* KEGANASAN JARINGAN / SEL DARAH PUTIH , DITANDAI ADANYA :

- PROLIFERASI TAK TERKONTROL SALAH SATU TIPE SEL/

MUNGKIN MELIBATKAN BEBERAPA JALUR SEL DARI SEL STEM SUMSUM TULANG. - PERTUMBUHAN SEL TAK TERKONTROL - DAPAT MENGINFILTRASI KEJARINGAN TUBUH LAIN. * DISCOVERED BY DR. ALFRED VELPEAU IN FRANCE, 1827 * NAMED BY PATHOLOGIST RUDOLF VIRCHOW IN GERMANY, 1845

OVERVIEW
KONSEP BIOLOGI EPIDEMIOLOGI/ INSIDENSI GEJALA KLINIK DAN LABORATORIUM DIAGNOSIS PENETALAKSANAAN PROGNOSIS

INSIDENSI :
* LEULKEMIA AKUT DPT TERJADI PD SEMUA UMUR : - ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) > ANAK - ACUTE MYELOBLASTIC LEUKEMIA (AML) > DEWASA

* LEUKEMIA KRONIS BIASANYA PADA DEWASA :

- CLL (CHRONIC LYMPHOCYTIC LEUKEMIA) JARANG PADA ANAK, PADA ORANG DEWASA < 40 TAHUN - CML (CHRONIC MYELOBLASTIC LEUKEMIA) PADA DEWASA, PUNCAK PD UMUR 30-50 TAHUN.

* COMPARISON ACUTE AND CHRONIC LEUKEMIAS:

ACUTE AGE CLINICAL ONSET COURSE (UNTREATED) LEUKEMIC CELLS ANEMIA THROMBOCYTOPENIA WBC COUNT LYMPHADENOPATHY SPLENOMEGALY ALL AGES SUDDEN 6 MO. OR LESS
IMMATURE >30% BLASTS

CHRONIC USUALLY ADULTS INSIDIOUS 2-6 YEARS

MORE MATURE CELLS

PROMINENT PROMINENT VARIABLE MILD MILD

MILD MILD INCREASED PRESENT;OFTEN PROMINENT PRESENT;OFTEN PROMINENT

MENURUT PERJALANAN PENYAKIT :

LEUKEMIA DIKELOMPOKAN 2 GRUP UTAMA : - AKUT : - MUNCULNYA MENDADAK - PERJALANANNYA SANGAT AGRESIF. - TERDIRI SEL BERDEFERENSIASI JELEK DENGAN TIMBUNAN SEL BLAST (SEL MUDA ). - KRONIS : - MUNCULNYA PERLAHAN - KURANG AGRESIF - DIDOMINASI SEL DEWASA, TDPT BBRP SEL MUDA (LIMFOBLAST / MIELOBLAST) .

Types of Leukemia * chronic (worse slowly) or acute ( worse quickly):

* Chronic leukemia : * Acute leukemia :

- Early in the disease, - Abnormal blood cells can still do their work - May not have any symptoms, - gets worse slowly

- Blood cells are very abnormal. - They cannot carry out their normal work. - Number of abnormal cells increases rapidly. - Worsens quickly.

*Types leukemia are also grouped by, type of white blood cell that is affected. - lymphoid cells lymphocytic leukemia, myeloid cells myeloid

leukemia or myelogenous leukemia.

* There are four

common types: - Chronic lymphocytic leukemia (chronic lymphoblastic leukemia, CLL),

- About 7,000 new cases of leukemia each year. - Most often, people diagnosed over age 55. - It almost never affects children.

- Chronic myeloid leukemia (chronic myelogenous leukemia, CML).

- Accounts for about 4,400 new cases each year. - It affects mainly adults.

- Acute lymphocytic leukemia (acute lymphoblastic leukemia, ALL).

- Accounts about 3,800 new cases each year. - Common young children. - - It also small affects adults.

- Acute myeloid leukemia (acute myelogenous leukemia, AML).

