141330774-keganasan-hematologi

KEGANASAN HEMATOLOGI CML – CLL

Dr. Diana Paramita Sp.PD

Tumor ganas = Kanker

Tumor Solid = kanker Padat

Tumor non Solid = Kanker “Cair”

Maturasi dan Diferensiasi Stem Sel

Kelainan cytogenetic mulai pd semua tingkat stem cell

Pendahuluan :

Kegasanan hematologi :

Muncul dari single sel , sumsum tulang, thymus atau sistem limfoid perifer.

- Sel , mengalami mutasi genetiktransformasi maligna sel maligna.

- mengalami membelah (mitosis) tidak terkendali (excessive) clone sel

malignant. Dan atau resisten terhadap Apoptosis

-Mutasi lajut clone sel maligna subclone sel maligna

(Atul Mechta-Victor Hoffbrand, Hematoloogi at a Glance)

Klasifikasi :

Dasar Klasifikasi :

Berdasarkan karakter penyakit, keganasan hematologi dan limfoid dapat

dibagi :

3 KARAKTER UTAMA :

• Aggressiveness: Acute versus Chronic

• Lineage: Lymphoid versus Myeloid

• Predominant Site of Involvement: Blood and Bone Marrow versus

Tissue

masukkan diagnosis dalam kombinasi diatas , maka akan didapat

kerangka dasar klasifikasi keganasan hematologi.

Keganasan Hematologi

• LEKEMIA : Akut Mieloblastik

Limfoblastik

Kronik Mielositik

Limfositik

• Plasma Cell Myeloma= Multiple Myeloma

• Limfoma Non Hodgkin

Hodgkin(Hodgkin’s Disease)

Lain lain; Polisitemia vera

Essential Thrombocytosis

Diagnosa Keganasan Hematologi

DPL: Retikulosit

Hitung jenis manual

• Bone Marrow

• Aspirasi

• Cytomorphology

• Cytogenetic (molecular genetics)

• Immunophenotyping

• Histologi/Biopsi

KimiaDarah:elektrolit,creatinin,uric

acid,Ca,LDH

• Serologi Virus

• APTT, PT, Fibr.,D-Dimer

• SPEP pd MM atau Bcell

malignancy

• Blood Bank

•HLA

L.P. pd ALL

•CT Scan (Whole Body/mediastinum)

AM

Proposed WHO Classification of Myeloid

Neoplasms

Myeloproliferative diseases

• Chronic myelogenous leukemia, Philadelphia chromosome positive (t(9;22)(qq34;q11), BCR/ABL)

• Chronic neutrophilic leukemia

• Chronic eosinophilic leukemia/hypereosinophilic syndrome

• Chronic idiopathic myelofibrosis

• Polycythemia vera

• Essential thrombocythemia

• Myeloproliferative disease, unclassifiable JCOvol 17 no 12,1999: 3835-3849

AM

Myeloproliferatie syndrome

• CML (in chronic phase)

• CML in accelerated phase/ blastic crisis

• Myelofibrosis

• Polycythemia vera

• Essential thrombocytemia

Monosit Limfosit

Warna

Bentuk

Inti biru-ungu spt ginjal

Sitoplasma:<<granula halus kemerahan

Sel yang paling besar

Inti biru-ungu tua,>>dari sel

Sitoplasma tidak bergranula

Bentuk bulat/agak tak beraturan

Fungsi Makrofag Limfosit B : antibodi

Limfosit T : cell mediated immune response

Masa Hidup

Bulanan-tahunan

Dikutip dari Sherwood1Thibodeau,Patton2

Limfosit B : harian-tahunan

Limfosit T : 100 - 300 hari

Gambar 3. Keterangan :

1. Neutrofil 2.Eosinofil 3. Limfosit 4.Monosit 5.Basofil

Dikutip dari Atlas Hematologi3

Tipe –Tipe Leukosit Normal dalam sediaan darah

CML

• 1845: John Hughes Bennett

• Specific chromosomal abnormality Philadelphia (Ph) chromosome

• t(9;22) reciprocal chromosomal translocation – ABL1 (Abelson) protooncogene in chromosome 9

