Incidence of Acute Myeloid Leukemia in Children in Haji Adam Malik Hospital Medan
Selvi Nafianti dkk.
Insidence of Acute Myeloid…
Incidence of Acute Myeloid Leukemia in Children in Haji Adam Malik
Hospital Medan
Selvi Nafianti, Nelly Rosdiana, dan Bidasari Lubis
Division Hematology-Oncology Child Health Department Medical Faculty
University of Sumatera Utara / Haji Adam Malik Hospital Medan Indonesia
ackground: Leukemia is the most common malignancy in childhood and about 15
percent of childhood leukemia cases are acute myelogenous leukemia (AML). It is reported in
more than 13,000 people newly diagnosed each year. The overall survival rate has reached a
plateau at approximately 60%, suggesting that further intensification of therapy per se will not
substantially improve survival rates. Methods: This study was retrospective with all the children
who came to Division Hematology-Oncology Haji Adam Malik Hospital during January 2001 December 2006 with diagnosis Acute Myeloid Leukemia (AML) were enrolled to this study. The
diagnosis of AML was established based on morphology. There were 45 children meet the
criteria. Results: in our study there were 25 boys and 20 girls. Age range 1-14 years (median age 9
yrs). Most patient were in group age more than 10 years old, followed by group age 1-5 and 5-10
years as much as 13 cases each. There were 14 children suffered from severe malnutrition, 13
mild malnutrition and 13 moderate malnutrition. There were total of 39 patient had
chemotherapy, and 6 patient refused to have chemotherapy with one and another reason. Only 6
from 45 were survival, death in 20 cases mostly in induction phase 10 cases, consolidation 7 cases
and maintenance 3 cases. There were 19 cases who refused to follow the chemotherapy protocol.
Conclusion: AML is remain a major problem in developing countries. Incidence may vary due to
the limitation of diagnostic tool and prognosis was still bad.
Keywords: acute myeloid leukemia, children
INTRODUCTION
Acute myeloid leukemia (AML), also
known as acute myelogenous or acute
myeloblastic leukemia, is a type of cancer that
starts from cells that normally develop into
1-5
blood cells. AML mainly develops from two
types of white blood cells: granulocytes or
monocytes. AML is caused by genetic damage
to these developing cells in the bone marrow.
The result is uncontrolled growth and
accumulation of undeveloped cells called
"leukemic blasts," which fail to function as
normal blood cells. As these cells accumulate,
they block the production of normal marrow
cells, leading to a deficiency of red cells,
blood-clotting platelets and normal infection6-8
Acute myelogenous
fighting white cells.
leukemia (AML) is the most common form of
leukemia with more than 13,000 people
diagnosed each year, according to National
Cancer Institute estimates. About 15 percent
of childhood leukemia cases are AML. Older
individuals, however, are more likely to
develop the disease. The median age at
diagnosis is 67. Of those with AML, less than
6 percent are younger than 20 when
diagnosed; more than 55 percent are
diagnosed at 65 or older. About 0.38 percent
of people will be diagnosed with AML during
9-12
their lifetimes.
Each year in the United States 500 to 600
individuals younger than 21 years develop
acute myeloid leukemia (AML). Current
treatment for AML typically consists of 3 or 4
courses of intensive, myelosuppressive
chemotherapy with or without bone marrow
transplantation from a histocompatible family
donor.This therapy cures about half the
children with AML; of the other half, most
succumb to AML-related causes, but 5% to
13-16
15% die from toxic effects of treatment.
17-23
It is not
The cause of AML is unknown.
contagious and is not inherited, but several
factors have been linked to increased risk of
the disease. These include exposure to very
high doses of radiation, exposure to the
Majalah Kedokteran Nusantara Volume 41 y No. 2 y Juni 2008
104
Karangan Asli
chemical
benzene
and
exposure
to
chemotherapy. Smoking is another proven
risk factor, which causes about 1 in 5 cases of
AML. Uncommon genetic disorders, such as
Fanconi anemia and Down syndrome, are
associated with an increased risk of AML.
Identifying risk factors for childhood leukemia
(e.g., environmental, genetic, infectious) is an
important step in the reduction of the overall
burden of the disease. In general, benzene and
ionizing radiation are two environmental
exposures strongly associated with the
development of childhood AML or ALL.
