leukemia kul

7/28/2019 Leukemia Kul

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LEUKEMIA

Dr. SUHAEMI, SpPD, FINASIM


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8 Parameter Cell Counter

WBC: White BloodCells

RBC: Red Blood Cells HgB: Hemoglobin

Hct: Hematocrit

MCV: Mean Cell

Volume

MCH: Mean CellHemoglobin

MCHC: Mean CellHemoglobinConcentration

RDWt: Red Blood Cell

Distribution Width

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


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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


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PENDAHULUAN

Leukemia merupakan penyakit keganasan seldarah yang berasal dari sumsum tulang ditandaioleh proliferasi sel sel darah putih, denganmanifestasi adanya sel sel abnormal dalamdarah tepi.

Leukosit dalam darah berpoliferasi secara tidakteratur dan tidak terkendali dan fungsinyapunmenjadi tidak normal

Oleh karena proses tsb fungsi-fungsi lain dari seldarah normal juga terganggu hinggamenimbulkan gejala leukemia yang dikenaldalam klinik


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What Is Leukemia?

Cancer of the white blood cells

Acute or Chronic

Affects ability to produce normal blood cells

Bone marrow makes abnormally largenumber of immature white blood cells called

blasts


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Leukemia

Hallmark: proliferation of malignant cells inthe bone marrow

Divided into: acute v. chronic

lymphoblastic v. myeloid (non-lymphoblastic)

Each type of leukemia has a differentpresentation, natural history, prognosis, andtreatment.


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Classification of leukaemias

Acute Chronic

Myeloidorigin

Lymphoidorigin

Acute MyeloidLeukaemia (AML)

Acute LymphoblasticLeukaemia (ALL)

Chronic Myeloid Leukaemia (CML)

Chronic Lymphocytic Leukaemia(CLL)


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Leukemia

Acute leukemias: rapid onset, rapid death iftreatment is not successful

Chronic leukemias: natural history measuredin years, even without initial treatment


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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 (DiGuglielmos)

M7 -- Megakaryoblastic Leukemia


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M1 and M2


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M3

M5

M4


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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, skininfiltration, chloromas (tumors composed ofmalignant marrow cells)


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Acute Leukemia

Diagnosis: >20% blasts in the bone marrow

Categorized by

H&E staining Cytochemical stains (myeloperoxidase, NSE)

Flow cytometry

Cytogenetics


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Acute Leukemia

No evidence of maturation withinblood or marrow


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What is AML?

The term Myelogenous

denotes what type of

cell is being affected:

Monocytes andNeutrophils

Acute refers to rapid

progression formingimmature cells

Results from acquired

genetic damage to the

DNA of the bone

marrow

Immature cells

produced are known as

blast cells


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SIMPLIFIED SCHEMA OF

HEMATOPOETIC CANCERS

Hematopoetic

Stem Cell

Myeloid

Lymphoid

Acute and chronic

Myeloid Leukemias

Lymphomas

Hodgkins (30%)

Non Hodgkins (70%)

WBC

RBC

Platelets

B Cells

T cells


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Haematopoiesis

PLURIPOTENT

STEM CELL

COMMITTED

PROGENITOR

CELL

RECOGNIZABLE

BONE MARROW

PRECURSOR CELL

MATURE

BLOOD

CELL

myeloblast

monoblast

pronormoblast red cell

neutrophil

monocyte

basophil

platelet

CFU-Baso

CFU-Eos

CFU-GM

BFU-E/CFU-E

eosinophil

pre-T

pre-B

myeloid

progenitor

cell

lymphoid

progenitorcell

lymphoblast

lymphoblast

T-cell

B-cell& plasma cell

MIXED

PROGENITOR

CELL

CFU-Meg megakaryocyte

pluripotent

stem cell


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Hematopoieticstem cell

Neutrophils

Eosinophils

Basophils

Monocytes

Platelets

Red cells

Myeloidprogenitor

Lymphoidprogenitor

B-lymphocytes

T-lymphocytes

Plasmacells

nave

ALL

AML


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Where AML Originates


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Genetic Associations

Research states that AML is caused by geneticaberrations such as translocations betweenchromosomes that alter the function oftranscriptory regulatory factors

These translocations are a direct result ofchimeric fusion proteins which are caused by theabnormal cells and its inability to allow furthergrowth, proliferation, maturation and

differentiation. Class 1 and 2: mutations responsible for the

development of the neoplastic process ofmyeloproliferation and de-differentiation


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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)