– BCR (breakpoint cluster region) in chromosome 22

• CML treatment: small molecules that target the tyrosine kinase activity of Bcr-Abl pioneered the development of targeted therapies in cancer medicine

Philadelphia Chromosome

2 3 4 5 1

7 8 9 10 11 12 6

13 14 15 16 17 18

20 21 22 X Y 19

The Ph Chromosome:

t(9;22) Translocation

Fusion protein

with tyrosine

kinase activity

bcr-abl

Ph

9+ 9

22

bcr

abl

Epidemiology

• US (2004): ± 4600 new cases

• 14% of all leukemia

• Annual incidence: 1.6 cases per

100,000 adults

• Male-female ratio 1.4:1

• Median age at diagnosis: 65 years

Etiology

• No known hereditary, familial, geographic, ethnic,

or economic associations with CML neither

preventable nor inherited

• Factor that induce Ph chromosome unknown

• Increased frequency:

– Exposure to atom bomb explosion (Japan, 1945)

– Radiologists

– Radiation therapy for ankylosing spondilitis

Clinical Presentation

• Chronic phase (CP)

• Accelerated phase (AP)

• Blast phase (BP)

Chronic Phase • Nearly 90% patients diagnosed in CP incidentally

• Competent immune system asymptomatic for

prolonged periods

• Symptoms:

– Expansion of CML cells: malaise, weight loss, discomfort

caused by splenomegaly

– Leukocytosis signs and symptoms of hyperviscosity:

retinal hemorrhage, priapism, CVA, tinnitus, confusion,

stupor

Accelerated Phase

• Increasing arrest of maturation that

usually heralds transformation to CML-

BP

• Transformation from CP to AP is usually

subclinical

• Laboratory monitoring necessary for

detection of disease progression

Criteria for AP MDACC IBMTR WHO

Blasts (%) ≥15 ≥10 10-19

Blasts and

promyelocytes (%)

≥30 ≥20 NA

Basophils (%) ≥20 ≥20 ≥20

Platelets (x109/L) <100 Unresponsive increase or

persistent decrease

<100 or >1000 unresponsive to

treatment

Cytogenetics CE CE CE not at the time of diagnosis

White blood cell NA Difficult to control or

doubling in <5 d

NA

Anemia NA Unresponsive NA

Splenomegaly NA Increasing NA

Other NA Chloromas, myelofibrosis Megakaryocyte proliferation,

fibrosis

Blast Phase

• Aggressive form of acute leukemia, highly refractory to chemotherapy, rapidly fatal

• Classic criteria – ≥30% blasts in the peripheral blood / bone marrow

– Presence of extramedullary blastic foci

• WHO: ≥20% blasts

• Immunophenotypically – Lymphoid CML-BP 20-30%

– Myeloid CML-BP 50%

– Undifferentiated 25%

Blast Phase, cont’d

• Signs and symptoms related to

increasing tumor burden

– Inability to control WBC counts with

previously stable doses of medication

– Marked constitutional symptoms (fever,

night sweats, anorexia, malaise, weight

loss)

– Splenic infarcts due to massive

splenomegaly

– Bone pain

– Increased risk of infections and bleeding

Natural History • After 3-5 years, untreated CML-CP patients inevitably

progress to CML-BP

• Risk of transformation to CML-BP: ±3-4% per year

• Most will remain in AP for 4 to 6 months before

progressing to BP

• CML-AP: median survival 1-2 years

• Lymphoid CML-BP: median survival 3-6 months,

slightly better prognosis than myeloid CML-BP

Laboratory and Pathological Features

• Leukocytosis with a remarkable left

shift, basophilia, and eosinophilia

• Platelet count: either high or low

• Mild anemia

• Leukocyte alkaline phosphatase activity

– Reduced

– May increase with infection, clinical

remission, or at the onset of BP

Laboratory and Pathological Features,

cont’d

• Increased WBC pool marked

elevation of serum B12 and unsaturated

B12- binding capacity

• During transformation to BP

increased circulating basophils and

histamine levels


cont’d

• Bone marrow

– Hypercellular and devoid of fat

– All stages of myeloid maturation, myelocytes predominant

– CP: myelocytes and promyelocytes <10%

– Megakaryocytes may increase

– Gaucher-like cells 10% of cases

– Reticulin fibrosis interaction between megakaryocytes and cytokines

– High number of blood vessels, large vascular area


cont’d

• Lymphoid CML-BP

– Blasts exhibit a B-cell immunophenotype:

