FARMAKOTERAPI KANKER

LIMFOMA NON HODGKINS

 Haematopoietic Malignancies

Myeloproliferative Malignant
diseases Leukaemias lymphomas

chronic myeloid Acute myeloid Hodgkin’s

leukaemia leukaemia lymphoma
(CML) (AML)

Polycythemia Chronic myeloid Non-hodgkin’s

vera leukaemia lymphoma
(PV) (CML) (NHL)

Idiopathic Acute lymphatic

myelofibrosis leukaemia Burkitt's lymphoma
(MF) (ALL)
cutaneous T-cell
Essential Chronic lymphatic lymphoma (CTCL)
thrombocythemia leukaemia
(ET) (CLL)

hairy cell
leukaemia
(HCL)
 I. DEFINISI
Haematopoietic Malignancies

Myeloproliferative Malignant
Leukaemias
diseases lymphomas
 Family of chronic  Neoplastic  Neoplastic
neoplastic disease of a disease of
diseases haematopoietic lymphatic tissue
precursor cell
 Due to a clonal  Originates in
disorder arising  Characterised by lymph node or
at the level of the replacement of spleen
pluripotent stem normal bone
 Hodgkin’s (15%)
cell marrow
 non-Hodgkin’s
 Characterised by  Often infiltration
abnormal into other organs (85%)
proliferation of 1
 Malignant clones
or more blood cell
lines suppress normal
cell formation
II. EPIDEMIOLOGI

 LNH menempati urutan kelima saat ini d

Amerika,
di Indonesia sendiri LNH bersama LH dan
leukemia menempati urutan keenam
tersering.
 Insiden usia puncak LH : usia 20-30 tahun
dan usia diatas 50 tahun
 Insiden LNH mencapai puncak pada usia
80-84 tahun
III. ETIOLOGI

1. Etiologi sebagian besar LNH tidak diketahui.

Namun terdapat beberapa faktor resiko terjadinya
LNH, antara lain :
a. Imunodefisiensi
kelainan herediter langka, seperti : severe
combined immunodeficiency, hypogamma-
globulinemia, seringkali dihubungkan pula
dengan Epstein-Barr virus (EBV)
2. Agen Infeksius : Epstein-Barr virus (EBV)
3. Paparan Lingkungan dan Pekerjaan :
paparan herbisida dan pelarut organik.
4. Diet dan Paparan Lainnya
 Resiko LNH meningkat pada orang
yang mengkonsumsi makanan tinggi
lemak hewani, merokok, dan yang terkena
paparan unlraviolet.
IV. MANIFESTASI KLINIK
Limfoma memilki gejala relatif yang khas, berupa :
 Demam tinggi 38oC tanpa sebab jelas (pada LH
disebut panas Pel-Ebstein)
 Keringat malam hari,
 Penurunan berat badan 10% dalam waktu 6 bulan
 Tampak limfedenopati bagian leher, aksila,
inguinal, dan kelenjar limfe mandibula.
Limfedenopati sering kali asimetri, konsistensi
padat dan kenyal, tidak nyeri.
V. PENENTUAN STADIUM

Perbandingan Penggolongan stadium Lymphoma Non Hodgkins menurut

European Guideline VS American Guideline VS Indonesian Guideline

European Guideline 2019 VS American Guideline 2019

VS Indonesian Guideline 2019

 Revised European-American Lymphoma
(REAL) Classification: B-Cell Neoplasms

Indolent Aggressive Very Aggressive

CLL/SLL PLL Precursor
Lymphoplasmacytic/ Plasmacytoma/ B-lymphoblastic
IMC/WM Multiple myeloma lymphoma/
Leukemia
HCL MCL
Burkitt’s
Splenic marginal Follicle centre
lymphoma/
zone lymphoma lymphoma, follicular,
B-cell acute
MZL grade III
leukemia
- Extranodal (MALT) DLCL Plasma cell
- Nodal Primary mediastinal leukemia
Follicle center large B-cell lymphoma
lymphoma, follicular, High-grade B-cell
grade I-II lymphoma/Burkitt’s-
like

Hiddemann. Blood. 1996;88:4085.

 REVISED STAGING SYSTEM FOR
PRIMARY NODAL LYMPHOMAS

Stage Involvement Extranodal status (E)

Limited
Single extranodal lesion without nodal
Stage I One node or group of adjacent nodes
involvement
Two or more nodal groups on the same Stage I or II by nodal extent with limited,
Stage II
side of the diaphragm contiguous extranodal involvement

Stage II bulky II as above with bulky disease N/A

Tonsils, Waldeyer’s ring, and spleen are considered nodal tissue.

