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PPT MA - Revisi
PPT MA - Revisi
1. The discovery of recently identified molecular features has yielded new perspectives
regarding diagnostic and prognostic markers that provide novel insights for the
understanding of the pathobiology of these disorders.
2. Improved characterization and standardization of morphological features aiding in
the differentiation of disease groups, particularly of theBCR-ABL1 myeloproliferative
neoplasms (MPNs), has increased the reliability and reproducibility of di-agnoses.
3. A number of clinical-pathological studies have now validated the WHO postulate of
an integrated approach that includes hematologic, morphologic, cytogenetic, and
molecular genetic findings.
Arber D.A, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016; 127(20)
Arber D.A, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016; 127(20)
Arber D.A, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016; 127(20)
Myeloproliferative Neoplasm Classification
Hematopoietic
JAK2V617F mutation
stem cell (HSC)
THE CHRONIC MYELOPROLIFERATIVE DISORDERS
JAK2V617F
Transition between ET
phenotypes common with PV
latency period of decades
PMF
JAK2 V617F in Myeloid Disease
One mutation, many phenotypes
Stat5 Stat5
P P
X Gene Transcription
P P
JAK2V617F JAK2V617F
P P
Stat5 Stat5
P P
Stat5 Stat5
P P
X Gene Transcription
Polycythemia Vera
A neoplastic, clonal
overproduction of
erythrocytes,
granulocytes, and
platelets to some degree
(primary problem is too
many RBCs)
The clonal neoplastic
transformation arises in a
pluripotential
hematopoietic stem cell
RBCs are very sensitive to
erythropoietin for cell
growth
17
Kriteria Diagnostik
Polychytemia Vera
Leukoerythroblastosis on smear
Splenomegaly
Anemia
Kriteria Diagnostik…
Pre PMF
Overt PMF
Sampel :
Whole blood (2 tabung @3cc)
Frekuensi kerja
1 x seminggu
72 jam (suhu ruang)
Stabilitas : 7 hari (2 – 8 oC)
ARMS-PCR
Amplification refractory mutation system
polymerase chain reaction
merupakan metode deteksi SNP yang melibatkan PCR dan gel electrophoresis
menggunakan prinsip tetra-primer PCR dan teknik ARMS.
Sensitivitas :
Mendeteksi sampai 0.54% mutan dalam wildtype
Menggunakan primer allele spesifik
Tidak ditemukan negatif palsu maupun positif palsu
Guidelines (Bench, et al. 2012)
Source Undetermined
Sources Undetermined
Stephen B. Marley and Myrtle Y. Gordon. Chronic myeloid
leukaemia: stem cell derived but progenitor cell driven
Clinical Science (2005) 109, (13*25)
Bcr-Abl expression alone is necessary and sufficient for the development of CML
Chronic Phase ~ 85% Accelerated Phase
and Blast crisis
Common symptoms:
fatigue
More aggressive disease
weight loss/anorexia
with increased blasts and
Early satiety
poorer prognosis
asymptomatic in ~ 50%
Common signs:
palpable splenomegaly
basophilia
Faderl et al. Ann Intern Med. 1999;131:207. Goldman. Curr Opin Hematol. 1997;4:277.
CML PHASES
CML PHASES
Source Undetermined
Interphase Metaphase
Source Undetermined
Metode yang digunakan untuk
manajemen pasien CML
Untuk pemantauan
respon pengobatan
Pemeriksaan Genetik
pada CML BCR-ABL KUANTITATIF
Jabbour E. Chronic myeloid leukemia: First-line drug of choice. American Journal of Hematology. 2015;91(1):59-66.
Kembalinya jumlah
darah ke nilai normal
Reduksi dan eliminasi
kromosom Philadelphia
(Ph)
Reduksi dan eliminasi
ekspresi gen BCR-ABL
Cortez, et al. Cancer. 2011 March 15; 117(6): 1113–1122. Press, The Oncologist 2010;15:744–749
Respon terhadap terapi dapat didefinisikan dengan : hematologic,
cytogenetic, dan molecular
57
1. Deteksi Residu Penyakit
Studi CML IV
Studi pada 1.303 pasien yg baru didiagnosis CML yang diobati dengan
imatinib
BCR-ABL >10% (IS) pada bulan ke-3 dan BCR-ABL >1% (IS) pada bulan ke-6
setelah pengobatan imatinib secara signifikan berkaitan dengan buruknya
OS dan PFS dalam 5 tahun
Kelebihan multiplex-PCR :
cepat, sensitif
memudahkan deteksi secara simultan dari dua atau
lebih gen pada reaksi yang sama
mengidentifikasi tipe transkrip, baik b3a2 dan b2a2,
atau e1a2
Jenis fusi yang dideteksi:
Metode Pemeriksaan
Two Steps Reverse Transcription Multiplex
PCR
Reverse transcription
RNA menjadi DNA
Persyaratan :
Pasien sudah pernah melakukan pemeriksaan
BCR-ABL kualitatif dengan hasil fusi p210
Jenis fusi yang dideteksi:
Metode Pemeriksaan
Real-Time reverse transcriptase quantitative
polymerase chain reaction (RT-qPCR)
Hasil :
Diekspresikan sebagai rasio jumlah transkrip BCR-ABL
terhadap jumlah transkrip gen kontrol
Respon molekular dikuantifikasi dengan mengukur reduksi
transkrip BCR-ABL relatif terhadap baseline standar.
Hasil diekspresikan berdasarkan International Scale
(BCR-ABLIS (%))
Cortez, et al. Cancer. 2011 March 15; 117(6): 1113–1122. NCCN
Guideline Chronic Myeloid Leukemia Version 1.2016
CONTOH HASIL
TREATMENT