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Leukemia

dr Putra Hendra SpPD


UNIBA
Proses hemopoiesis
Proses hemopoiesis

AML

ALL
ALL
nave

B-lymphocytes

Plasma
Lymphoid cells
progenitor T-lymphocytes

AML
Hematopoietic Myeloid Neutrophils
stem cell progenitor

Eosinophils

Basophils

Monocytes

Platelets

Red cells
What Is Leukemia?
Cancer of the white blood cells
Acute or Chronic
Bone marrow makes abnormally large
number of immature white blood cells
called blasts
produksi normal blood cells
Demographics of Leukemia
Patients (2001 Data)
CLL=Chronic
Lymphocytic
ALL=Acute ALL
others
Lymphocytic 11%
17%
CML=Chronic
Mylogenous
AML=Acute
Mylogenous CML CLL
15% 26%

AML
31%

Sources from Leukemia, Lyphoma,


Total Reported Cases = 31,500
Myeloma Facts 2001
Hematologic Malignancies
Lymphoid Cell Line (B or T cells)
ALL
CLL
Lymphoma
Myeloma
Myeloid Cell Line (granulocytes, monocytes,
erythrocytes, megakaryocytes)
AML
CML
Polycythemia Vera
Essential Thrombocythemia
Myelofibrosis with metaplasia
Atypical chronic myeloid disorders
Risk Factors
Age
Older adults are more likely to develop AML
Smoking
20% of AML cases are linked to smoking
Doubles the risk of disease in people older than 60
Genetic disorders
Down syndrome, Fanconis anemia
High doses of radiation
Long-term survivors of atomic bombs
Previous chemotherapy treatment
Breast cancer, ovarian cancer, lymphoma
Exposure to industrial chemicals
Benzene
Classification of leukemias

Acute Chronic

Myeloid Acute Myeloid Chronic Myeloid Leukemia


Leukemia (AML) (CML)
origin

Lymphoid Acute Chronic Lymphocytic


origin Lymphoblastic Leukemia (CLL)
Leukemia (ALL)
AML cytochemistry
Reaction M0 M1 M2 M3 M4 M5 M6 M7

Peroxidase - + + + +/- - +/- -


(POX)
Sudan Black - + + + +/- - +/- -
B
Unspecific - - - - + + - -
esterases
PAS - - - - - - + -
AML- immunocytology
FAB Immunological markers
M0 HLA-DR, CD33, MPO
M1 HLA-DR, CD13, CD33, MPO
M2 HLA-DR, CD13, CD33, CD15, CD34, MPO
M3 HLA-DR, CD33, CD15, MPO
M4 HLA-DR, CD13, CD14, CD15, CD33
M5 CD13, CD33, CD14, CD15, CD34
M6 CD13, CD33, glicophorin A
M7 CD41, CD61
Diagnosis
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
Physical Findings
hepatosplenomegaly
Pallor, petechiae, ecchymoses
Bone tenderness
Retinal hemorrhage
CNS infiltration
Skin, soft tissue infiltration (ginggiva, otak,
tulang lien)
Leukostasis : CNS, priapismus, Infarc miokard,
dyspneu
Gum hypertrophy
Gingival Infiltration of AML

Mani, A, Lee, DA. Leukemic Gingival Infiltration. N Engl J Med 2008; 358(3): 274. Copyright 2008 Massachusetts Medical Society
Tests For Diagnosis
Blood sample
Blood dye
Bone marrow sample
Spinal Tap/Lumbar Puncture
Laboratory features
WBC usually elevated, but can be normal
or low
blasts in peripheral blood
normocytic anemia
thrombocytopenia
neutropenia
DIC
CML
Ph +ve
BCR-abl +ve

Ph: Philadelphia chromosome


BCR: Breakpoint cluster region; abl : Abelson oncogene
Diagnosis
> 20% blasts on BM aspirate ( kriteria WHO)

Pasien dengan cytogenic abnormalities are considered


to have AML regardless of blast percentage
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
How to distinguish AML vs CML
from looking at peripheral blood

Myeloid cell CML AML normal


blasts q q
promyelocytes q
myelocytes q
metamyelocytes q
bands q
neutrophils q q
Acute Myeloid Leukemia (AML):
Morphology and Cytology:

> 20% myeloblasts in blood and/or bone marrow

Auer Rods (cytoplasmic granules)

