LEUKEMIA LIMFOBLASTIK

AKUT
Leukemia Limfoblastik Akut (LLA)

LLA: Keganasan klonal sel prekursor limfoid

> 80% kasus: berasal dari limposit B
Insiden 1/60.000 pertahun
75% pada usia <15 th, puncak pada 3-5 th
Lebih banyak pada pria
Saudara kandung berisiko 4x lipat.
 Epidemiologi

LLA Dewasa
5% dari semua leukemia
20% dari acute leukemia

Insiden Berdasarkan Usia

• 5,3 per 100.000/th usia <5 thn
• <1 per 100.000/th usia 20-65 thn
• 2,3 per 100.000/th usia >80 thn

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 Etiologi

Penyebab: tidak diketahui

Faktor2 yg meningkatkan resiko LLA:
 Radiasi ionik: orang2 yg selamat dari bom

hirosima beresiko 9,1 kali  LLA

 Paparan benzene

 Merokok

 Obat kemoterapi

 Infeksi EBV

 Pasien sindroma Down & Wiscott-Aldrich

 Patogenesis
Translokasi kromosom 9 dan 22 {t(9;22) (q34;q11)}
fusi gen BCR-ABL  aktivasi jalur transduksi sinyal
 proliferasi dan pertumbuhan sel meningkat.

Terjadinya delesi, mikrodelesi, rearrangement pada

gen supresor tumor yaitu: p16(INK4A) dan
p16(INK4B)  hilang/inaktivasi kontrol terhadap
progresi siklus.

Ph chromosom + : 5% pada anak

30% pada dewasa
Prevalence of the Ph Chromosome
in Haematological Malignancies

Leukaemia % of Ph+ Patients

CML 95

ALL (Adult) 15–30

ALL (Paediatric) 5

AML 2

Faderl S et al. Oncology (Huntingt).

1999;13:169-180.
Cytogenetic Abnormality of ALL:
The Ph Chromosome

1 2 3 4 5

6 7 8 9 10 11 12

13 14 15 16 17 18

19 20 21 22 x Y
 The Ph Chromosome and the bcr-abl Gene

Chromosome 22 Chromosome 9
9 q+
9 c-bcr 1 2-11 c-abl

Ph (or 22q-)
22
2-11 p210Bcr-Abl
bcr 2-11 p185Bcr-Abl
bcr-abl
Exons
abl
FUSION Introns
PROTEIN
WITH CML Breakpoints
TYROSINE
KINASE
ALL Breakpoints
ACTIVITY

t(9;22) translocation bcr-abl gene structure

 Common Cytogenetic Abnormalities in
Acute Lymphoblastic Leukemia

Lineage Karyotype

Early pre-B t(4;11)(q21;q23)

t(9;22)(q34;q11)
Pre-B t(1;14)(q32;q11)
t(1;19)(q23;p13)
t(9;22)(q34;q11)
C ALL t(9;22)(q34;q11)
B ALL t(8;14)(q24;q32)
t(2;8)(p12;q24)
t(8;22)(q24;q12)
T ALL t(8;14)(q24;q11)
t(10;14)(q24;q11)
t(11;14)(p13;q11)
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 Gambaran klinis
Anemia: mudah lelah, letargi, pusing, sesak, nyeri dada.
Anoreksia
Nyeri tulang & sendi (infiltrasi Ss tlg oleh sel lekemia)
Demam, banyak keringat (gejala hipermetabolisme)
Infeksi mulut, ISPA atas & bawah, selulitis< sepsis.
Perdarahan pada kulit, gusi, sal cerna, otak, hematuria.
Hepatomegali
Spleenomegali
Limfadenopati
Massa di mediastinum (sering pd LLA sel T)
Leukemia SSP (nyeri kepala , muntah (gejala TIK),
perubahan status mental, kelumpuhan syaraf otak, kelainan
neurologik fokal
Keterlibatan organ lain: testis, retina, kulit, pleura,
perikardium, tonsil
 Gambaran Laboratorium

Umumnya: anemia & trombositopenia (15%

penderita trombosit <25.000)
Hitung leukosit: normal, meningkat, menurun.
Lekosit > 100.000 pada 15% penderita.
Proporsi sel blas bervariasi (0-100%).
Sumsum tulang hiperseluler dengan blas
leukemia > 30%
LLA & LMA sulit dibedakan dengan melihat
morfologi sel blas pada apus darah tepi / BMP
BMP

BMP:
hiperseluler dg
limfoblas yg
sangat banyak,
>90% sel berinti
pada LLA
dewasa.
Klasifikasi Morfologi FAB
L1: Sel Blas berukuran kecil,
seragam, sitoplasma sedikit, dan
nukleoli tidak jelas.