Future studies, when appropriate, should
attempt to use common questionnaires,
address timing and route of exposure,
document evidence that exposure has actually
been transferred from the workplace to the
child, and store biological samples when
3
possible. Scheneider et al , reported in
patients with AML after treatment for Germ
cell tumor (GCT), several pathogenetic
mechanisms must be considered. AML might
evolve from a malignant transformation of
GCT components without any influence of
the chemotherapy. On the other hand, the
use of alkylators and topoisomerase II
inhibitors is associated with an increased risk
of t-AML. Future studies will show if the
reduction of treatment intensity in the current
protocol reduces the risk of secondary
5-8
leukemia in these patients.
A
combination
of
morphologic,
immunophenotypic, and cytogenetic studies is
usually required to establish the diagnosis of
AML. Immunophenotype is important,
particularly in establishing a diagnosis of acute
megakaryoblastic leukemia (AMKL), myeloid
leukemia with minimal differentiation, and
myeloid/lymphoid (mixed, biphenotypic)
leukemia. Recently, the World Health
Organization (WHO), in conjunction with
the Society for Hematopathology and the
European Association of Hematopathology,
has proposed a new classification for
hematopoietic
neoplasms.
The
WHO
classification defines subsets of AML on the
basis of both morphologic and cytogenetic
characteristics. Although the current AML
classification schemes, including the WHO
scheme, have been developed for adult AML,
the concepts underlying these classifications
can be applied to pediatric AML. Recent gene
105
expression profiling studies demonstrated
distinct expression signatures for each of the
known prognostic subtypes of AML.
Importantly, some of the pediatric AML
subtype specific expression signatures were
essentially the same as those of selected adult
AML
cases,
suggesting
a
shared
8-14
11
leukemogenesis. Creutzig U et al , Stem
cell transplantation (SCT), as applied in highrisk patients with a matched related donor,
did not significantly improve the outcome
compared to chemotherapy alone. In spite of
treatment intensification, the therapy related
death rate decreased from trial to trial, mainly
during induction. The future aim is to reduce
long-term sequelae, especially cardiotoxicity,
by administration of less cardiotoxic drugs,
and toxicity of SCT by risk-adapted
indications. The AML-BFM studies performed
in three European countries with >70
cooperating
centers
have
significantly
improved the outcome in AML children;
nevertheless, increasing experience with these
intensive treatment is of fundamental
6-12
importance to reduce fatal complications.
Despite several strategies to increase the
intensity of therapy, the overall survival rate
has reached a plateau at approximately 60%,
suggesting that further intensification of
therapy per se will not substantially improve
survival rates. It appears that the “one-sizefits-all” treatment strategy will not further
improve current AML survival rates. The
merit of individualized therapy for AML has
been clearly demonstrated in the treatment of
APL. The introduction of ATRA and the
tailored use of specific treatment components
(increased dose-intensity of anthracycline
during induction and consolidation; use of
ATRA plus 6-mercaptopurine and methotrexate
during
maintenance)
has
resulted
in
reproducible 5-year survival rates exceeding
80%. Despite intensive induction and
postremission chemotherapy, 5-year eventfree survival (EFS) of children with acute
myeloid leukemia (AML) is only 40% to 50%.
Bone marrow transplantation (BMT) from
HLA-matched sibling donors is associated
with lower relapse risk and superior overall
survival (OS) compared with other types of
postremission therapy, including consolidation
therapy, maintenance chemotherapy, and
autologous BMT. Drug resistance is a major
Majalah Kedokteran Nusantara Volume 41 y No. 2 y Juni 2008
Selvi Nafianti dkk.
Insidence of Acute Myeloid…
obstacle to effective AML treatment. The
rates of early death (ED) and treatmentrelated mortality (TRM) are unacceptably
high in children undergoing intensive
chemotherapy for acute myeloid leukemia
(AML). Better strategies of supportive care
might help to improve overall survival in
7-13
these children.
METHODS
This was a retrospective study, we review
all the children who came to Division
Hematology-Oncology Haji Adam Malik
Hospital during January 2001 - December
2006 with diagnosis Acute Myeloid Leukemia
(AML) were enrolled to this study. The
diagnosis of AML was established based on
morphology. There were 45 children meet the
criteria.