CD10, CD19, CD22

– May express CD13 and CD33

• Myeloid CML-BP

– Resembles AML

– Blasts stain with myeloperoxidase

– Myeloid markers: CD13, CD33, CD117

Prognostic Systems • Sokal score

– Hazard ratio < 0.8 survival ± 2.5 years

– Hazard ratio 0.8-1.2 survival ± 3.5 years

– Hazard ratio > 1.2 survival ± 4.5 years

• Hasford score more applicable to

patients treated with interferon alfa

• Gratwohl score for patients undergoing

stem cell transplantation

Cytogenetics

• Ph chromosome t(9;22)(q34.1;q11.21) – Detected in 95% of patients with CML

– 5% of children and 15-30% of adults with ALL

– ±2% of patients with newly diagnosed AML

– Variant Ph chromosome translocation involves 3 or more chromosomes

• BCR-ABL1 hybrid gene – Present in 5% of patients with typical CML phenotype

but undetectable Ph chromosome

– Same biology and outcome as those who express Ph chromosome

Cytogenetics, cont’d

• Clonal evolution additional

cytogenetic abnormalities in Ph

chromosome-positive cells

– Trisomy 8 c-Myc overexpression

– Isochromosome 17 loss of 17p

– Duplicate Ph chromosome BCR-ABL1

overexpression

– Trisomy 19, trisomy 21, trisomy 17,

deletion 7 <10%

Cytogenetics, cont’d • Progression of CML to BP

– BCR-ABL1 amplification

– Acquisition of resistance to apoptosis

– Genomic instability

– Escape from innate and adaptive immune responses

– Activation of β-catenin in granulocyte-macrophage progenitors self-renewal capacity

– Gene methylation (Pa promoter, p15 promoter, cadherin-13)

Molecular Biology

of BCR-ABL1 • ABL1 gene human homologue of v-abl

oncogene in Abelson murine leukemia virus,

encodes a nonreceptor tyrosin kinase

• BCR encodes a protein with serine-threonine

kinase activity

• The fusion of ABL1 and BCR results in the

activation of the c-ABL protooncogene to its

oncogenic form

• BCR-ABL1 is an oncogene that promotes CML

pathogenesis

Activation of signal transduction pathways by BCR/ABL. AKT = protein kinase B; ERK =

extracellular signal-regulated kinase; JAK = Janus kinase; MEK = mitogen-activated

protein kinase; PI3K = phosphatidylinositol 3-kinase; SAPK = stress-activated protein

kinase; STAT = signal transducer and activator of transcription

Breakpoints within ABL1 gene

• Span an area of more than 300 kb

– Upstream of exon Ib

– Downstream of exon Ia

– Between exon Ia and Ib more frequent

Breakpoints within BCR • Major breakpoint cluster region (M-bcr)

– Within a 5.8 kb area spanning BCR exons e12-e16 (b1-b5)

– In most patients with CML and ⅓ with Ph-chromosome positive ALL

– Giving rise to a 210-kd hybrid protein (p210BCR-ABL)

• Minor breakpoint cluster region (m-bcr)

– An area of 54.4 kb between exons e2’ and e2

– In 2/3 of patients with Ph-chromosome positive ALL, rarely in CML

– Giving rise to an e1a2 mRNA 190-kd fusion protein p190BCR-ABL

– Marked monocytosis, may have worse prognosis than p210BCR-ABL

• μ-bcr downstream of exon 19

– Giving rise to 230-kd fusion protein (p230BCR-ABL)

– Linked to chronic neutrophilic leukemia

Chronic Myelocitic Leukemia (Leukemia granulositik kronik=LGK)

Gangguan mieloproliferasi, ditandai dengan meningkatnya netrofil dan sel

muda di perifer dan hiperseluler di sumsum tulang akibat meningkatnya seri

granulositik.

