapa bulan
sebelum timbul ekimosis,pucat dan panas
badan.
 Perasaan lemah, BB tidak bertambah/menurun,
nafsu makan menurun, kadang kadang
epistaksis atau perdarahan gusi dapat
merupakan keluhan tambahan.
PEMERIKSAAN FISIK

 Anak terlihat pucat, tampak sakit berat,


takikardi dan bisa dijumpai perdarahan
fundus oculi.
 Limfadenopati di leher,aksila dan inguinal,
bisa bersifat simetris.
 Hepatosplenomegali.
 Stadium awal CNS tidak terlibat
 Stadium lanjut terlihat gejala rangsangan
meningens dan gejala serebral dgn timbulnya
refleks patologis
TERAPI

 Kemoterapi
 Radiasi CNS
ALL
ALL-L1
ALL-L2
LEUKEMIA LIMFOSITIK KRONIK

 LLK adalah jenis leukemia yg paling sering


pada orang tua, biasanya asimtomatik.
 Biasanya ditemukan pada saat pemeriksaan
darah rutin atau pada seseorang dgn
hepatosplenomegali atau limfadenopati yg
asimptomatik.
 Keadaan asimptomatik dapat berlangsung
bertahun tahun sampai timbul keluhan
leukemianya
Chronic Lymphocytic leukemia

 Commonest leukemia in the western world


 Clonal proliferation of the B-Lymphocytes
 Disease of the elderly
 Younger patients now seen
 M:F ratio, 2:1
 CLL is highly variable disorder
 75% cases, diagnosis by chance on a routine
blood test
Chronic Lymphocytic Leukemia

 Age: the elderly


 Prognosis: may live for many years even
without treatment
 Treatment: Watchful waiting, purine
nucleoside analogues (fludarabine), alkylators
Lymphocytosis

Chronic Lymphocytic Leukemia


Chronic Lymphocytic Leukemia

 Clonal proliferation of lymphocytes


 -95 % with B-cell phenotype
 Usually detected as an asymptomatic
lymphocytosis
CLL
PB and BM
Chronic Lymphocytic Leukemia

 Hypogammaglobulinemia is common
 Infection is the most common cause of death
 Complications can include AIHA & ITP
 May transform into an aggressive lymphoma

Two staging systems exist: Rai & Binet


Early stage disease has a survival equivalent to age-
and sex-matched controls
Chronic Lymphocytic Leukemia

 Most patients do not require specific treatment


 Indications for treatment
 anemia
 thrombocytopenia
 unsightly adenopathy
 other complications

When treatment is needed, alkylators or


purine nucleoside analogues are used
Aetiology

 Cause unknown

 Not associated with radiation or exposure to


occupational hazards

 Among the leukemias, CLL has the strongest


tendency for familial incidence
Chronic Myelogenous Leukemia

 CML adalah leukemia yang sering mengenai


orang dewasa, kadang kadang pada anak dan
usila.
 Gejala yg diketemukan adalah penurunan
berat badan, nafsumakan berkurang,
perasaan cepat letih, cepat kenyang ok
splenomegali
Chronic Myelogenous Leukemia

 Age: adults
 Prognosis: 3-4 years without BMT, cures
possible with BMT
 Treatment:
 Imatinib (Gleevec)
 Bone marrow transplant
 Hydroxyurea +/- interferon;
Chronic Myelogenous Leukemia

 Leukocytosis with all degrees of myeloid


differentiation in blood and marrow
 Often associated with eosinophilia,
basophilia, thrombocytosis
 Splenomegaly is characteristic
Chronic Myelogenous Leukemia:
Philadelphia Chromosome
 9;22 translocation yields a chimeric gene
termed bcr-abl
 bcr derived from chromosome 22
 abl derived from c-abl oncogene on chrom. 9
 Encodes a 210,000 MW protein - a tyrosine
protein kinase
 Ability to detect transcript by PCR may
enable us to detect molecular remissions
Chronic Myelogenous Leukemia
 Disease terminates in “blast crisis” in 3-4 years; this
responds to treatment poorly, and is rapidly fatal
 Blast crisis may have the phenotype of non-myeloid cells
 Leukocyte count > 200 x 109/L may be associated
with leukostasis
 Allogeneic BMT has been the treatment of choice if
the patient is a candidate
 Imatinib is a new option
Chronic Myelogenous Leukemia:
Results of BMT
 Five year survival > 60% with allogeneic BMT
 < 25% of patients have an HLA-matched
sibling
 Matched unrelated donors (MUD) may be
used
Chronic Myelogenous Leukemia
Other approaches
 Imatinib (Gleevec): Abl tyrosine kinase inhibitor:
dramatic responses
 A classic example of targeted therapy
 Probably not a cure, but a remarkable advance
 87% major genetic response in chronic phase
 55% response in blast crisis
 Alpha-interferon
 34.7 % major genetic response
 Hydroxyurea or alkylators can control leukocytosis
Band

PMN
Eosinophil

Early Myeloid
Cells

Basophil

Chronic Myelogenous Leukemia


BCR-ABL translocation

Chronic Myelogenous Leukemia


FISH showing the BCR (green), ABL (orange), and BCR-ABL fusion signals (arrow):
A=positive (contains a residual ABL signal), B=normal
Jemshidi trephine &
Salah aspiration needle
 Chemotherapy - Uses drugs to kill leukemia cells.

 Radiation therapy - uses high-energy rays to kill


leukemia cells.
 Stem cell transplant - treated with high doses of drugs,
radiation, or both which destroy both leukemia cells and normal
blood cells in the bone marrow. Later, the patient receives
healthy stem cells and new blood cells develop from the
transplanted stem cells. (Ex. Bone Marrow Transplant)