RESULTS
Table 1. Characteristic of study subject
N=45
Sex
Boys
25
Girls
20
Age group (years)
10
17
Nutritional State
Normal
5
Mild
13
Moderate
13
Severe
14
Table 2. Distribution sample based on FAB Classification
N=45
FAB Classification
M1
28
M2
2
M3
0
M4
10
M5
1
M6
4
M7
0
Majalah Kedokteran Nusantara Volume 41 y No. 2 y Juni 2008
106
Karangan Asli
Table 3. Chemotherapy
N=45
Chemotherapy phase
Induction
17
Consolidation
12
Maintenance
10
Discontinued
6
Table 4. Treatment outcome
N=45
Survival
6
Induction
10
Death
Consolidation
7
Maintenance
3
Before chemotherapy
6
During chemotherapy
13
Drop out
Table 1 showed that in our study there
were 25 boys and 20 girls. Most patient were
in group age more than 10 years old, followed
by group age 1-5 and 5-10 years as much as
13 cases
each. There were 14 children
suffered from severe malnutrition, 13 mild
malnutrition and 13 moderate malnutrition.
From table 3, found that there were total
of 39 patient had chemotherapy, and 6
patient refused to have chemotherapy with
one and another reason
Only 6 from 45 were survival, death in
20 cases mostly in induction phase 10 cases,
consolidation 7 cases and maintenance 3 cases.
There were 19 cases who refused to follow
the chemotherapy protocol.
107
DISCUSSION
The effect of BMI on outcome in
pediatric AML is not a trivial problem: the
reduced survival in underweight and
overweight patients is roughly equal to the
improved survival accomplished by 10 years
of progress in pediatric AML. Treatmentrelated mortality is the worst possible
outcome for an individual enrolled in a clinical
trial, and if treatment-related mortality is not
countered by a net gain in survival, excess
treatment related mortality is also the worst
possible outcome for a clinical trial. These
results have implications for clinicians and
clinical investigators. This is the first example
of immediate rather than impending lifeshortening effects of excess weight in the
young and a confirmation of the risks of
Majalah Kedokteran Nusantara Volume 41 y No. 2 y Juni 2008
Selvi Nafianti dkk.
undernutrition in other pediatric cancers.
Interventions currently available that could
reduce the treatment related mortality in
underweight and overweight groups include
formal
nutritional
and
immunologic
assessment at diagnosis. Underweight patients
could benefit from preemptive nutritional
intervention or intravenousglobulin. In
overweight patients, correction of persistent
moderate hyperglycemia and hypertension
may remediate 2 important comorbidities.
15
Lange et al , in their study to compare
survival rates in children with AML who at
diagnosis are underweight (body mass index
[BMI] _10th percentile), overweight (BMI
_95th percentile), or middleweight (BMI =
11th-94th percentiles). Eighty-four of 768
patients (10.9%) were underweight and 114
(14.8%) were overweight. After adjustment
for potentially confounding variables of age,
race, leukocyte count, cytogenetics, and bone
marrow transplantation, compared with
middleweight patients, underweight patients
were less likely to survive and more likely to
experience treatment related mortality.
Similarly, overweight patients were less likely
to survive and more likely to have treatmentrelated mortality than middleweight patients.
Infections incurred during the first 2 courses
of chemotherapy caused most treatmentrelated deaths. The study noted that
treatment-related complications significantly
reduce
survival
in
overweight
and
underweight children with AML. Becton et
16
al , reported that intensifying induction with
high-dose DAT and the addition of CsA to
consolidation chemotherapy did not prolong
the durations of remission or improve overall
survival for children with AML. O’Brian et
17
al , found that improvements in remissioninduction rates, decreased treatment related
toxicity, and improved outcomes with
allogeneic
sibling
transplantation
have
contributed to higher survival rates.
Nevertheless, further improvements are
needed. Unlike AML trials in adults, AML in
children results do not support an advantage
of idarubicin over daunorubicin in the
treatment of pediatric AML in terms of
remission induction or overall survival rates.
In addition, it’s found greater toxicity with
idarubicin than with daunorubicin.
Insidence of Acute Myeloid…
Creutzig et al, found that idarubicin
when used for remission induction in
childhood AML was associated with more
bone marrow toxicity, with a greater number
of days to neutrophil recovery, than patients
treated with daunorubicin. The study shown
that greater renal, gastrointestinal, and
pulmonary toxicity occurred in patients
receiving
idarubicin
during
remission
induction. Gastrointestinal toxicity in our
patient group was dose related and entailed
significantly more toxicity in patients
receiving the higher dosage of idarubicin. This
may
reflect
different
pharmacokinetic
parameters in pediatric patients than those
used in previously published studies in adults.
