Profile Of BCR-ABL Transcipt Levels Based on Sokal prognostic Score in Chronic Myeloid Leukimia Patients Treated With lmatinib Repository - UNAIR REPOSITORY

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Acta Medica Indonesiana. Volume 45 . Number

EDITORIAL
ORIGINAL

ARTICLES

2. April2013

The Practice of Evidence-based Medicine: Time for us to Change..
Esthika Dewiasty

Distribution of Dimethylarginine-Dimethylaminohydrolase-ll
Gene Polymorphism in Hemodialysis Patients.....

... . .8'1

(DDAH2)

.........83

Muhammad Thaha, Muhammad Yusuf, Maulana A. Empitu,
Achmad Bakarman, Yasuhiko Tomino
Role of Procalcitonin and Lipopolysaccharide-binding Protein as
Prognostic Markers of Mortality in Patients with Ventilator-associated

Pneumonia.......

................................89

Cleopas M. Rumende, Dinajani Mahdi
Effect of Allopurinol on Oxidative Stress and HypoxicAdaptation

Response During Surgical Correction of Tetralogy of Fal|ot................94
Fathema D. Rachmat, Jusuf Rachmat, Sudigdo Sasfroasmoro,
Septelia l. Wanandi
Detection of Carbapenemase Encoding Genes in Enterobacteriace,
Pseudomonas aeruginosa, and Acinetobacter baumanii lsolated
from Patients at lntensive Care Unit Cipto Mangunkusumo Hospital
in

2011.............

..............................101

Anis Karuniawati, Yulia R. Saharman, Delly C. Lestari

,i,,

Profile of BCR-ABL Transcript Levels Based on Sokal prognostic
Score in Chronic Myeloid Leukemia PatientsTreated with lmatinib.......107

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Ami Ashariati, S. Ugroseno
=i-

Predictive Value of Different Estimated Glomerular Filtration Rates
on Hospital Adverse Events FollowingAcute Myocardial lnfarction.....114
Anggoro B. Haftopo, Budi Y. Setianto, Putrika P.R. Gharini
Safety and Efficacy of Lansoprazole lnjection in Upper Gl Bleeding:
a Postmarking Surveillance Conducted in lndonesia...... .. ... .. . . ..122
Ari F. Syam, Arini Setiawati

CASE

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Virilization Due to Androgen Hypersecretion in a Patient with Ovarian
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Achmad Z. Juniafto, Bestari A. Setyawati, Annastasia Ediati,
Yvonne G. van der Zwan, Leendhert H.J. Looijenga, Frank H. de Jong,
Arianne Dessens, Sfenverf L.S. Drop, Sultana M.H. Faradz
Giant Primary Psoas Abscess: Masquerading peritonitis for Diagnosis and Treatment..

..........136

Rikki Singal, Amit Mittal, Samita Gupta, Bikash Naredi, Maihait Singh
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The Role of Antioxidants in the pathophysiotogy, Complications, and
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................141
St. Rabiul Zatalia, Harsinen Sanusi

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Laurentius A. pramono, Drajad priyono, pringgodigdo Nugroho,
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.......148

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ORIGINAL ARTICLE

Profile of BCR-ABL Transcript Levels Based on Sokal
Prognostic Score in Chronic Myeloid Leukemia Patients
Treated with lmatinib
Ami Ashariati,

S. IJgroseno

DePartment Internal Medicine, Faculty of Medicine, Airlangga University-Dr. Soetomo Hospital, Surabaya,
Indonesia.
Correspond.ence maiL

DePattment lnternal Medicine, Faculty of Medicine, Airlangga IJniversity-Dx Soetomo Hospital.
dr Moatopo 6-8, Surabaya 60286, Indonaia. email: amiashariati@yahoo.com.