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differentiationblock

enhancedproliferation

AcuteLeukemia

+

Gain of function mutations oftyrosine kinases

eg. FLT3, c-KIT mutations

N- and K-RAS mutationsBCR-ABL

TEL-PDGFbR

Loss of function oftranscription factorsneeded for differentiation

eg. AML1-ETOCBFb-SMMHCPML-RARa

Two-hit model of

leukemogenesis


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Tyrosine Kinases

Tyrosine kinases are alsoknown as oncogenes

Oncogenes are present inthe mutated neutrophilsand moncytes

AML activates themcausing uncontrollable

proliferation, apoptosis,decreased adhesion, andinhibits differentiation


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Causes of acute leukemias

idiopathic (most)

underlying hematologic disorders

chemicals, drugs ionizing radiation

viruses (HTLV I)

hereditary/genetic conditions


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AML and its Impact on the

Immune System AML affects the innate immune system

Secondary Immune System kicks in

The proliferation of immature neutrophilsand moncytes takes place

Unable to leave the bone marrow to go intoblood stream and tissues to fight offinfections


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Main Types

Acute Lymphocytic Leukemia (ALL)

Acute Mylogenous Leukemia (AML)

Chronic Lymphocytic Leukemia (CLL)

Chronic Mylogenous Leukemia (CML)


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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


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Tests For Diagnosis

Finger prick

Blood sample

Blood dye

Bone marrow sample

Spinal Tap/Lumbar Puncture


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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


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Coagulogramm:

elevated prothrombin time

decreased fibrinogen levels

presence of fibrin split products

Chemistry profile:

elevated lactic dehydrogenase level

elevated uric acid levelliver function tests

BUN/creatinine determinations

Lab Studies


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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 worksfine- so ideal when marrow unavailable

rtPCR- for 15;17

rtPCR for BCR:ABL in ALL


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Cytogenetics

Good (thats 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 riskcytogenetics.


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Cytogenetics

Intermediate

Normal

One or two abnormalities


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Cytogenetics

Bad

Chromosome 7

Chromosome 5

Complex (3 or more)

11q23

Any trisomy?


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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 fungalinfection

-IV antibiotics for infection

-Blood transfusion if anemia and thrombocytopenia.


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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


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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 withan anthracycline or epipodophyllotoxin.

Maintenance

CNS prophylaxis


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AML therapy

Cytarabine Infusional or high-dose

Anthracycline Any will do- dauno, ida, mitoxantrone

Other active agents Etoposide

Cyclophosphamide

Hydroxyurea

6MP/TG

Topotecan


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Replacement of blood products: packed red bloodcells, platelets, fresh frozen plasma

Antibiotics: a third-generation cephalosporin (orequivalent) with an aminoglycoside. Patients with

persistent fever after 3-5 days of antibacterialantibiotics have amphotericin added to their regimen.

The use of prophylactic antibiotics in neutropenicpatients who are not febrile is controversial. Acommonly used regimen includes ciprofloxacin (500

mg orally twice daily, fluconazole (Diflucan) (200 mgorally daily), and acyclovir (200 mg orally 5 times/d).

Supportive Care


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Growth factors

Allopurinol 300 mg 1-3 times/d

Central venous catheter

Supportive Care


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Prognosis

Good risk includes (1) no adverse cytogenetics, (2) ageyounger than 30 years, (3) WBC count of less than30,000/mL, and (4) complete remission within 4weeks.

Intermediate risk does not meet the criteria for eithergood 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.


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Prognosis

Genetic abnormalities:

t(9;22) - poor outlook

t(4;11) - younger age, female predominance,

high white cell counts, and L1 morphologyt(8;14) - older age, male predominance, frequent

CNS involvement, and L3 morphology

Both are associated with a poor prognosis.


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Prognosis in AML

parameters Favorable unfavorable

Cytogentics T(15;17).

T(8;21).Inv(16).

Deletion of chromosome5or7.

11q23T(6;9)

Abn(3q)complex

rearrangments

BM response toremission induction

20% blasts after first course.

age 60yrs


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Differential diagnosis of Acuteleukemias:

Lymphoma.

Myelodysplastic syndrome.

Multiple myeloma. Aplastic anemia

Sever megaloblastic anemia due to B12

defeciency. Severe lymphocytosis due to infections.


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Myeloid maturation

myeloblast promyelocyte myelocyte metamyelocyte band neutrophil

MATURATION

Adapted and modified from U Va website


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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.


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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.


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Thrombocytes

Smallest cells in

the blood.