No difference in acute cardiotoxicity was
noted, but long-term follow-up is needed to
establish any evidence of benefit that
idarubicin may provide in that regard.
Bone marrow transplantation from a
matched sibling donor for patients in first
complete remission is now established as the
treatment of choice for high-risk AML. The
cytogenetic profile of the leukaemic cells at
diagnosis is important in defining high- and
low-risk subgroups. For most children with
standard-risk AML in first remission without a
fully matched sibling donor, either autologous
transplantation or further intensive postremission chemotherapy is used. Some studies
have shown a survival advantage for patients
undergoing
autologous
transplantation.
However, several recent studies have shown
that intensive chemotherapy is just as
effective, with the issue remaining unresolved.
Unrelated allogeneic transplants result in
lower relapse rates but higher treatmentrelated mortality, making this option suitable
for high-risk patients only. Since only 15% to
20% of children with AML have suitable
related donors, other strategies are necessary
to improve overall survival. Several adult and
pediatric studies explored the benefits of
modifying induction therapy in AML. Some
included
substituting
idarubicin
or
mitoxantrone for daunorubicin, increasing the
dose or duration of cytarabine, and
administering the second course of induction
chemotherapy on days 10 to 14.13,14. The
latter approach is referred to as timed
sequential therapy and theoretically may
recruit residual leukemic cells into cell cycle,
Majalah Kedokteran Nusantara Volume 41 y No. 2 y Juni 2008
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Karangan Asli
making them more susceptible to cytarabine
and other cell-cycle–specific agents.
AML is the most common leukaemia
seen in children with Down’s syndrome. The
risk of increased deaths from infection during
induction and remission means that there has
to be very good supportive and nursing care.
There must also be extreme vigilance as these
children are vulnerable to life-threatening
infections during their treatment although
they do have a very good chance of cure and a
very low risk of relapse. AML in children with
Down’s syndrome is quite an indolent disease.
Clinical problems may be slow to children
with Down’s syndrome and AML respond
unusually well to intensive treatment. The
need for aggressive cytotoxic chemotherapy
has been questioned and debated worldwide.
Some do well on less intensive regimens but
some die. An international trial would be
necessary to establish whether it is indeed safe
to use less intensive protocols. In the early
days of the AML trials, four children with
Down’s syndrome had bone marrow
transplants (BMT). However the excellent
response to intensive cytotoxic therapy which
is now reported suggests that BMT should no
longer be necessary for any child with Down’s
syndrome. Children with Down’s syndrome
get a unique form of myeloid leukaemia –
megakaryoblastic leukaemia – which is
extremely rare in other children. It is very
sensitive to agressive chemotherapy, which
gives a high chance of cure. BMT is not
needed as these children do very well on
18
chemotherapy. Gujral et al , concluded that
diagnostic work-up of proptosis must include
a full haemogram, meticulous peripheral
blood smear examination, repeated if
necessary, and bone marrow examination
where relevant. Refractory anaemia with
excess blasts in transformation (RAEB-t )
cases with extramedullary myeloid cell
tumour should be classified as acute myeloid
leukaemia.
19
Ziegler et al , suggested that much has
changed over the past decade in front-line
treatment, identifying relapse risk and in our
understanding of leukaemogenesis in AML.
The genome revolution, molecular drug
targeting and computer-aided drug design
techniques will reshape this field yet again
over the next decade in ways which may allow
109
for further individualisation of therapy to
enhance efficacy and reduce toxicity. Perel et
20
al , reported that more than 50% of patients
can be cured of AML in childhood. Either
drug intensity or each of the induction and
postremission phases may have contributed to
the outstanding improvement in outcome.
Lowdose MT is not recommended. Exposure
to this lowdose MT may contribute to clinical
drug resistance and treatment failure in
patients
who
experience
relapse.
21
Abrahamsson et al found the survival was
62±6% in 64 children given stem cell
transplantation (SCT) as part of their relapse
therapy. A significant proportion of children
with relapsed AML can be cured, even those
with early relapse. Children who receive reinduction therapy, enter remission and
proceed to SCT can achieve a cure rate of
60%.
22
Creutzig et al , found that late
subclinical
cardiomyopathy
occurred
temporarily in seven patients. The risk of
developing late clinical cardiotoxicity was
highest in patients with early cardiotoxicity
and in patients with secondary malignancy.