- Accounts for about 10,600 new cases each year. - Affects both adults and children. - Hairy cell leukemia is a rare type of chronic leukemia. - Together, these rare leukemias account for about 5,200 new cases of leukemia each year.

Demographics of Leukemia Patients (2001 Data)

CLL=Chronic Lymphocytic ALL=Acute Lymphocytic CML=Chronic Mylogenous AML=Acute Mylogenous
CML 15% CLL 26% others 17% ALL 11%

AML 31%

Sources from Leukemia, Lyphoma, Myeloma Facts 2001

Total Reported Cases = 31,500

EPIDEMIOLOGI :
Leukemia : 4-5% kanker dari seluruh Kelompok umur. Merupakan keganasan paling sering pada anak. USA.: 3-5/100.000 penduduk per tahun Sex: : = 1,4 : 1 LMA sering pada dewasa LLA > sering pada anak ( 75-80% )

PATOGENESIS
Perubahan molekul DNA sel hemopoetik Perubahan gen normal tertentu Transformasi maligna Proliferasi klonal abnormal sel induk/ sel progenitor

ETIOLOGI: - PENEYEBAB PASTI, BELUM JELAS ADA BBRP FAKTOR

PREDISPOSISI: FAKTOR HOST : - Indv dng peny. Heriditer , kejadian leukemia

- Peny. her dng kromosom fragil/abnormal jmlh. kromosom meningkat

(downs syndrome ) , atau bbrp peny dng translokali kromosom. * INSIDENSI MENINGKAT PD : - Peny. imunodefisiensi heriditer. - Imunosupresi/ kerusakan sel ssm. tulang kerusakan materi gen dalam sel. - Disfungsi sumsum tlg kronis: Peny. Mieloproliferatif, Anemia aplastika (AA) dan Paroksismal nokturnal hemoglibonuria (PNH). FAKTOR LUAR : Yang berpengaruh: - Radiasi dosis tinggi (nuklir,radioterapi) kerusakan gen. Misal: Sindroma Down, Bloom. - Imunosupresor, agent mutagenic lain: Bahan kimia (benzene), obat- obatan ,

virus, herediter (genetik).

DIAGNOSIS :
- GEJALA DAN

TANDA KLINIS

- LABORATORIUM - BMP (BONE MARROW PUNCTION/ BONE MARROW ASPIRATION ) - BMB (BONE MARROW BIOPTIE ).

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

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

Bone Marrow

Blood Lines by Donald Metcalf http://www.bloodlines.stemcells.com/img/Metcalf_Fig3_2.gif

Leukopoiesis : White Blood Cell Formation

Treatment
Chemotherapy Immunotherapy Radiation Bone marrow transplant

Research
New drugs
Cord blood and planceta

Classification of leukemias
Acute Myeloid origin Lymphoid origin
Acute Myeloid Leukemia (AML) ( M1 M7)

Chronic
Chronic Myeloid Leukemia (CML)

Acute Lymphoblastic Leukemia (ALL)

(T CELL,B CELL,NULL CELL) (L1,L2,L3)

Chronic Lymphocytic Leukemia (CLL)

OBJECTIVE :
Define acute leukemia Classify leukemia Understand the pathogenesis Understand the pathophysiology Able to list down the laboratory investigations required for diagnosis Understand the basic management of leukemia patients

ACUTE LEUKAEMIA
* Define : heterogenous group of malignant disorders which is characterised by uncontrolled clonal and accumulation of blasts cells in the bone marrow and body tissues Sudden onset If left untreated is fatal within a few weeks or months

Causes :
HIGH LEVEL RADIATION/TOXIN EXPOSURE IONIZING RADIATION VIRUSES (HTLV I) UNDERLYING HEMATOLOGIC DISORDERS HEREDITARY/GENETIC CONDITIONS CHEMICALS, DRUGS MOSTLY UNKNOWN IDIOPATHIC (MOST) CANT BE CAUGHT

* Develop as a result of a genetic alteration within single cell in the bone marrow a). Epidemiological evidence : 1. Hereditary Factors - Fanconis anaemia - Downs syndrome - Ataxia telangiectasia 2. Radiation, Chemicals and Drugs 3. Virus related Leukemias - Retrovirus :- HTLV 1 & EBV b). Molecular Evidence * Oncogenes : - Gene that code for proteins involved in cell proliferation or differentiation * Tumour Suppressor Genes : - Changes within oncogene or suppressor genes are necessary to cause malignant transformation. - Oncogene can be activated by : chromosomal translocation point mutations inactivation *In general, several genes have to be altered to effect neoplastic transformation.