L2: Sel blas berukuran besar,

heterogen, nukleoli jelas, ratio inti-
sitoplasma rendah.

L3: Sel blas dengan sitoplasma

bervakuola dan basofilik
 Table Morphologic Classification of Acute Lymphoblastic Leukemia
L1 L2 L3
Cell Size Small cells Large cells, Large &
predominate heterogeneous in size homogeneous
Nuclear chromatin Homogenous in any Variable-heteroge- Finely stippled and
one case neous in any one case homogeneous
Nuclear shape Regular occasional Irregular; clefting and Regular—oval to
clefting or indentation indentation common round
Nucleoli Not visible, or small One or more present; Prominent; one or
and inconspicuous often large more vesicular
Amount of Scanty Variable; often Moderately abundant
cytoplasm moderately abundant
Basophilia of Slight or moderate, Variable; deep in some Very deep
cytoplasm rarely intense
Cytoplasmic Variable Variable Often prominent
vacuolation
In 1976 the French-American-British Cooperative group, using morphology lone, divided ALL into three
subtypes. This classification gained acceptance, and some modifications have been introduced.

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 Sitokimia
Pewarnaan sudan black dan
myeloperoksidase: (+) pada
LMA (membedakan dari LLA)

Pewarnaan asam fosfatase: (+)

pada LLA sel T yg ganas

Pewarnaan periodic acid schiff

(PAS): (+) pada LLA sel B
 Imunofenotif

Berguna untuk diagnosis dan klasifikasi

Reagen yg dipakai utk identifikasi subtipe
imunologi adalah antibodi terhadap:
 Utk sel prekursor B: CD10 (common ALL
antigen), CD19, CD79A, CD22, cytoplasmic m-
heahy chain, & TdT
 Utk sel T: CD1a, CD2, CD3, CD4, CD5, CD7,
CD8. & TdT
 Utk sel B: kappa & lamda, CD19, CD20, &
CD22
 Klasifikasi Imunologi

Klasifikasi imunologi (berdasarkan ada / tidak adanya

berbagai antigen permukaan sel, yaitu:
 Precursor B-acute Lymphoblastic Leukaemia

(70%)
Common ALL,
Null ALL (banyak pada dewasa),
Pre-B ALL
 T-ALL (25%)

 B-ALL (5%), merupakan penyakit yg jarang, dg

morfologi L3, sering berprilaku sbg limfoma agresif

(varian burkitt)
 Table Immunologic Classification of Acute Lymphoblastic Leukemia
Subtype % Usual Immunophenotype
Morphology
B Lineage

Early pre-B 11 L1 or L2 CD19+,CyD22+CD24+HLADR+TdT+,CyIgM-

Pre-B 9 L1 CD10±CD19,CyCD22+CD24+CyIgM+,HLADR+Td
T+
C- ALL 52 L1 or L2 CD10+CD19,CyCD22+CD24+,CyIgM-,HLADR+
TdT+
B- ALL 4 L3 CD10±CD19,CyCD22+CD24+,CyIgM-,HLADR+,
TdT-
T Lineage

Pre-T 6 L1 or L2 CD7+,CD3+,CD2-,HLADR±,TdT+

Pre-T 18 L1 or L2 CD7+,CD3+,CD2+,HLADR-,TdT±

The Immunologic classification of ALL is based on the expressions of surface (S) and cytoplasmic (Cy)
markers. The morphologic subtypes were added to show the fact that the microscopic characteristics of the
lymphoblasts are not completely specific.
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 Pemeriksaan Lain

Parameter koagulasi: biasanya normal

Asam urat: hiperurikemia terutama pada
pasien dengan sel2 leukemia yg cepat
membelah.
Pungsi lumbal. Definisi keterlibatan SSP:
bila >5 lekosit/ml LCS dg morfologi sel
blas pada spesimen yang sudah di
sentrifugasi.
 Diagnosis Banding

Limfositosis, limfadenopati dan

hepatosplenomegali yang berhubungan
dengan infeksi virus dan limfoma.