Normal range

130,000-400,000. Active role in

coagulation and

hemostasis.

i f


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Pictures Of Blood

Normal human blood

White Cell Red Cell

Platelet

Blood with leukemia

BlastsRed Cell

Platelet

White Cell

Sources fromArginine.umdnj.eduSources from beyond2000.com


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Acute Myelogenous Leukemia:

Auer Rod

Blasts


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Blasts

Acute Myelogenous Leukemia with differentiation


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Petechiae


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Infiltration of

tissues/organs enlargement of liver, spleen, lymph nodes

gum hypertrophy

bone pain other organs: CNS, skin, testis, any organ


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Gum hypertrophy


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AML gingival hypertrophy

Gi i l I filt ti i


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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


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A

B

C

Chloromas

NEJM 1998


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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


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Causes

High level radiation/toxin exposure

Viruses

Genes

Chemicals

Mostly unknown Cant be caught


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Treatment

Chemotherapy

Immunotherapy

Radiation

Bone marrow transplant


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Research

New drugs

Cord blood and planceta


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Myeloblasts with auer rods


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Lymphoblast

AML


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Auer rods in AML


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LEUKEMIA LIMFOBLASTIK AKUT

LLA merupakan leukemia yg paling seringdijumpai pada anak anak.

Pada anak kecil ditandai dgn mendadakpanas,pucat dan memar di kulit.

Sering dijumpai nyeri di tulang beberapa bulansebelum timbul ekimosis,pucat dan panasbadan.

Perasaan lemah, BB tidak bertambah/menurun,

nafsu makan menurun, kadang kadangepistaksis atau perdarahan gusi dapatmerupakan keluhan tambahan.


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PEMERIKSAAN FISIK

Anak terlihat pucat, tampak sakit berat,takikardi dan bisa dijumpai perdarahanfundus 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 timbulnyarefleks patologis


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TERAPI

Kemoterapi

Radiasi CNS

ALL


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ALL-L1


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ALL-L2


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LEUKEMIA LIMFOSITIK KRONIK

LLK adalah jenis leukemia yg paling seringpada orang tua, biasanya asimtomatik.

Biasanya ditemukan pada saat pemeriksaandarah rutin atau pada seseorang dgnhepatosplenomegali atau limfadenopati ygasimptomatik.

Keadaan asimptomatik dapat berlangsungbertahun tahun sampai timbul keluhanleukemianya


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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 routineblood test


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Chronic Lymphocytic Leukemia

Age: the elderly

Prognosis: may live for many years evenwithout treatment

Treatment: Watchful waiting, purinenucleoside analogues (fludarabine), alkylators

Lymphocytosis


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Lymphocytosis



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Clonal proliferation of lymphocytes

-95 % with B-cell phenotype

Usually detected as an asymptomaticlymphocytosis


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CLLPB and BM


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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 & BinetEarly stage disease has a survival equivalent to age-

and sex-matched controls


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Most patients do not require specific treatment

Indications for treatment

anemia

thrombocytopenia

unsightly adenopathy

other complications

When treatment is needed, alkylators or

pur ine nucleoside analoguesare used

Aetiology


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Aetiology

Cause unknown

Not associated with radiation or exposure tooccupational hazards

Among the leukemias, CLL has the strongesttendency for familial incidence


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h i l k i


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Chronic Myelogenous Leukemia

CML adalah leukemia yang sering mengenaiorang dewasa, kadang kadang pada anak danusila.

Gejala yg diketemukan adalah penurunanberat badan, nafsumakan berkurang,perasaan cepat letih, cepat kenyang ok

splenomegali

h i l k i


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Age: adults

Prognosis: 3-4 years without BMT, curespossible with BMT

Treatment:

Imatinib (Gleevec)

Bone marrow transplant

Hydroxyurea +/- interferon;

h i l k i


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Leukocytosis with all degrees of myeloiddifferentiation in blood and marrow

Often associated with eosinophilia,

basophilia, thrombocytosis

Splenomegaly is characteristic

Ch i M l L k i


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Chronic Myelogenous Leukemia:

Philadelphia Chromosome

9;22 translocation yields a chimeric genetermed bcr-abl

bcr derived from chromosome 22

abl derived from c-abl oncogene on chrom. 9

Encodes a 210,000 MW protein - a tyrosineprotein kinase

Ability to detect transcript by PCR mayenable us to detect molecular remissions

Ch i M l L k i


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Disease terminates in blast crisis in 3-4 years; thisresponds 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 ifthe patient is a candidate

Imatinib is a new option

Ch i M l L k i


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Chronic Myelogenous Leukemia:

Results of BMT

Five year survival > 60% with allogeneic BMT

< 25% of patients have an HLA-matchedsibling

Matched unrelated donors (MUD) may beused

Ch i M l L k i


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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


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PMN

Band

Eosinophil

Basophil

Early Myeloid

Cells


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BCR ABL translocation


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BCR-ABL translocation



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FISH showing the BCR (green), ABL (orange), and BCR-ABL fusion signals (arrow):A=positive (contains a residual ABL signal), B=normal

Jemshidi trephine &


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p

Salah aspiration needle


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Chemotherapy - Uses drugs to kill leukemia cells.

Radiation therapy - uses high-energy rays to killleukemia cells.
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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)

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