Positive myeloperoxidase reaction in > 3% blasts


Auer Rods in Leukemia cells (AML)
Philadelphia Chromosome (Ph)
9 and 22 translocation almost specific to CML
(>95%)
Karyotype to visualize Ph chromosome
Produces BCR/c-abl fusion oncogene
Gene product p190 is a hyperactive tyrosine
kinase
Translocation t(9;22)(q34;q11)
Philadelphia Chromosome in CML
FISH showing the BCR (green), ABL (orange), and BCR-ABL fusion
signals (arrow): A=positive (contains a residual ABL signal), B=normal
KOMPLIKASI
Complications
Leukostasis
DIC
Necrotizing enterocolitis usually at time
of neutrophil nadir post chemotx
Joint involvement in setting of leukemic
blast synovial membrane infiltration
<4% of those with AML
Leukostasis
accumulation of blasts in microcirculation
with impaired perfusion
lungs: hypoxemia, pulmonary infiltrates
dyspnea, chest pain
CNS: stroke, headaches, altered mentation, ,
ocular symptoms
Priapism
Myocardial Infarction
Leukostasis
Leukostasis
Dapat terjadi bila WBC > 50,000
Bila WBC counts > 100,000 (10% of patients)
Most common in those with M4 or M5 leukemia
Function of the blast cells being less deformable than
mature myeloid cells. As a result, intravascular plugs
develop.
High metabolic activity of blast cells and local
production of various cytokines contribute to
underlying hypoxia
The next thing that occurred was
a procedure called leukopheresis.

This procedure lasted 4 hours and


cut Ds white blood cell (WBC)
count in half--to about 250,000.
DIC SYSTEMIC
ACTIVATION OF
COAGULATION
An acquired
syndrome
characterized by
systemic Intravascula
r deposition
Depletion of
platelets and
intravascular of fibrin coagulation
coagulation factors

Coagulation is always
the initial event Thrombosis of
small and Bleeding
midsize vessels

Organ failure DEATH


Lab Tests
Hemostasis CBC-Plt
BT,(CT)
BV Injury PT
Tissue PTT
Neural Factor

Blood Vessel Platelet Coagulation


Constriction Aggregation Cascade
Primary hemostatic plug

Reduced Platelet
Activation Fibrin
Blood flow formation
Plt Study
Morphology
Stable Hemostatic Plug Function
Antibody
Screening Tests of Blood Coagulation
Mekanisme DIC

Systemic activation
of coagulation

Intravascular Depletion of platelets


deposition of fibrin and coagulation factors

Thrombosis of small Bleeding


and midsize vessels
with organ failure
Conditions Associated With DIC

Malignancy Pulmonary
Leukemia ARDS/RDS
Metastatic disease Pulmonary
Cardiovascular embolism
Post cardiac arrest Severe acidosis
Acute MI
Severe anoxia
Prosthetic devices
Hypothermia/Hyperth Collagen vascular
ermia disease
Anaphylaxis
Conditions Associated With DIC

Infectious/Septicemia Tissue Injury


Bacterial trauma
Gm - / Gm + extensive surgery
Viral tissue necrosis
CMV head trauma
Varicella
Hepatitis
Obstetric
Fungal Amniotic fluid emboli
Placental abruption
Intravascular
Eclampsia
hemolysis
Missed abortion
Acute Liver Disease
Clinical Manifestations of DIC
Laboratory diagnosis
Thrombocytopenia
plat count <100,000 or rapidly declining
Prolonged clotting times (PT, APTT)
Presence of Fibrin degradation products or
positive D-dimer
Low levels of coagulation inhibitors
AT III, protein C
Low levels of coagulation factors
Factors V,VIII,X,XIII
Fibrinogen levels not useful diagnostically
DIC
Treatment
1. Supportive therapy
Platelets
Cryoprecipitate (fibrinogen)
FFP
2. Treatment for obvious thrombosis (e.g thrombophlebitis,
mural thrombus)
UFH or LMWH; often resistant to coumadin
activated protein C
Heparin
3. Treatment of underlying malignancy
In the case of AML M3 All-Trans Retinoic Acid (PML-
RAR)
Induces differentiation beyond promyelocyte phase
Only with the more common t(15;17) translocation;
t(11;17) and t(5;17) do not respond to ATRA
Remission rates of greater than 90% with AML M3 patient
treated with ATRA and chemotx (eg, anthracyclines
(idarubicin)) with 60-70% disease free survival
TERAPI LEUKEMIA
Treatment
Chemotherapy
Immunotherapy
Radiation
Bone marrow transplant
TERAPI FARMAKOLOGI
Alkilator :klorambusil dan
siklofosfamid
Antrasiklin :
daunorubisin,doksorubisin
Antimetabolit: metotreksate,
merkaptopurin
Enzim : asparaginase
Produk alamiah : alkaloid vinka,antibiotik
Chronic Leukemia Treatment:
CVP Regimen:

Cyclophosphamide

Vincristine

Prednisone
Chronic Leukemia Treatment:
CHOP Regimen:

Cyclophosphamide

Doxorubicin

Vincristine

Prednisone
PENATALAKSANAAN TERAPI
Terapi non farmakologi :