ll. Mayjen Prof

ABSTRAK
Tujuan: mengevaluasi pola dari respons molekularyang dinilai dengan reduksi kadar transkrip BCR-ABL
berdasarkan skor prognosis sokal pada pasien leukemia mietoid lvonis (LMK)fase taonis yang mendapat terapi
Imatinib. Metode: penelitian dengan desainpotong lintang dilakukan di Instalasi Rmat Jalan Hematologi, RSu
Dr Soetomo Surabaya, pada semua pasien LMKfase kronis, sejak Juni 2008 hingga Juni 201 2. Skoring Sokal
ditentukan saat sebelum terapi. Dala yang dikumpulkan meliputi karaheristiksubjek Qtsia,jenis kelamin), kadar
hemoglobin, trombosit, lekosit, sel muda mieloblas, dan ukuran limpa. Pemeriksaan real-time kuantatifPCR
(RTqPCR) digtnakan untukmendeteksi residual molekularrespons dari BCR-ABL. Hasil RT-qPCRyang dicatat
mempakan rasio dari BCR-ABL dan gen acuan (G6PDH) sebagai standar internal. Perbedaan proporsi respons
molekuler lengkap pada kelompok risiko Sokal rendah dan tinggi dianalisis dengan uji kai kuadrat, sementara
perbedaan kadar translaip BCR-ABL di antara kelompok risiko Sokat dianalisis dengan uji Kruskal-Wallis.
Hasil: 40 subjek me4telesaikan penelitian. Setelah I 8 bulan terapi Imatinib, kadar tanskrip BCR-ABL tidak
terdetel*i (molekuler respons lengkap) pada 7(70%o), 8(66,7%0), dan 9(50%o) bertumt-turut pada kelompok
subjek risiko Sokal rendah-, sedang-, dan tinggi (p=0,417). Respons molekuler lengkap pada kelompok risiko
Sokal rendah didapatkan lebih tinggi dibanding isiko Sokal tinggi (70%o vs 50%o), secara statistik tidak berbeda
bermakna (p=0,557). Analisis statistik menggunakan Kruskall-Wallis menunjzkkan tidak ada perbedaan
secara bermakna distribusi kadar transkrip BCR-ABL di antara subkelompokskor prognostik Sokal (p=0,734).
Kesimpulan: tidak ada perbedaan kadar transkrip BCR-ABL antara subkelompok skor prognostik sokal pada
pasien LMKfase kronik yang diterapi dengan imatinib.
Kata kunci: LMK, imatinib, kadar transkrip BCR-ABL, skor sokal.

ABSTRACT

Aim: lo elucidate the pattern of molecular response assessed by logarithmic reduction in BCR-ABL
transciption levels based on Sokal prognostic score in chronic phase chronic myeloid leukemia (CML) patients
receiving Imatinib treatment. Methods: cross-sectional study was conducted in the Hematologic Outpatient
Clinic, Dr. Soelomo Hospital Surabaya in all chronic phase CW patientsfrom June 2008 to June 2012. Data
on subject characterislics (age and sex). complete blood count with dffirential and spleen size were collected.
Patients were stratifed according to Sokal score at diagnosis. Real-time quantitative PCR (RT-qpCR) were
used to monitor BCR-ABL levels in patients who ftlfilled study. Proportion diff*ence of complete molecalar

response (MR) was analyzed by chi-square test, while diferences of BCR-ABL transcript level among Sokal
Acta Medica Indonesiana - The Indonesian fournal of Internal Medicine

I

107

Acta Med Indones-lndones ) Intern Med

Ami Ashariati

18
40 stbjectsfnished the study' After

tesr..Results:
prognostic scole subgroups was analyzed by Knskal-wallis
7(70%o)' 8(66
BCR-ABL rranscript level (complete MR) were
months oflmatinib treatment, the undetected

7%o)'

andg(50%")inlow.,intemediate-,andhighriskgrouppatients,respectively(p:0,417).Althoughproportion
groups (7094
ii sokal low risk group compared to in sokal high risk
of subjects with complete
v.s. 50%o), br.n this

W

is higher

(p:0'557)' Kruskal-Waltis
dffirence is noi statistically significant

test showed

that there

wasnosignificanrdffirenceofBCR.ABLtranscriptlevelamongSokalprognosticscoresubgroup(p=0.7j4).
Conclusion:therewasnodffirenceofBCR-ABLtranscriptlevelamongsokalprognosticscoreriskgroupsin
Imatinib'
chronic phase CML patients teated with
Key words:

tanscript'
CW, Imatinib' Sok'l p'ognosti' score' BCR-ABL/G6PDH

is seen

INTRODUCTION

Chronic myeloid leukemia (CML) is the
first malignancy associated with a specific
chromosome abnormality with an annual
incidence of