Anemia aplastik: pansitopenia

ITP: petekie, ekimosis, dan perdarahan yg

bersifat akut.
 Terapi

 Keberhasilan terapi LLA tgt: Kontrol

sutul & peny. sistemik
 Lama terapi:1,5 – 3 th eradikasi
 Dibagi:
 Induksi remisi

 Intensifikasi atau konsolidasi

 Profilaksis susunan saraf pusat (SSP)

 Pemeliharaan jangka panjang

Terapi induksi

Tujuancapai remisi komplit hematologi =

eradikasi sel lekemia  tidak terdeteksi dl darah
& sutul & parameter hematologi kembali normal
Prednison, vinkristin, antrasiklin (daunorubisin),
L-asparginase
Prednison & vinkristin  CR 50%  +antrasiklin
 70-80%
Mortalitas tergantung  th/ suportif & GSCF
mempersingkat netropeni & trnkan insiden
infeksi
Induksi:
 CR 75-80%: V,A, P = 70%
 CR >80% : V, A, Cy, La, Ara-C
 HYPERCVAD : CR 91%
(Hd.MTX)
 INTENSIVE ANTHRACYCLINE: CR 93%
 PEG L.A.+V,P,D = CR 93%
Terapi Intensifikasi / Konsolidasi
Tujuan eliminasi sel lekemia residual cegah
relaps & sel resisten obat
Dilakukan 6 bln kemudian

Profilaksis SSP
Jk tdk profilaksis 50-70% relaps SSP
Busulpan kombinasi kemotherapi intratekal,
radiasi kranial (Mtx, sitarabin) dosis tinggi

Pemeliharaan jangka panjang

 6-merkaptopurin/hr & Mtx/mgg slm 2-3th
Sebelum kemoterapi perbaiki:
Metabolik: hiperurisemia, hiperfosfatemia,
hipokalsemiahidrasi i.v, alkaliniasi urin, alupurinol
Infeksi: ok imunitas seluler tertekan pencegahan
Hematologik: hiperlekositosis transf sdm (-)
viskositas darah mngktleukofaresis & prednison 7
hr / vinkristin (sbl th/ induksi remisi dimulai)
Hiperlekositosis low dose CS, vincristin,
cyclofospamid
 Protokol Terapi ALL dewasa

Protokol OPAL modified

Hiper-CVAD
LALA 87
CALGB
 Transplantasi

Transplantasi sutul allogenik pd remisi

komplit pertama
Risisko tinggi relaps:
 Kromosom philadelphia
 Perubahan susunan sel MLL
 Hiperleukositosis
 Gagal remisi komplit dl 4 mgg
 Pilihan Terapi & Pengelolaan
Baru Untuk LLA Dewasa

Induksi terapi yang singkat

erapi molekuler: inhibisi direk aberasi
molekuler yg terlibat dalam patogenesis
Transplantasi sutul non mieloblast
Evaluasi minimal residual disease
Analisis mikroarray
THE MANAGEMENT OF ADULT ALL
New Strategies:

 Shortened and intesified induction therapy

 High dose consolidation with stem cell
apheresis
 New modalities for stem cell
transplantation,
including allogeneic “mini” transplants
 Treatment adapted to minimal residual
disease
 Most recently new”causative” treatment
approaches, such as STI-571 ini Ph/BCR-
NEJM1998:339;9
 Prognosis

30% bertahan hidup lama.

15-20%  sembuh dg kemotherapi (15-
20th)
30% masa bebas penyakit semua usia
Usia > 60 th masa bebas penyakit 10%
Anak: 90% CR

75% LTS

Dewasa: 65-80% CR

30-40% LTS

LTS = Long Time Survival

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Faktor Yang Berkorelasi Dengan Durasi Remisi
Factor Good Prognosis Bad Prognosis
Time to complete <4 weeks >4 weeks
remission
Age <35 years >35 years
Leukocyte count <30,000/l >30,000/l (B-liniage)
>100,000/μl (T-
liniage)
Immunophenotype c-ALL Pro B-ALL
T-ALL Pre/Pro T-ALL
Mature T ALL (?)
Cytogenetic t(4;11)/ALL1-AF4
abnormalities Normal Diploid Karyotipe (?)
t(9;22)/BCR-ABL
Hiperdiploid Karyotipe (?)

