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KEGANASAN HEMATOLOGI CML – CLL Dr. Diana Paramita Sp.PD

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Page 1: KEGANASAN HEMATOLOGI

KEGANASAN HEMATOLOGICML – CLL

Dr. Diana Paramita Sp.PD

Page 2: KEGANASAN HEMATOLOGI

Tumor ganas = Kanker

Tumor Solid = kanker Padat

Tumor non Solid = Kanker “Cair”

Page 3: KEGANASAN HEMATOLOGI

Maturasi dan Diferensiasi Stem Sel

Kelainan cytogenetic mulai pd semua tingkat stem cell

Page 4: 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)

Page 5: KEGANASAN HEMATOLOGI

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.

Page 6: 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

Page 7: KEGANASAN HEMATOLOGI

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

Page 8: KEGANASAN HEMATOLOGI

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

Page 9: KEGANASAN HEMATOLOGI

Myeloproliferatie syndrome

• CML (in chronic phase)• CML in accelerated phase/ blastic crisis• Myelofibrosis• Polycythemia vera• Essential thrombocytemia

Page 10: KEGANASAN HEMATOLOGI

Monosit Limfosit

WarnaBentuk

Inti biru-ungu spt ginjalSitoplasma:<<granula halus kemerahanSel yang paling besar

Inti biru-ungu tua,>>dari selSitoplasma tidak bergranula

Bentuk bulat/agak tak beraturan

Fungsi Makrofag Limfosit B : antibodiLimfosit T : cell mediated immune response

Masa Hidup

Bulanan-tahunan

Dikutip dari Sherwood1Thibodeau,Patton2

Limfosit B : harian-tahunanLimfosit T : 100 - 300 hari

Page 11: KEGANASAN HEMATOLOGI

Gambar 3. Keterangan :1. Neutrofil 2.Eosinofil 3. Limfosit 4.Monosit 5.Basofil

Dikutip dari Atlas Hematologi3

Tipe –Tipe Leukosit Normal dalam sediaan darah

Page 12: KEGANASAN HEMATOLOGI

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

Page 13: KEGANASAN HEMATOLOGI

Philadelphia Chromosome

2 3 4 51

7 8 9 10 11 126

13 14 15 16 17 18

20 21 22 X Y 19

Page 14: KEGANASAN HEMATOLOGI

The Ph Chromosome: t(9;22) Translocation

Fusion proteinwith tyrosine

kinase activity

bcr-abl

Ph

9+9

22

bcr

abl

Page 15: KEGANASAN HEMATOLOGI

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

Page 16: KEGANASAN HEMATOLOGI

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

Page 17: KEGANASAN HEMATOLOGI

Clinical Presentation

• Chronic phase (CP)• Accelerated phase (AP)• Blast phase (BP)

Page 18: KEGANASAN HEMATOLOGI

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

Page 19: KEGANASAN HEMATOLOGI

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

Page 20: KEGANASAN HEMATOLOGI

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

Page 21: KEGANASAN HEMATOLOGI

Criteria for APMDACC 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

Page 22: KEGANASAN HEMATOLOGI

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%

Page 23: KEGANASAN HEMATOLOGI

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

Page 24: KEGANASAN HEMATOLOGI

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

Page 25: KEGANASAN HEMATOLOGI

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

Page 26: KEGANASAN HEMATOLOGI

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

Page 27: KEGANASAN HEMATOLOGI

Laboratory and Pathological Features, 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

Page 28: KEGANASAN HEMATOLOGI

Laboratory and Pathological Features, 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

Page 29: KEGANASAN HEMATOLOGI

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

Page 30: KEGANASAN HEMATOLOGI

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

Page 31: KEGANASAN HEMATOLOGI

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

Page 32: KEGANASAN HEMATOLOGI

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%

Page 33: KEGANASAN HEMATOLOGI

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)

Page 34: KEGANASAN HEMATOLOGI

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

Page 35: KEGANASAN HEMATOLOGI

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

Page 36: KEGANASAN HEMATOLOGI

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

Page 37: KEGANASAN HEMATOLOGI

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

Page 38: KEGANASAN HEMATOLOGI

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)

Page 39: KEGANASAN HEMATOLOGI

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.

Page 40: KEGANASAN HEMATOLOGI

Chronic Myelocitic Leukemia (Leukemia Granulositik Kronik.)

Page 41: KEGANASAN HEMATOLOGI

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.

Page 42: KEGANASAN HEMATOLOGI

Diferensial diagnosis

Page 43: KEGANASAN HEMATOLOGI

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).

Page 44: KEGANASAN HEMATOLOGI

Fase kronik

Page 45: KEGANASAN HEMATOLOGI

Fase akselerasi.

Page 46: KEGANASAN HEMATOLOGI

Krisis blastik

•Gambaran sesuai lekemia akut

•Ada 2 type krisis blastik: myloid type

• lymphoid type

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

Page 47: KEGANASAN HEMATOLOGI

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.

Page 48: KEGANASAN HEMATOLOGI
Page 49: KEGANASAN HEMATOLOGI

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)

0III

III

IV

Risiko rendahRisiko sedang

Risiko sedang

Risiko Tinggi

Risiko Tinggi

Hanya limfositosisLimfositosis , limfadenopatiLimfositosis + splenomegali +/-

limfadenopatiLimfositosis + anemia +/-

limfadenopati atau splenomegali

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

>10>86

2

2

Page 50: KEGANASAN HEMATOLOGI

• 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

Page 51: KEGANASAN HEMATOLOGI

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

Page 52: KEGANASAN HEMATOLOGI

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.

Page 53: KEGANASAN HEMATOLOGI

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

Page 54: KEGANASAN HEMATOLOGI

Staging menurut system Binet

Page 55: KEGANASAN HEMATOLOGI

Staging menurut Rai

Page 56: KEGANASAN HEMATOLOGI

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).

Page 57: KEGANASAN HEMATOLOGI

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 .

Page 58: KEGANASAN HEMATOLOGI

• 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

Page 59: KEGANASAN HEMATOLOGI

Variant CLL

• Prolymphocytic leukemia

• Hairy cell leukemia

• T-cell variant

• Leukemia /lymphoma syndrome

Page 60: KEGANASAN HEMATOLOGI

Variant atau differensial diagnosis CLL

Page 61: KEGANASAN HEMATOLOGI

Perjalanan penyakit berbagai stadia CLL.

Page 62: KEGANASAN HEMATOLOGI

Tumor ganas = Kanker

Tumor Solid = kanker Padat

Tumor non Solid = Kanker “Cair”

Page 63: KEGANASAN HEMATOLOGI

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.

Page 64: KEGANASAN HEMATOLOGI

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).

Page 65: KEGANASAN HEMATOLOGI

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.

Page 66: 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)

Page 67: KEGANASAN HEMATOLOGI

Tumor ganas = Kanker

Tumor Solid = kanker Padat

Tumor non Solid = Kanker “Cair”

Page 68: KEGANASAN HEMATOLOGI
Page 69: KEGANASAN HEMATOLOGI

Tumor ganas = Kanker

Tumor Solid = kanker Padat

Tumor non Solid = Kanker “Cair”