1

to 2 cases per 100'000 per year

and a median onset in the fifth oi sixth decade
of life.rr The Philadelphia (Ph) chromosome is
a
a shortened chromosome 22 that results from
reciprocal translocation between the long arms
of chromosomes 9 and 22. The consequence
of this translocation is the fusion of the c-abl
gene
oncogene from chromosome 9 with bcr
fused
a
to
rise
giving
22,
chromosorle
from

bcr-ab1 gene. The different fusion proteins
encoded by BCR-ABL vary in size depending
a
on the breakpoint in the BCR gene and share
part
responsible
in
high tyrosine kinase activity,
foi the leukemogenesis. The Philadelphia (Ph)
chromosome is seen in 95%" of patients with
CML.'?J Tyrosine kinases are enzymes that
transfer phosphate from AIP to tyrosine residues
on substrate proteins that in tum regulate cellular
processes such as proliferation, differentiation,

and survival. Therefore,

it is not

surprising

that deregulated tyrosine kinase activiry has a
central role in malignant transformation' Until
the last decade before targeted therapy, the
prospect for patients diagnosed with CML had
been relatively unfavorable. Imatinib mesylate
(STI57l/Gleevec) is the first therapy to target

tyrosine kinase activity. The introduction of
imatinib has led not only to more favorable
outcomes, but has driven the development of
advances in monitoring response to therapy at
molecular level. The total number of ieukemia
cells in the body is reduced very substantially

in CML patients with BCR-ABL-positive

responding to imatinib. This reduction
first as restoration of Ph negativity in blood
BCRand marrow and there after as decreasing
quantitative
by
assayed
levels
ABL transcript
with
polymerase chain reaction. Most patients

chronic-phase CML who receive imatinib

(CCyR)
achieve complete cytogenetic response
a status
and low levels of BCR-ABL transcripts,
survival
long
relatively
for
that seems to predict
compared with previous treatments'a

Cytogenetic remission with monitoring of
the percentage of Philadelphia chromosomeposiiive cells is the best validated system for
the assessment ofresponse to interferon-cr and
kinase inhibitors, since the cltogenetic
ryrosine

response is the best surrogate marker ofsurvival'
For patients who achieve a CCyR to interferon-cr'

the 10-year survival is about 75%' For patients
who achieve a CCyR to imatinib, the S-year
survival rate is close to 100% The response

is conventionaliy determined by chromosome
banding analysis of marrow cell metaphases'
If there are fewer than 20 metaphases, the
cytogenetic response can be validated by
determining the leve1 of BCR-ABL transcripts
with quantitative techniques PCR'a
More recently, real-time quantitative PCR
(RT-qPCR) has been developed' Results of
RT-qPCR usually report the ratio of BCRABL transcript level to a reference gene

(recommended genes include ABL, BCR, and
(MR)
G6PDH). The level of molecular response
predictive
be
to
confirmed
was
months
12-18
at
of long-term clinical outcomes'a Patients treated
with 400 mg daily who achieved a reduction in
BCR-ABL transcript numbers equal or greater
tha"n 3 logs compared

with

a

baseline value have

Acta Med Indones-Indones

Ami Ashuiati

J

Intern Med
After I 8

the stldy'
prognostic scole subgroups was analyzed by Kruskal-Wallis test. Results: 40 stbjectsfinished
(complete MR) were 7(70%o'l' 8(66'7%)'
months of lmatinib tredtment, the undetected BCR-ABL ffanscript level
(p:0-417)' Atthot'rgh proportion
and 9(50%o) in low-, intermediate-, ancl ftigh risk grot'q patients, respecti,-ely
to
in sokal high risk groups (7096
group
compared
risk
lotv
in.sokal
is
higher
MR
of nbjects reith complere
test showed that there
Kntskal-Wallis
(p:0.557).
v.s. 50%o), bd this dffirence is not statistical|l signifcanl
ntbgroup (p=0'7i4)'
prognostic
score
Sokal
among
level
transcript
was no signifcant dffirence of BCR-ABL
level among sokal prognostic score risk groups in
transcript
BCR-ABL
of
difference
no
was
there
conclusion:

chronic phase CML Patients treated with Imatinib'