Whether stage II bulky disease is treated as limited or advanced disease may be determined
by histology and a number of prognostic factors.

Cheson BD, et al. JCO 2014;32(27):3059-68

 REVISED STAGING SYSTEM FOR
PRIMARY NODAL LYMPHOMAS

Stage Involvement Extranodal status (E)

Advanced
Nodes on both sides of the diaphragm
Stage III Nodes above the diaphragm with spleen N/A
involvement
Additional non-contiguous extranodal
Stage IV N/A
involvement

Cheson BD, et al. JCO 2014

Ann Arbor Classification & Costwold
Modification
non-Hodgkin Lymphoma
Ann Arbor Staging

A= no symptoms
B= fever (unexplained)
night sweats
weight loss >10%
Staging of NHL
Staging of NHL
VI. DIAGNOSIS

 History/ Physical examination

 CT scan thorax
 CT scan abdomen
 PET scan: aggressive lymphomas
 Bone marrow biopsy
CT scans in lymphoma
PET scan in lymphoma
VII. PENATALAKSANAAN

General Principles :
 It is (still ) not possible to select a specific treatment for
each type of NHL

 Therefore NHL are divided into major subgroups:

 Indolent types (follicular lymphoma)

 Aggressive types (diffuse large B cell lymphoma)
 Very aggressive types (Burkitt)
Treatment of non-Hodgkin
lymphoma
considerations as to choice of therapy
 Type of lymphoma (REAL classification)
 Ann Arbor stage (I to IV)
 localizations
 Risk profile/prognostic score of the patient
 Which treatment is possible?
Treatment of non-Hodgkin
lymphoma

Indolent (stage II-IV)* Aggressive (stage II-IV)

**
 “Wait and see”
• CHOP chemotherapy
1x / 3 weeks,8x
 (mild) chemotherapy

 (low dose) radiotherapy

* Stage I(II): high dose radiotherpy ** Stage I: 3x CHOP + radiotherapy
 Therapy of aggressive NHL

 polychemotherapy
 golden standard : CHOP

Drug Dose Route Day

Cyclophosphamide 750 mg/m2 i.v. 1

Doxorubicin 50 mg/ m2 i.v. 1

(hydroxydaunorubicine)
Vincristine (oncovin) 1.4 mg/ m2 * i.v. 1

Predniso(lo)ne 100 mg p.o. 1-5

* max. dose per cycle: 2 mg

Survival of NHL patients (till 2004)

100%

indolent

50%
aggressive

very aggressive

10 20
Years since diagnosis
The results of the treatment of
patients with NHL have been
improved impressively by the use
of antibodies directed against the
lymphoma cells
Rituximab (mabthera®) : a mouse/ human
chimeric anti- CD20 monoclonal antibody
Murine variable regions
bind specifically to CD20 on
normal/ malignant B-cells

Human K constant regions

Human IgG1 Fc domain

• interacts with human effector
mechanisms (ADCC, CDC)
• low immunogenicity
 Anti-CD20 (Rituximab= Mabthera®)
mechanism of action

CD20 Malignant B-cell

Killer Complement
Leukocyte

CD20

Direct
induction of
apoptosis

Adapted from Male D, et al., Advanced Immunology 1996: 1.1–1.16

 New developments in the treatment of lymphoma

 New monoclonal antibodies (HumaxCD20, CD22)

 Radio-immunotherapy

 New agents (bortezomib, lenalidomide, bendamustine, apoptosis-

inducers, small molecules)

 New combinations

 Allogeneic SCT (RIST)

 non-Hodgkin’s lymphoma
Why treatment with antibodies?

