KEGANASAN HEMATOLOGI

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

Tumor gana ganass

=

Kanker Kank er

Tumor Solid = kanker Padat

Tumor non Solid = Kanker “Cair”

Maturasi dan Diferensiasi Stem Sel

Pendahuluan : Kegasanan hematologi :

Muncul dari single sel , sumsum tulang, thymus atau sistem limfoid perifer. - Sel , mengalami mutasi genetik transformasi 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 Mechta-Victor Hoffbrand, Hematoloogi at a Glance)

Klasifikasi : Dasar Klasifikasi : Berdasarkan karakter penyakit, keganasan hematologi dan limfoid dapat dibagi : 3 KARAKTER UTAMA : • Aggressivenes Aggressiveness: s: Acute Acute versus Chronic • Lineage: Lymphoid Lymphoid versus versus Myeloid • Predominant Site of Involvement: Blood and Bone Marrow versus Tissue masukkan diagnosis dalam kombinasi diatas , maka akan didapat kerangka dasar klasifikasi keganasan k eganasan 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

AM

Diagnosa Keganasan Hematologi DPL: Retikulosit Hitung jenis manual • Bone Marrow • Aspirasi • Cyto Cytom morphology • 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 of Myeloid 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

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

Monosit Warna Inti biru-ungu spt ginjal Bentuk Sitoplasma:<
Fungsi Makrofag

Masa Hidup

Bulanan-tahunan

Limfosit Inti biru-ungu tua,>>dari sel Sitoplasma tidak bergranula Bentuk bulat/agak tak beraturan

Limfosit B : antibodi Limfosit T : cell mediated immune response Limfosit B : harian-tahunan Limfosit T : 100 - 300 hari

Tipe – Tipe –T Tipe Leukosit Normal dalam sediaan darah

Gambar 3. Keterangan : 1. Neutrofil 2.Eosinofil

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 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 Chromosom Chromosome e 1

2

3

6

7

8

13

14

15

19

20

9

21

4

5

10 10

11

12

16

17

22

X

18

Y

The Ph Chromosome: t(9;22) Translocation 9

9+

22

Ph

b c r bcr-abl

ab l

Fusion protein with tyrosine kinase activity

Epidemiology • US (2004): ± 4600 new cases • 14% of all leukemia • Annual incidence: incidence: 1.6 cases 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 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 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 (%)

≥15

≥10

10-19

Blasts and promyelocytes 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

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 eosinophili eosinophilia a • 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 – 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

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



– Hazard ratio 0.8-1.2 – Hazard ratio > 1.2

survival ± 2.5 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 overexpression



BCR-ABL1

– 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 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 transduction pathway pathways s by BCR/ABL. AKT = protein protein kinase B; 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 transcript transcription ion

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 Ph-chromosome positive ALL – Giving rise to a 210-kd hybrid protein (p210 BCR-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 positive ALL, rarely in CML – Giving rise to an e1a2 mRNA  190-kd fusion protein p190BCR-ABL – Marked monocytosis, may have worse prognosis than p210 BCR-ABL • μ-bcr downstream of exon 19 – Giving rise to 230-kd fusion protein (p230 BCR-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 Chr.9 .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 Fa se kro ron nik ik(( be beb ber erap apaa bu bula lan n

2.

Akselerasi Akseler asi (lek (lekuos uosit it men mening inggka gkatt deng dengan an cep cepat, at, rel relativ ativee res resiste isten n dengan pengobatan)

3.

Kris Kr isii blast blastik ik (bl (blas as >30 >30%, %, dap dapat at ser serii limfo limfoid id ata atau u mielo mieloid id). ).

–

10 tahun, rata rata (3-4 tahun)

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

0 I II

Tingkat Penyakit

III

Risiko rendah Risiko sedang Risiko sedang

IV

Risiko Tinggi Risiko Tinggi

Deskripsi

Hanya limfositosis Limfositosis , limfadenopati Limfositosis + splenomegali +/limfadenopati Limfositosis + anemia +/limfadenopati atau splenomegali Limfositosis + trombositopenia +/- anemia +/- splenomegali +/- limfadenopati

Median survival (dalam tahun) >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 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 perifer < dari 10x109 10x109 maka kriteria 2 atau 3harus ada.

Chronicc lymphocytic leukemia .(small lymphocitic lymphoma) Chroni Limphoproliferative Limphoproliferat ive clone sel B

•

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

Umumnya pada usia tua ,55-60th , jarang <40 th. ( western.) 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 oncogenapoptosis 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 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 cente r (buruk). •

Terapi .

Stadium A: observasi atau simptomat simptomatik ik

•

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 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 gana ganass

=

Kankerr Kanke



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 Fa se kro ron nik ik(( be beb ber erap apaa bu bula lan n

2.

Akselerasi Akseler asi (lek (lekuos uosit it men mening inggka gkatt deng dengan an cep cepat, at, rel relativ ativee res resiste isten n dengan pengobatan)

3.

Kris Kr isii blast blastik ik (bl (blas as >30 >30%, %, dap dapat at ser serii limfo limfoid id ata atau u mielo mieloid id). ).

–

10 tahun, rata rata (3-4 tahun)

Klasifikasi : Dasar Klasifikasi : Berdasarkan karakter penyakit, keganasan hematologi dan limfoid dapat dibagi : 3 KARAKTER UTAMA : • Aggressivenes Aggressiveness: s: Acute Acute versus Chronic • Lineage: Lymphoid Lymphoid versus versus Myeloid • Predominant Site of Involvement: Blood and Bone Marrow versus Tissue masukkan diagnosis dalam kombinasi diatas , maka akan didapat kerangka dasar klasifikasi keganasan k eganasan hematologi.

Pendahuluan : Kegasanan hematologi :

Muncul dari single sel , sumsum tulang, thymus atau sistem limfoid perifer. - Sel , mengalami mutasi genetik transformasi 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 Mechta-Victor Hoffbrand, Hematoloogi at a Glance)

Tumor gana ganass

=

Kanker Kank er



Tumor gana ganass

=

Kankerr Kanke



KEGANASAN HEMATOLOGI

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