PATHOPHYSIOLOGY
Acute leukemia cause morbidity and mortality through : A. Deficiency in blood cell number and function B. Invasion of vital organs C. Systemic disturbances by metabolic imbalance

A.Deficiency in blood cell number or function * Infection - Most common cause of death - Due to impairment of phagocytic function and neutropenia. * Hemorrhage - Due to thrombocytopenia or 2o DIC or liver disease. * Anaemia - normochromic-normocytic - severity of anaemia reflects severity of disease - Due to ineffective erythropoiesis

B. Invasion of vital organs - vary according to subtype * Hyperleukocytosis - cause increase in blood viscosity - Predispose to microthrombi or acute bleeding - Organ invole : brain, lung, eyes - Injudicious used of packed cell transfusion precipitate hyperviscosity. * Leucostatic tumour - Rare - Blast cell lodge in vascular system forming macroscopic pseudotumour erode vessel wall cause
bleeding

* Hidden site relapse

- testes and meninges

METABOLIC IMBALANCE :

- Due to disease or treatment - Hyponatremia vasopressin-like subst. by myeloblast - Hypokalemia due to lysozyme release by myeloblast - Hyperuricaemia- spont lysis of leukemic blast release purines into plasma.

EPIDEMIOLOGI:
Leukemia : 4-5% kanker dari seluruh kelompok umur. Merupakan keganasan paling sering pada anak. USA.: 3-5/100.000 penduduk per tahun Sex: : = 1,4 : 1 LMA sering pada dewasa LLA > sering pada anak ( 75-80% )

SIGNIFICANCE OF ADULT ACUTE LEUKEMIA:

A hematologic urgency Usually fatal within weeks to months without chemotherapy With treatment, high mortality due to disease or treatment-related complications (unlike childhood acute leukemia) Notify Hematologist promptly if acute leukemia is suspected

Causes of acute leukemias :

Idiopathic (most) Underlying hematologic disorders Chemicals, drugs Ionizing radiation Viruses (HTLV I) Hereditary/genetic conditions

 symptoms due to:

Clincal manifestations :
marrow failure tissue infiltration leukostasis constitutional symptoms other (DIC)

usually short duration of symptoms * Marrow failure :

neutropenia: infections, sepsis anemia: fatigue, pallor thrombocytopenia: bleeding

INFILTRATION OF TISSUES/ORGANS :

Enlargement of liver, spleen, lymph nodes Gum hypertrophy Bone pain Other organs: CNS, skin, testis, any organ.

Gum hypertrophy

Patogenesis
Perubahan molekul DNA sel hemopoetik

Perubahan gen normal tertentu

Transformasi maligna Proliferasi klonal abnormal sel induk/ progenitor

*Klasifikasi LMA (FAB)

M0 : tanpa diferensiasi (Dx:imunologik) M1 : tanpa diferensaisi (Dx.sitokimia dan imunologik M2 : dengan diferensiasi M3 : Leukemia PromielositikAkut M4 : Leukemia Mielomonositik Akut M5 : Leukemia Monositik Akut M6 : Eritroleukemia M7 : Leukemia Megakariositik Akut

* Klasifikasi LLA

L1 : morfologi sel relatif homogen, bentuk sel kecil, sitoplasma sedikit, nukleoli kecil/ tidak jelas L2 : morfologi sel relatif heterogen, sel besar, sitoplasma lebih banyak, nukleoli jelas L3 : seperti Limfoma Burkit,sel besar, sitoplasma biru, vakuola ()

LLA : Klasifikasi Imunologik

Null ALL
Common ALL

T ALL
B ALL

Tanda khas akibat infiltrasi organ:

Nyeri tulang ( terutama pada anak ) Limfadenopati superfisial, hepatomegali, splenomegali (LLA). Hipertrofi dan infiltrasi gingiva, kulit (M4 dan M5). Sindroma meningeal: nyeri kepala, mual, tumpah, penglihatan kabur, diplopia, edema papil dan perdarahan retina sering ditemukan pada LLA: M4, M5.