Kqt words: CW, Imatinib,

Sokal prognostic score' BCR-ABL/G6PDH

INTRODUCTION

Chronic myeloid leukemia (CML) is the

first malignancy associated with a specific

chromosome abnormality with an annual
incidence of I to 2 cases per 100.000 per year
and a median onset in the fifth or sixth decade
of life.r2 The Philadelphia (Ph) chromosome is
a shorteDed chromosome 22 that results from a
reciprocal translocation between the long arms

of chromosomes 9 and 22. The consequence
of this translocation is the fusion of the c-ab1
oncogene from chromosome 9 with bcr gene
from chromosome 22, giving rise to a fused
bcr-abl gene. The different fusion proteins
encoded by BCR-ABL vary in size depending
on the breakpoint in the BCR gene and share a
high tyrosine kinase activiry, in part responsible
for the leukemogenesis. The Philadelphia (Ph)

chromosome is seen in 95% of patients with
CML.Z3 Tyrosine kinases are enzymes that
transfer phosphate fromAIP to tyrosine residues
on substrate proteins that in turn regulate ce11u1ar
processes such as proliferation, differentiation,

and survival. Therefore, it is not surprising
that deregulated tyrosine kinase activity has a
central role in malignant transformation' Until
the last decade before targeted therapy, the
prospect for patients diagnosed with CML had
been relatively unfavorable' Imatinib mesylate
(STl571/Gleevec) is the first therapy to target

tyrosine kinase activity. The introduction of
imatinib has ied not only to more favorable
outcomes, but has driven the development of
advances in monitoring response to therapy at
molecular level. The total number of leukemia
cells in the body is reduced very substantially

. in CML patients with BCR-ABl-positive
108

tanscript'

responding to imatinib. This reduction is seen

first as restoration of Ph negativity in blood
and marrow and there after as decreasing BCR-

ABL transcript levels assayed by quantitative

polymerase chain reaction. Most patients with

chronic-phase CML who receive imatinib
achieve complete cytogenetic response (CCyR)
and low levels of BCR-ABLtranscripts, a status
that seems to predict for relatively long suwival
compared with previous treatments.4

Cytogenetic remission with monitoring of
the percentage of Philadeiphia chromosomepositive cells is the best validated system for
the assessment ofresponse to interferon-cr and
tyrosine kinase inhibitors, since the cytogenetic
response is the best surogate marker of survival'
For patients who achieve

a

CCyR to interferon-cr,

the 10-year survival is about 75%. For patients
who achieve a CCyR to imatinib, the 5-year
survival rate is close to 100%. The response

is conventionally determined by chromosome
banding analysis of marrow cell metaphases'
If there are fewer than 20 metaphases, the

cytogenetic response can be validated by
determining the level of BCR-ABL transcripts
with quantitative techniques PCR.a
More recently, reai-time quantitative PCR
(RT-qPCR) has been developed. Results of
RT-qPCR usually report the ratio of BCRABL transcript level to a reference gene
(recommended genes include ABL, BCR, and
G6PDH). The level of molecularresponse (MR)
at 12- 1 8 months was confirmed to be predictive
of long-term clinical outcomes.4 Patients treated
with 400 mg daily who achieved a reduction in
BCR-ABL transcript numbers equal or greater
than 3 logs compared with

a

baseline value have

Vol 45 . Number 2 . April

2013

Profile ofBCR-ABL transcript levels based on Sokal prognostic score in CML

a significantly better progression-free survival

than those who achieved lesser degrees

of

respons.4

Two scoring systems (Sokal and the

peripheral blood cells ofpatients using the acid
guanidinium thiocyanate and phenolchloroform
method and a commercially available extraction
kit. oDNA synthesis was performed according

Hasford score), are available for prognostic risk
evaluation of CML. Both scores have confirmed
their predictive value. The Sokal scoring system

to the manufacturer's instructions using random

by risk
in a1l the largest clinical Imatinib trials in CML.
The cytogenetic response monitoring require
bone marrow aspirates and the accuracy of
this test depend on metaphase number, while
the Sokal score only require clinical data and

Roche Diagnostic, Mannheim, Germany). oDNA

peripheral blood as the source of residual cells.
Moreover, as far as we know, this is the first
study on Sokal prognostic score tlat was ever

real-time RT-PCR usually report the ratio of
BCR-ABL transcripts level to a reference gene

conducted in Surabaya. Based on these facts, the
purpose of this study is to investigate residual

G6PDH).