• With present chemotherapy no or insufficient

cure
• Treatment of minimal residual disease after
chemotherapy might improve prognosis
• Antibodies are more specific than cytostatic
drugs
• Antibodies are less toxic
• Antibodies have a different mechanism of action
DLCL in the elderly :
Rituximab improves overall survival
Probability of overall survival

1.
0

0.
8 59% Rituximab + CHOP

0.
6
47% CHOP
0.
4

0.
2 p=0.01

0 0 1 2 3 4 5
Years

Coiffier et al.
B Cell Neoplasm
TATALAKSANA
I. Precursor B-cell neoplasm : Precursor B-
Pilihan terapi bergantung pada beberapa hal, antara lain: tipe
Acute Lymphoblastic Leukemia/lymphoblastic lymphoma
II. Peripheral B-cell neoplasms limfoma (jenis histologi), stadium, sifat tumor (indolen/agresif), usia,

A. B-cell chronic lymphocytic leukemia/small lymphocytic dan keadaan umum pasien.

lymphoma
B. Lymphoplasmacytic lymphoma
C. Mantle cell lymphoma
D. Follicular lymphoma
E. Extranodal marginal zone B-cell lymphoma or MALT
type
F. Nodal marginal zone B-cell lymphoma
G. Splenic marginal zone lymphoma
H. Plasmacytoma/ plasma cell myeloma
I. Diffuse large B-cell lymphoma, NOS
J. Diffuse large B cell lymphoma variants.
K. Burkitt’s lymphoma
L. B cell lymphoma inclassifiable
features intermediate between DLBCL and Burkitt
lymphoma
M.B cell lymphoma inclassifiable with features intermediate
between DLBCL and classical Hodgkin lymphoma
I. LNH INDOLEN / Low grade: (Ki-67 < 30%)
Yang termasuk dalam kelompok ini adalah:
 SLL/small lymphocytic lymphoma/CLL
=chronic
lymphocytic lymphoma
 MZL (marginal zone lymphoma), nodal, ekstranodal
dan splenic)
 Lymphoplasmacytic lymphoma
 Follicular lymphoma gr 1-2
 Mycosis Fungoides
 Primary cutaneous anaplastic large cell lymphoma )
A. LNH INDOLEN STADIUM I DAN II
with
Radioterapi memperpanjang disease free survival
pada beberapa pasien. Standar pilihan terapi :
1. Iradiasi
2. Kemoterapi dilanjutkan dengan radiasi
3. Kemoterapi (terutama pada stadium ≥2 menurut
kriteria
5
 GELF) (cyclofosfamid, chlorambucil)
4. Kombinasi kemoterapi dan imunoterapi 4. Rituximab maintenance dapat dipertimbangkan
5. Observasi 5. Kemoterapi intensif ± Total Body irradiation (TBI) diikuti
B. LNH INDOLEN / low grade STADIUM II bulky, dengan stem cell resque dapat dipertimbangkan pada
III, IV Standar pilihan terapi : kasus tertentu
1. Observasi (kategori 1) bila tidak terdapat indikasi untuk 6. Raditerapi paliatif, diberikan pada tumor yang besar
terapi. (bulky) untuk mengurangi nyeri/obstruksi.
Termasuk dalam indikasi untuk terapi: C. LNH INDOLEN/ low grade
 Terdapat gejala RELAPS Standar pilihan terapi:
 Mengancam fungsi organ 1. Radiasi paliatif
 Sitopenia sekunder terhadap limfoma 2. Kemoterapi
 Bulky 3. Transplantasi sumsum tulang
 Progresif
 Uji Klinik II. LNH AGRESIF / High grade: (Ki-67 > 30%)
2. Terapi yang dapat diberikan: Yang termasuk dalam kelompok ini adalah:
1. Rituximab dapat diberikan sebagai kombinasi terapi lini  MCL (Mantle cell lymphoma, pleomorphic variant)
pertama yaitu R-CVP. Pada kondisi dimana Rituximab  Diffuse large B cell lymphoma, Follicular lymphoma gr III, B
tidak dapat diberikan maka kemoterapi kombinasi cell lymphoma unclassifiable with features between diffuse
merupakan pilihan pertama misalnya: COPP, CHOP dan large B cell and Burkitt,
FND.  T cell lymphomas
2. Purine nucleoside analogs (Fludarabin) pada LNH primer A. LNH STADIUM I DAN II
3. Alkylating agent oral (dengan/tanpa steroid), Pada kondisi tumor non bulky (diameter tumor <7.5cm)
bila kemoterapi kombinasi tidak dapat dengan kriteria: pasien muda risiko rendah atau
diberikan/ditoleransi rendah- 6

