Upload
kapingroup-mentari
View
202
Download
10
Embed Size (px)
Citation preview
KEGANASAN HEMATOLOGICML – 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
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
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 51
7 8 9 10 11 126
13 14 15 16 17 18
20 21 22 X Y 19
The Ph Chromosome: t(9;22) Translocation
Fusion proteinwith 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
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 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
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
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
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
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
• 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)
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
• 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.
Tumor ganas = Kanker
Tumor Solid = kanker Padat
Tumor non Solid = Kanker “Cair”
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)
Tumor ganas = Kanker
Tumor Solid = kanker Padat
Tumor non Solid = Kanker “Cair”
Tumor ganas = Kanker
Tumor Solid = kanker Padat
Tumor non Solid = Kanker “Cair”