ALL
nave B-lymphocytes Plasma cells T-lymphocytes

Lymphoid progenitor

AML
Hematopoietic stem cell Myeloid progenitor Neutrophils Eosinophils Basophils Monocytes Platelets

Red cells

MYELOID MATURATION:
myeloblast promyelocyte myelocyte metamyelocyte band neutrophil

MATURATION
Adapted and modified from U Va website

Pemeriksaan Laboratorium
Anemia (normokrom normositer) Hitung Leukosit: menurun/normal/meningkat hingga 200.000/mm3 Trombositopenia Darah tepi: sel blast (+), auer rods, promielosit, neutrofil agranuler, sel pseudopelger, eritroblast dalam jumlah banyak (M5) Sumsum tulang : hiperselular, sel blast (50-75%). Pada LLA aspirasi sulit (serabut retikulin ). Pada M7 khas : pansitopeni mendadak dan fibrosis sumsum tulang. Pemeriksaan faal hemostasis : DIC (M3) Leukemia otak : LP tekanan cairan otak meningkat dan mengandung sel leukemia

 Kimia klinik: peningkatan as.Urat, LDH.

Tes faal hati dan ginjal dilakukan sebagai persiapan pemberian sitostatika.

Foto R : proses lisis tulang (LLA anak),

massa mediastinum ( pembesara timus/ kel.limfe mediastinum), infiltrasi paru (infeksi/sel leukemia)

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PICTURES OF BLOOD :
Platelet
White Cell Red Cell White Cell Red Cell

Platelet
Blasts

Normal human blood

Sources from Arginine.umdnj.edu

Blood with leukemia

Sources from beyond2000.com

ALL L1.

ALL L2 .

ALL L3.

ALL. ..L2.

Auer rods in AML

Membedakan LMA dengan LLA

Sebagian besar kasus, denan gambaran klinik, morfologi sel (pengecatan rutin) sudah dapat membeda-kan LMA dengan LLA. Sebagian kecil sulit dibedakan. Untuk membedakan LMA dengan LLA serta menentukan sub-tipe dari Leukemia perlu : Pemeriksaan tambahan:Pengecatan sitokimia (Sudan- black, mieloperoksidase, esterase, PAS /Perodik-Acid-Shiff, acid phosphatase), pemeriksaan marker imunologik, pemeriksaan kromosom, pemeriksaan denga mikroskop elektron.

FAB. CLASSICATION OF AML. LEUKEMIA PEROKSIDASE/ SUDAN BLACK ESTERASE SPESIFIK . CAE ++ ++ +++ + +++ - ++ NON SPESIFIK ANAE, ANBE + +++ +++ - ++ - (+ FOR CLL OR T- ALL) +++ +/+++++ +++ ++ +++ +++ +++ + /+++ +/++ ++ +++ +++ -/+ +++ f

ASSAY PAS. MURAMIDASE

TdT.