The investigators concluded that the
frequency
of
anthracyclineassociated
cardiomyopathy was low in patients treated
23
on the AML-BFM protocols. Leung et al
concluded that late sequelae are common in
long-term survivors of childhood AML. Our
findings should be useful in defining areas for
surveillance of and intervention for late
sequelae and in assessing the risk of individual
late effects on the basis of age and history of
treatment. To reduce the high incidence of
ED and TRM in children with AML, early
diagnosis and adequate treatment of
complications are needed. Children with
AML should be treated in specialized
pediatric cancer centres only. Prophylactic and
therapeutic regimens for better treatment
management of bleeding disorders and
infectious complications have to be assessed in
future trials to ultimately improve overall
survival in children with AML.
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D, Dworzak M, Stary J, Lehrnbecher T.
Early deaths and treatment realted
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for acute myeloid leukemia: Analysis of
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15. Lange BJ, Gerbing RB, Feusner J, Skolnik
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17. O’Brien TA, Russel SJ, Vowels MR,
Oswald CM, Tiedemann K, Shaw PJ, et
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Arya LS, Ghose S, et al. Brief report.
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19. Perel Y, Auvrignon A, Leblanc T, Vannier
JP, Michel G, Nelken B, et al. Impact of
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Hovi L, Jonmundsson G, Zeller B, et al.
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111
Majalah Kedokteran Nusantara Volume 41 y No. 2 y Juni 2008
Insidence of Acute Myeloid…
Incidence of Acute Myeloid Leukemia in Children in Haji Adam Malik
Hospital Medan
Selvi Nafianti, Nelly Rosdiana, dan Bidasari Lubis
Division Hematology-Oncology Child Health Department Medical Faculty
University of Sumatera Utara / Haji Adam Malik Hospital Medan Indonesia
ackground: Leukemia is the most common malignancy in childhood and about 15
percent of childhood leukemia cases are acute myelogenous leukemia (AML). It is reported in
more than 13,000 people newly diagnosed each year. The overall survival rate has reached a
plateau at approximately 60%, suggesting that further intensification of therapy per se will not
substantially improve survival rates. Methods: This study was retrospective with all the children
who came to Division Hematology-Oncology Haji Adam Malik Hospital during January 2001 December 2006 with diagnosis Acute Myeloid Leukemia (AML) were enrolled to this study. The
diagnosis of AML was established based on morphology. There were 45 children meet the
criteria. Results: in our study there were 25 boys and 20 girls. Age range 1-14 years (median age 9
yrs). Most patient were in group age more than 10 years old, followed by group age 1-5 and 5-10
years as much as 13 cases each. There were 14 children suffered from severe malnutrition, 13
mild malnutrition and 13 moderate malnutrition. There were total of 39 patient had
chemotherapy, and 6 patient refused to have chemotherapy with one and another reason. Only 6
from 45 were survival, death in 20 cases mostly in induction phase 10 cases, consolidation 7 cases
and maintenance 3 cases. There were 19 cases who refused to follow the chemotherapy protocol.
Conclusion: AML is remain a major problem in developing countries. Incidence may vary due to
the limitation of diagnostic tool and prognosis was still bad.
Keywords: acute myeloid leukemia, children
INTRODUCTION
Acute myeloid leukemia (AML), also
known as acute myelogenous or acute
myeloblastic leukemia, is a type of cancer that
starts from cells that normally develop into
1-5
blood cells. AML mainly develops from two
types of white blood cells: granulocytes or
monocytes. AML is caused by genetic damage
to these developing cells in the bone marrow.
The result is uncontrolled growth and
accumulation of undeveloped cells called
"leukemic blasts," which fail to function as
normal blood cells. As these cells accumulate,
they block the production of normal marrow
cells, leading to a deficiency of red cells,
blood-clotting platelets and normal infection6-8
Acute myelogenous
fighting white cells.
leukemia (AML) is the most common form of
leukemia with more than 13,000 people
diagnosed each year, according to National
Cancer Institute estimates. About 15 percent
of childhood leukemia cases are AML. Older
individuals, however, are more likely to
develop the disease. The median age at
diagnosis is 67. Of those with AML, less than
6 percent are younger than 20 when
diagnosed; more than 55 percent are
diagnosed at 65 or older. About 0.38 percent
of people will be diagnosed with AML during
9-12
their lifetimes.
