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(Hodgkins Disease) Lain lain; Polisitemia vera Essential Thrombocytosis

AM

Diagnosa Keganasan Hematologi

DPL: Retikulosit Hitung jenis manual
Bone Marrow Aspirasi Cytomorphology Cytogenetic (molecular genetics) Immunophenoty ping 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

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

Monosit
Warna Inti biru-ungu spt ginjal Bentuk Sitoplasma:<<granula
halus kemerahan Sel yang paling besar

Limfosit
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

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

Masa Hidup

Bulanan-tahunan
Dikutip dari Sherwood1Thibodeau,Patton2

Tipe Tipe Leukosit Normal dalam sediaan darah

Gambar 3. Keterangan : 1. Neutrofil 2.Eosinofil

Dikutip dari Atlas Hematologi3

3. Limfosit

4.Monosit

5.Basofil

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
1 2 3 4 5

10

11

12

13

14

15

16

17

18

19

20

21

22

The Ph Chromosome: t(9;22) Translocation

9

9+

22

Ph

bcr bcr-abl abl

Fusion protein with tyrosine kinase activity

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 CMLBP 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 CMLBP Transformation from CP to AP is usually subclinical Laboratory monitoring necessary for detection of disease progression

Criteria for AP
MDACC IBMTR WHO

Blasts (%)
Blasts and promyelocytes (%) Basophils (%) Platelets (x109/L) Cytogenetics White blood cell Anemia

15
30 20 <100 CE NA NA

10
20 20 Unresponsive increase or persistent decrease CE Difficult to control or doubling in <5 d Unresponsive

10-19
NA 20 <100 or >1000 unresponsive to treatment CE not at the time of diagnosis NA NA

Splenomegaly
Other

NA
NA

Increasing
Chloromas, myelofibrosis

NA
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, contd

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

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, contd

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, contd

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, contd

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, contd
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, contd
Progression of CML to BP
BCR-ABL1 amplification Acquisition of resistance to apoptosis Genomic instability Escape from innate and adaptive immune responses Activation of -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 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 -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. 2. 3. Fase kronik( beberapa bulan 10 tahun, rata rata (3-4 tahun) Akselerasi (lekuosit meninggkat dengan cepat, relative resisten dengan pengobatan) 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
Tingk at Tingkat Penyakit Deskripsi Median survival (dalam tahun) >10 >8 6 2 2

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

Chronic Lymphocytic Leukemia

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.(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 .

Chronic Lymphocytic Leukemia

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.

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. 2. 3. Fase kronik( beberapa bulan 10 tahun, rata rata (3-4 tahun) Akselerasi (lekuosit meninggkat dengan cepat, relative resisten dengan pengobatan) 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