HSCT (transplantasi stem cell)


a. Autologous :
ekstraksi HSC dari pasien dan penyimpanan sel ke dalam
freezer kemoterapi dosis tinggi dengan atau tanpa
radioterapi Stem cell dikembalikan ke dalam tubuh
pasien memperbaiki jaringan yang rusak dan
mengembalikan produksi sel darah menjadi normal
kembali.
b. Allogenic
transplantasi stem cell dari pasien donor (sehat) ke
pasien resipien (sakit). Syarat pendonor adalah memiliki
tipe jaringan (HLA) yang cocok dengan resipien. Sumber
stem cell dapat diambil dari umbilical cord blood.
Radioterapi
Irradiasi splenic untuk mengurangi ukuran splenic
dan meringankan nyeri abdominal.

Pembedahan (splenektomi)
untuk pasien dengan splenomegali masif yang
menunjukkan gejala, ataupun refractory cytopenia
(karena autoimun atau hipersplenism).
Respon : pengurangan gejala karena spenomegali,
dan perbaikan cytopenia.
The Future
Clinical trials
New drug treatments
Vaccines
Immunotherapy
Cord blood and planceta
Gene therapy
Block encoding instructions of an oncogene
Target the oncoprotein
Blood and marrow stem cell transplantation
Bone marrow transplantation provides long-
term, disease-free survival among patients in
remission
Prognosis for AML

Survival rates greatly improved over past 25 years.


Majority of patients still succumb to the disease.
Remission rates inversely related to age.
5-year survival rate in adults under 65 is 33%
5-Year survival rate in adults over 65 is 4%
Dependent upon several factors.
Age
White blood cell count
Presence of translocations in bone marrow
Polisitemia
Erythrocytosis
Definition: An increase in the number
of circulating RBCs per volume of
blood.
Synonym = polycythemia.
Reflected as an elevated hemoglobin
and hematocrit.
Causes are classified as:
Secondary (Polyclonal)
Primary (clonal)
Secondary Causes of Increased
Red Cell Mass (Erythrocytosis)
Chronic pulmonary or cardiac disease
Decreased 2,3-diphosphoglycerate
High oxygen affinity hemoglobinopathy
Increased carboxyhemoglobin (in smokers) and
methemoglobin
Residence at high altitude
Adrenal cortical hypersecretion
Hydronephrosis
Tumors producing erythropoietin or anabolic
steroids
Relative (stress)
Disorders associated with decreased plasma
volume (e.g., diarrhea, emesis, renal diseases)
Diagnosis: Other Signs and Symptoms
of Polycythemia Vera

More Common Less Common


Hematocrit level >52 Bruising/epistaxis
percent (0.52) in white Budd-Chiari syndrome
men, >47 percent (0.47) in Erythromelalgia
blacks and women
Hemoglobin level >18 g per Gout
dL (180 g per L) in white Hemorrhagic events
men, >16 g per dL (160 g Hepatomegaly
per L) in blacks and Ischemic digits
women) Thrombotic events
Plethora Transient neurologic
Pruritus after bathing complaints (headache,
Splenomegaly tinnitus, dizziness, blurred
Weight loss vision, paresthesias)
Weakness Atypical chest pain
Sweating
Diagnosis
PV should be suspected when hemoglobin
and/or hematocrit levels are elevated
(> than 18 g per dL [180 g per L] in white
men and > than 16 g per dL [160 g per L] in
blacks and women)
hematocrit level greater than 52 percent
(0.52) in white men and 47 percent (0.47)
in blacks and women
A diagnosis of polycythemia vera is made when a patent
fulfills
all three of the major criteria
Or
any two major and any two minor criteria

Major Criteria
total RBC vol
Men > or = to 36 mL/kg
Women > or = to 32 mL/kg
arterial 02 saturation > or = to 92%
Splenomegaly
Minor Criteria
Thrombocytosis with platelet count > 400,000/mL
Leukocytosis with WBC > 12,000/mL
Increased leukocyte alkaline phosphatase LAP > 100U/L
(no infection)
Serum B12 > 900 pg/mL or binding capacity UB12 BC >
2200 pg/mL
Komplikasi
Examples of thrombotic events include
arterial and venous thrombosis,
cerebrovascular accident, deep venous
thrombosis, myocardial infarction,
peripheral arterial occlusion, and
pulmonary infarct
P vera - Treatment
Phlebotomy
Myelosuppressive agents
Hydroxyurea
Alkylating agents such as busulfan
32P

Interferon alpha
P vera - phlebotomy
Generally, the best initial treatment for P vera
No increase in progression to AML
Rapid onset
No BM suppression
Remove 500 cc blood 1-2x/wk to target Hct
45%, then maintain
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