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

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
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 Sherwood
1
Thibodeau,Patton
2


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 Hematologi
3


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
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 (x10
9
/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, 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
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,
contd
Increased WBC pool marked
elevation of serum B
12
and unsaturated
B
12
- 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 (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 ALL, rarely in CML
Giving rise to an e1a2 mRNA 190-kd fusion protein p190
BCR-ABL
Marked monocytosis, may have worse prognosis than p210
BCR-ABL

-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.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
Tingk
at
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 ,55-60
th
, 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