95% terjadi translokasi Chr.9 dan 22,t(9;22)

Gambaran klinis.

•Semua usia , (25-45) tahun

•Terdapat fase krinik, akselerasi dan krisis blastik

•Gejala;BB.menurun,keringat malam,gatal,sakit kepala, pandangan kabur dan

hiperviskositas (leuko.>250 ribu/ml)

•Splenomegali

•Kadangkala terjadi priapismus, oleh karena leukostasis.

Chronic Myelocitic Leukemia (Leukemia Granulositik Kronik.)

Laboratorium :

•Leukositosis > 50 ribu/ml, terutama netrofil dan terdapat metamielosit, mielosit.

•Basophilia

•Dapat disertai penggian eritrosit dan trombosit.

•Score leukosit alkali fosfatase(LAP) rendah , disertai peningkatan kadar B12

serum

•Asam urat meningkat

•Sitogenetik, terdapat Philadelphia kromosom.

Diferensial diagnosis

Perjalanan penyakit .

1. Fase kronik( beberapa bulan – 10 tahun, rata rata (3-4 tahun)

2. Akselerasi (lekuosit meninggkat dengan cepat, relative resisten

dengan pengobatan)

3. Krisi blastik (blas >30%, dapat seri limfoid atau mieloid).

Fase kronik

Fase akselerasi.

Krisis blastik

•Gambaran sesuai lekemia akut

•Ada 2 type krisis blastik: myloid type

• lymphoid type

•Blas sumsum tulang >30% (menurut WHO>20%)

Terapi.fase kronik

•Myleran

•Hydroxyurea

•Alfa interferon

•Imatinib (anti bcr-abl) (dapat digunakan pada semua fase)

•Transplantasi sumsum tulang.

•Prevensi hiperuricacidemia allopurinol.

•Pada krisis blastik sesuai dengan terapi leukemia akut.

Chronic Lymphocytic Leukemia • Insiden

– 30% dari seluruh leukemia

– Usia 50-55 tahun, pria: wanita = 2:1

• Klasifikasi

Tingkat

Tingkat Penyakit

Deskripsi Median survival

(dalam tahun)

0

I

II

III

IV

Risiko rendah

Risiko sedang

Risiko sedang

Risiko Tinggi

Risiko Tinggi

Hanya limfositosis

Limfositosis , limfadenopati

Limfositosis + splenomegali +/- limfadenopati

Limfositosis + anemia +/- limfadenopati atau splenomegali

Limfositosis + trombositopenia +/- anemia +/- splenomegali +/- limfadenopati

>10

>8

6

2

2

• Manifestasi Klinis

– Limfadenopati, splenomegali, hepatomegali, infiltrasi ke pau,

pleura, tulang, dan kulit, anemia hemolitik, trombositopenia,

hipogammaglobulinemia mudah infeksi

• Pemeriksaan Penunjang

– Kriteria:

• Hitung sel limfosit perifer > dari 10x109 (sebagian besar sel matur –

limfosit)

• BMP: >30% limfosit.

• Darah tepi perifer B-cells monoclonal.

Bila terdapat kriteria 1 + kriteria 2 atau 3. Bila Hitung sel limfosit perifer <

dari 10x109 maka kriteria 2 atau 3harus ada.

Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia.(small lymphocitic lymphoma)

•Limphoproliferative clone sel B

•Lymphocyte (kecil) terakumulasi di perifer, sumsum tulang, KGB dan

terkadang spleen.

•Umumnya pada usia tua ,55-60th , jarang <40 th. ( western.)

•Laki-laki > wanita , 1,5-2 kali lipat.

Etiology :

•Penyebab tidak diketahui pasti , dihubungkan dengan insektisida.

•Delesi Trisomy chromosome 12,a13q juga 11q.

•Mutasi atau delesi oncogenapoptosis tidak berfungsi

Gambaran klinik CLL:

•Penyakit berada dalam stadium A,B,atau C tergantung klinis dan

laboratorium

•Stadium A , sering a-simptomatik atau terdiagnose dalam pemeriksaan darah

rutine

•Limfadenopati umumnya simetris,tidak nyeri dan bergerombol

•Keringat malam, berat badan menurun dan gejala kegagalan sumsum tulang.