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Terima kasih
 Protokol OPAL modified
Induksi Remisi:
 Vinkristin 1,5 mg/m2, hr I (max 2mg)
 Daunorubisin30 mg/m2 IV hr 1,2,14,21,28
 Prednison 40mg/m2 PO hr 1-28 tape of 2 mgg
 L-asparginase 10.000U/m2 IV sat remisi komplit 4 hr sbl
radiasi kranial (cek fibrinogen, jk <100mg/dl FFP)
 Pemberian Mtx intratekal protokol
 Aspirasi sutul mgg ke % jk trombo>100.000/mm3 & netr >
1000 (resp komplit)
Dosis pemeliharaan : 6 MP 70-90 mg/m2 PO, MTx 15
mg/m2 PO tiap mgg 3 thn cek Apus sutul, LCS,
biopsi testis remisi  obat di stop. Target leko: 3000-
3500/mm3 jk meningkat  dosis Mtx dinaikan
 Protokol OPAL modified
Pencegahan infiltrasi ke SSP
 Pd saat remisi lengkap
 Radiasi kranial 2400 rad dlm do terbagi (200 rad/kali)
 MTx intratekal 10mg/m2, 2 kali seminggu  5 dosis
Modifikasi dosis
 Vinkristin 1mg bl bilirubin > 2 mg%
 Doksorubisin turun 25%  BR 2-3mg%; 50% jk 3-4 mg%; 75%
jk >4mg%
 Mtx 25% jk kreatinin 1,5-2mg%; 50% jk >2 mg%
 HIDAC 1 gr/m2 jk
Usia > 60 th
Kreatinin > 2mg%
Kadar Mtx > 20 mmol/L
ALL
Four phases of thepay :
1. Remission induction
2. Prophylactic tretment of CNS
3. Consolidation
4. Maintenance

- Several camplex regimens have ben develop

- Sanctuary sites :
- CNS :
- Intrathecal chemotherapy as efficacious as
cranial irradiation ( IT methotrexat for low risk and
intermediate risk ALL, combined IT methe trexat,
hydrocortisone, cytosine arabinoside for highrisk ALL)
 - CNS relapse requires systemic therapy along
with treatment of CNS (cranial irradiation 24 Gy plus
combined triple IT therapy)

- testes
- Testicular relapse in first marrow remission in
accounts for 6% of treatment failure
- Early testicular relapse indicates poor prognosis
- Late relapse aftercessation of maintenance is
compatible with subsequent long disease free survival
after treatment.
- treatment recommended is 20 Gy in 2-Gy
fraction, and systemic reinduction
- Allogenic marrow transplantation is under study. May
be indicated if there is an appropriate donor in the
following situation :
- Refractory ALL
- Childhood ALL in second remission
- High risk adult ALL in first remission

- Allopurinol is administered to patients with

hiperuricemia or who appear likely to develop it.

- Patient who develop fever while reveiving antileukemic

therapy must be carefuly evaluated for infection and
receive antimicrobial therapi as appropriate
 - CNS relapse requires systemic therapy along
with treatment of CNS (cranial irradiation 24 Gy plus
combined triple IT therapy)

- testes
- Testicular relapse in first marrow remission in
accounts for 6% of treatment failure
- Early testicular relapse indicates poor prognosis
- Late relapse aftercessation of maintenance is
compatible with subsequent long disease free survival
after treatment.
- treatment recommended is 20 Gy in 2-Gy
fraction, and systemic reinduction
- Allogenic marrow transplantation is under study. May
be indicated if there is an appropriate donor in the
following situation :
- Refractory ALL
- Childhood ALL in second remission
- High risk adult ALL in first remission

- Allopurinol is administered to patients with

hiperuricemia or who appear likely to develop it.

- Patient who develop fever while reveiving antileukemic

therapy must be carefuly evaluated for infection and
receive antimicrobial therapi as appropriate