AML M 1 M2 M3 M4 M5 M6 M7 ALL

+ + +++ +++ ++ +++ + -

NETROFIL MONOSIT LIMFOSIT PLATELET

+++ + -

+++ -

Pengelolaan Leukemia Akut

Terapi suportif terhadap kegagalan ss.tulang Kemoterapi : berbeda antara LMA dan LLA, baik mengenai regimen maupun lama pengobatan. Kemoterapi LMA: induksi remisi, konsolidasi, intensifikasi (TST). Kemoterapi LLA: induksi remisi, konsolidasi, pencegahan leukemi ssp.maintenance/intensifikasi (TST)

 Pemasangan kateter v.sentral (Hickman), masuk vena cava superior melalui saluran bawah kulit dada. Memudahkan pemberian kemoterapi, produk darah, antibiotika, nutrisi parenteral, pengambilan sampel darah. Pencegahan mual dan muntah akibat kemoterapi: metoclopramide, benzodiazepin, antagonis reseptor 5-HT3 selektif (ondansentron,kytril,navoban,dll) Koreksi anemia: transfusi eritrosit (PRC) Perdarahan: bisa disebabkan oleh trombositopenia/ DIC. Transfusi trombosit diberikan bila hitung trom-bosit < 20.000/mm3, atau terdapat perdarahan ringan meskipun trombosit masih 20.000/mm3. Bila ter-dapat DIC perlu transfusi Fresh Frozen Plasma(FFP). Neutropenia merupakan resiko terjadinya infeksi terutama bila hitung neutrofil < 200/mm3. Pada pen-derita Leukemia Akut, neutrofil bisa mencapai 0 selama 2 minggu.

Terapi Suportif

 Perdarahan: bisa disebabkan oleh trombositopenia / DIC. Transfusi trombosit diberikan bila hitung trom-bosit < 20.000/mm3, atau terdapat perdarahan ringan meskipun trombosit masih 20.000/mm3. Bila ter-dapat DIC perlu transfusi Fresh Frozen Plasma(FFP). Neutropenia merupakan resiko terjadinya infeksi terutama bila hitung neutrofil < 200/mm3. Pada pen-derita Leukemia Akut, neutrofil bisa mencapai 0 selama 2 minggu. Mikroorganisme penyebab infeksi biasanya berasal dari flora komensal, bakteri gram (+), staphylococcus /streptococcus, gram (): Pseudomonas, E-coli, Proteus, Klebsiela dan golongan an-aerob. Mikro-organisme non patogen bisa berubah menjadi patogen: Staphylococcus epidermidis. bila neutrofil 0, lesi lokal superfisial dapat segera menjadi sepsis

 Virus : Herpes zooster, Herpes simplex Jamur : Candida, Aspergilosis. Protozoa: Toxoplasma gondii (bila neutropenia berlangsung lama, limfopenia, pemberian anti- biotika spektrum luas).

Pencegahan Infeksi
Isolasi penderita (reverse barriere isolation), filter udara. Sterilisasi usus: Cotrimoksasole,Neomycine, Colistine, Quinolone, Anti jamur (Fluconazole, Amphotericine B). Kultur dari urine,feses, sputum, tengorok, gusi, hidung, ujung kateter, axila, perineum. Antiseptik topikal: mandi, kumur

Pengelolaan Infeksi (lanjutan)

Panas merupakan tanda utama, segera ambil kultur, diberikan antibiotika secara empirik. Bila hasil kultur ada, segera sesuaikan anti-biotika yang sesuai.
Kombinasi antibiotika empirik: -laktam + Aminoglikosida Acylaminopenicillin + Aminoglikosida Cephalosporine + Aminoglikosida -laktam + -laktam -laktam + Aminoglikosida + Vancomycine
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Kemoterapi LLA
Induksi (hari 1-33) (Oncovin,Prednisone, Adriamycine, Mtx) Konsolidasi (hari 48-153) (Mtx.,Ara-C.,Thioguanine, Asparaginase,Cyclophosphamide). Maintanance ( 2,5 3,5 tahun ) Oncovin, Prednisone, Adramycine, 6-Mercaptopurine, Mtx., Dactinomycine. Oncovin, Prednisone, BCNU, Cyclophosphamide, 6Mercaptopurine, Mtx., Dactinomycine

Kemoterapi LMA
Ara-C + Daunorubicine ( 7+3 )

Ara-C + Daunorubicine + VP-16 (737)

Ara-C + Thioguanine

TAD (Thioguanine + Ara-C + Daunorubicine

HYDAC-37

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