5
6
 menengah (aaIPI score ≤1) dan risiko tinggi atau
menengah-tinggi (aaIPI ≥2), bila fasilitas memungkinkan,
kemoterapi kombinasi R-CHOP 6 siklus merupakan
protokol standar saat ini serta dapat dipertimbangkan
pemberian radioterapi (untuk atau
konsolidasi), kemoterapi 3 siklus dilanjutkan
dengan radioterapi.
B. •LNH STADIUM I-II (BULKY),
Bila memungkinkan, III DAN IVkemoterpi RCHOP
pemberian
6siklus ± radioterapi konsolidasi, dipertimbangkan
pada stadium I dan II
• Uji klinik pada stadium III dan IV

C. LNH REFRAKTER/RELAPS
• Pasien LNH refrakter yang gagal mencapai remisi,
dapat diberikan terapi salvage dengan radioterapi
jika area yang terkena tidak ekstensif. Terapi pilihan
bila memungkinakan adalah kemoterapi salvage
diikuti dengan transplantasi sumsum tulang
• Kemoterapi salvage seperti R-DHAP maupun R-ICE
III. LNH “LEUKEMIA-LIKE”: Lymphoblastic, Burkitt, “double hit”
lymphoma.
• High dose chemotherapy plus radioterapi diikuti
dengan transplantasi sumsum tulang

7
REGIMEN TERAPI YANG DISARANKAN17
Terapi Lini Pertama

Rituximab + CHOP (Cyclophosphamide, doxorubicine, vincristine, prednisone) (kategori 1)
 Dosed dense RCHOP 14 (Kategori 3)
 Dosed adjusted R- EPOCH (Rituximab, Etoposide, Prednison, Vincristin,
Cyclophosphamide, doxorubicin) (kategori 2B)
Terapi Lini Pertama pada pasien dengan fungsi ventrikuler kiri buruk atau sangat rentan

 RCEPP–rituximab, cyclophosphamide, etoposide, prednisone, procarbazine

 RCDOP–rituximab, cyclophosphamide, liposomal doxorubicin, vincristine, prednisone
 DA-EPOCH – etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin+ rituximab
 RCEOP – rituximab, cyclophosphamide, etoposide, vincristine, prednisone
 RGCVP – rituximab, gemcitabine, cyclophosphamide, vincristine, prednisolone

Pasien > 80 tahun dengan komorbiditas

 R-mini CHOP
 RGCVP – rituximab, gemcitabine, cyclophosphamide, vincristine, prednisolone

Terapi Lini Pertama Konsolidasi (Opsional)

 Age-adjusted IPI high risk disease: Terapi dosis tinggi dengan penyelamatan stem sel autolog
 Double-hit DLBCL: Terapi dosis tinggi dengan penyelamatan stem sel autolog

Keberadaan penyakit bersamaan dengan manifestasi pada SSP (CNS disease)

 Parenkimal: methotrexate sistemik 3 g/m2 atau lebih, pada hari ke-15 dari 21 hari pemberian
siklus R-CHOP yang didukung dengan pemberian growth factors
 Leptomeningeal : methotrexate/cytarabine intratekal, pertimbangkan pemasangan Ommaya
reservoir dan/atau methotrexate sistemik 15
(3 – 3.5 g/m2)
REGIMEN TERAPI YANG DISARANKAN17

Terapi Lini Kedua dan Terapi Lanjutan (dengan intensi untuk high-dose therapy)

 DHAP - dexamethasone, cisplatin, cytarabine + rituximab

 ESHAP - etoposide, methylprednisolone, cytarabine, cisplatin + rituximab
 GDP – gemcitabine, dexametason, cisplatin + rituximab atau gemcitabine,
dexametason, carboplatin + R
 GemOx – gemcitabine, oxaliplatin + rituximab
 ICE - ifosfamide, carboplatin, etoposide + rituximab
 miniBEAM – carmustine, etoposide, cytarabine, melphalan + rituximab
 MINE - mesna, ifosfamide, mitoxantrone, etoposide + rituximab

Terapi Lini Kedua dan Terapi Lanjutan (tanpa intensi untuk high-dose therapy)

 Bendmustine + rituximab
 Brentuximab vedotin untuk pasien dengan CD30+ (kategori 2B)
 CEPP + rituximab (cyclophosphamide, etoposide, prednisone, procarbazine) – PO
dan IV
 CEOP (cyclophosphamide, etoposide, vincristine, prednisone) + rituximab
 DA-EPOCH – etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin
+ rituximab
 GDP + rituximab atau gemcitabine, dexametason, carboplatin + rituximab
 GemOR + rituximab
 Lenalidomide + rituximab (non-GCB DLBCL) 16
 Rituximab
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