moiecular response assessed by logarithmic
reduction in BCR-ABL transcription levels

phase

through peripheral blood related with prognostic
risk score ofSokal in CML chronic phase treated
with Imatinib.3r-ra

evaluated after four weeks after commencement
of therapy. Mol'ecular response was assessed by

has been applied to stratiry the patient

METHODS

A cross-sectional study was conducted

at

the Hematology Outpatient Clinic, Dr. Soetomo

General Hospital Surabaya, between June
2008 and Jtne 2012. The study population
included all patients who fulfilled the inclusion
criteria: diagnosed as chronic phase CML
according WHO criteria and will be treated with
Imatinib more than 18 months, had Kamofsky's
performance status >60010, and agreed to be
included in this study. The exclusion criteria
were patients who stopped treatment >2 weeks
before evaluation, and had severe infection.
Data collected include subject characteristics
(age, sex). Before beginning treatment, patient's

history physical examination, complete blood
count with differential, blood chemistry and
bone marrow evaluation for morphology
and cytogenesis were perforrned at baseline.
Patients were stratified according to Sokal
score at diagnosis. Complete blood counts
were measured at baseline; at weeks 1,2, and
4 monthly until month 6; and every 3 months
thereafter until the end ofthe study. Molecular
snrdies: total RNA was extracted from 106-107

hexamer priming andAMV reverse transcriptase

(First Strand cDNA Synthesis Kit for RT-PCR,

was amplified using a LightCycler (Roche
Diagnostics). Primers and probes were included
in the kit and they designed to delectb3a2,bzaz
and ela2 fusion transcripts, covering 95%:o of
the described t(9;22) translocations. Resuits of

(recommended genes include

ABL, BCR, and

Al1 of the patients were in early chronic
of CML and had received 400 mg/day
Imatinib orally. Hematological response was

RI-qPCR at baseline, then every 3 months and
on 18 months of treament.
Measurement Methods
The calculation of Sokal prognostic score
is 0.0116 x (age in years - 43.4) + 0.0345 x

- 7.5 1) + 0. 1 88 x [(platelet count - 700)2
0.5631 + 0.0887 x (blast cells - 2. I 0); and risk

(spleen

-

by calculation are low score (1.2).8

Complete hematological response (CHR)
was defined as normalization ofthe bone marrow

(blast cells less than or equal to 5%) for at
least four weeks and the peripheral ieucocyte
count 0.05).'However, there

was no significant difference of BCR-ABL
transcript leve!/G6PDH among prognostic score
of Sokal in our study (p=0.734). These results
might be due to a smal1 sample size. In the future,

we hope that we will have more samples, so
results will be more accurate in representating
the population.

The outcome of Imatinib treatment in
CML patients has been improved. Until now,
monitoring outcome of Imatinib treatment is
still challenging. We did not do cytogenetic

response monitoring because it required bone
malTow aspirates and the accuracy of the test
depends on metaphase the number. It is much

more convenient for the patient io have their
peripheral blood as the source ofresidual cells to
be evaluated by real time quantitative PCR and
use the prognostic score of Sokal as treatment
monitoring first.

E
1,5

.

&
o

s

1,0

E
?,

a

F

!4
E

0,5
0,4
0,3
0,2
0,0

Figure 1. Distribution (scatteo of BCR-ABL transcript level and prognostic score of Sokal

tt2

Intern Med

versus 500%), in analysis, this difference is
not statistically significant (p:0.557) Similar

*E
4

J

Vol45. Number2.

April2013

ProfileofBCR-ABL transcriptlevelsbasedonSokalprognostic

CONCLUSION
Proportion of patients with complete MR are
higher in the Sokal low risk group compared to
Sokal high risk group, although this difference

is not statistically significant, and there is no
diffrence in BCR-ABL transcript leveVG6PDH

9.

score in

CML

Hughes TP, Saglio G. Using molecular monitoring
to optimize therapy for chronic myeloid leukemia.
EUTOS PCR. 2008;20: 1-l

1.

10. Mauro MJ, Deininger MWN. Chronic myeloid

I

l.

among Sokal risk groups.

leukemia in 2006: a perspective. J haematol. 2006;
9l(2):152-8.
Deininger MW Milestones and monitoring in patients
with CML reated with imatinib. Hematol. 2008:41926.

ACKNOWLEDGMENTS

12. Press RD. Major molecular response in CML
patients treated with tyrosine kinase inhibitors: The
paradigm for monitoring targeted cancer therapy. The

I am grateful to my colleagues, especially S
Ugroseno, and Sosiawan A; who conducted the
RQ-PCR, read various drafts ofthis paper, and
helped to improve it.

Oncologist. 20 I 0; I 5:744-9.

13. Kantarjian H, Cortes J. Considerations in the
management of patients with Philadelphia
chromosome-positiye chronic myeloid leukemia
receiving tyrosine kinase inhibitor therapy. J Clin

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