•Splenomegali sedang, hipogamaglobulinemia dan penurunan ,,cell mediated

immunity,,gampang infeksi bakteri dan virus.

Laboratorium

•Lymphocyte meningkat > 5000/ml,umumnya : 10-30 ribu/ml, jenis sel B, positive pada CD19,CD22 dan CD 5.

•Terdapat monoklonal IgM pada permukaan sel (pada pemeriksaan hanya terdapat rantai kappa atau rantai lamda saja)

•Serum immunoglobulin menurun

•Anemia dan trombositopenia, karena depressi sumsum tulang atau karena adanya auto antibodi atau gabungan keduanya

Staging menurut system Binet

Staging menurut Rai

Perjalanan penyakit dan prognosis

•Penyakit ditemukan pada fase awal stasioner.

•Progresi akan ditemukan pada fase lanjut

•Beberapa penderita tidak memerlukan terapi bertahun tahun.

•Pada fase agresiv transformasi menjadi large limfosit, disebut

Syndrome Richter (terminal case)

•Perjalanan penyakit berhubungan dengan asal sel; post germinal

center(baik) pre germinal center (buruk).

Terapi .

•Stadium A: observasi atau simptomatik

•Chlorambucil u/menurunkan lymphocyte ndan mengurangi

pembesaran KGB/limpa

•Corticosteroid u/ mengurangi bone marrow failure akibat infiltrasi

lymphocyte serta mengobati anemia hemolitik auto imun

/trombositopenia autoimun.

•Pada penyakit agresive:

•Purine analog(fludarabine), single / kombinasi.

•CHOP

•Spleenektomi bila limpa terlalu besar dan menggaggu.

•Terapi suportif selalu diperlukan .

• Penatalaksanaan

– Ankylating agents : klorambusil 0,1-0,4

mg/kgBB sehari per oral setiep 2 minggu.

– Radioterapi TBI(Total Body Irradiation) +

siklofosfamid & prednison tingkatkan

efektifitas terapi.

Chronic Lymphocytic Leukemia

Variant CLL

•Prolymphocytic leukemia

•Hairy cell leukemia

•T-cell variant

•Leukemia /lymphoma syndrome

Variant atau differensial diagnosis CLL

Perjalanan penyakit berbagai stadia CLL.

Terapi.fase kronik

•Myleran

•Hydroxyurea

•Alfa interferon

•Imatinib (anti bcr-abl) (dapat digunakan pada semua fase)

•Transplantasi sumsum tulang.

•Prevensi hiperuricacidemia allopurinol.

•Pada krisis blastik sesuai dengan terapi leukemia akut.

Perjalanan penyakit .

1. Fase kronik( beberapa bulan – 10 tahun, rata rata (3-4 tahun)

2. Akselerasi (lekuosit meninggkat dengan cepat, relative resisten

dengan pengobatan)

3. Krisi blastik (blas >30%, dapat seri limfoid atau mieloid).

Klasifikasi :

Dasar Klasifikasi :

Berdasarkan karakter penyakit, keganasan hematologi dan limfoid dapat

dibagi :

3 KARAKTER UTAMA :

• Aggressiveness: Acute versus Chronic

• Lineage: Lymphoid versus Myeloid

• Predominant Site of Involvement: Blood and Bone Marrow versus

Tissue

masukkan diagnosis dalam kombinasi diatas , maka akan didapat

kerangka dasar klasifikasi keganasan hematologi.

Pendahuluan :

Kegasanan hematologi :

Muncul dari single sel , sumsum tulang, thymus atau sistem limfoid perifer.

- Sel , mengalami mutasi genetiktransformasi maligna sel maligna.

- mengalami membelah (mitosis) tidak terkendali (excessive) clone sel

malignant. Dan atau resisten terhadap Apoptosis

-Mutasi lajut clone sel maligna subclone sel maligna

(Atul Mechta-Victor Hoffbrand, Hematoloogi at a Glance)

141330774-keganasan-hematologi

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