Each year in the United States 500 to 600
individuals younger than 21 years develop
acute myeloid leukemia (AML). Current
treatment for AML typically consists of 3 or 4
courses of intensive, myelosuppressive
chemotherapy with or without bone marrow
transplantation from a histocompatible family
donor.This therapy cures about half the
children with AML; of the other half, most
succumb to AML-related causes, but 5% to
13-16
15% die from toxic effects of treatment.
17-23
It is not
The cause of AML is unknown.
contagious and is not inherited, but several
factors have been linked to increased risk of
the disease. These include exposure to very
high doses of radiation, exposure to the
Majalah Kedokteran Nusantara Volume 41 y No. 2 y Juni 2008
104
Karangan Asli
chemical
benzene
and
exposure
to
chemotherapy. Smoking is another proven
risk factor, which causes about 1 in 5 cases of
AML. Uncommon genetic disorders, such as
Fanconi anemia and Down syndrome, are
associated with an increased risk of AML.
Identifying risk factors for childhood leukemia
(e.g., environmental, genetic, infectious) is an
important step in the reduction of the overall
burden of the disease. In general, benzene and
ionizing radiation are two environmental
exposures strongly associated with the
development of childhood AML or ALL.
Future studies, when appropriate, should
attempt to use common questionnaires,
address timing and route of exposure,
document evidence that exposure has actually
been transferred from the workplace to the
child, and store biological samples when
3
possible. Scheneider et al , reported in
patients with AML after treatment for Germ
cell tumor (GCT), several pathogenetic
mechanisms must be considered. AML might
evolve from a malignant transformation of
GCT components without any influence of
the chemotherapy. On the other hand, the
use of alkylators and topoisomerase II
inhibitors is associated with an increased risk
of t-AML. Future studies will show if the
reduction of treatment intensity in the current
protocol reduces the risk of secondary
5-8
leukemia in these patients.
A
combination
of
morphologic,
immunophenotypic, and cytogenetic studies is
usually required to establish the diagnosis of
AML. Immunophenotype is important,
particularly in establishing a diagnosis of acute
megakaryoblastic leukemia (AMKL), myeloid
leukemia with minimal differentiation, and
myeloid/lymphoid (mixed, biphenotypic)
leukemia. Recently, the World Health
Organization (WHO), in conjunction with
the Society for Hematopathology and the
European Association of Hematopathology,
has proposed a new classification for
hematopoietic
neoplasms.
The
WHO
classification defines subsets of AML on the
basis of both morphologic and cytogenetic
characteristics. Although the current AML
classification schemes, including the WHO
scheme, have been developed for adult AML,
the concepts underlying these classifications
can be applied to pediatric AML. Recent gene
105
expression profiling studies demonstrated
distinct expression signatures for each of the
known prognostic subtypes of AML.
Importantly, some of the pediatric AML
subtype specific expression signatures were
essentially the same as those of selected adult
AML
cases,
suggesting
a
shared
8-14
11
leukemogenesis. Creutzig U et al , Stem
cell transplantation (SCT), as applied in highrisk patients with a matched related donor,
did not significantly improve the outcome
compared to chemotherapy alone. In spite of
treatment intensification, the therapy related
death rate decreased from trial to trial, mainly
during induction. The future aim is to reduce
long-term sequelae, especially cardiotoxicity,
by administration of less cardiotoxic drugs,
and toxicity of SCT by risk-adapted
indications. The AML-BFM studies performed
in three European countries with >70
cooperating
centers
have
significantly
improved the outcome in AML children;
nevertheless, increasing experience with these
intensive treatment is of fundamental
6-12
importance to reduce fatal complications.
Despite several strategies to increase the
intensity of therapy, the overall survival rate
has reached a plateau at approximately 60%,
suggesting that further intensification of
therapy per se will not substantially improve
survival rates. It appears that the “one-sizefits-all” treatment strategy will not further
improve current AML survival rates. The
merit of individualized therapy for AML has
been clearly demonstrated in the treatment of
APL. The introduction of ATRA and the
tailored use of specific treatment components
(increased dose-intensity of anthracycline
during induction and consolidation; use of
ATRA plus 6-mercaptopurine and methotrexate
during
maintenance)
has
resulted
in
reproducible 5-year survival rates exceeding
80%. Despite intensive induction and
postremission chemotherapy, 5-year eventfree survival (EFS) of children with acute
myeloid leukemia (AML) is only 40% to 50%.
Bone marrow transplantation (BMT) from
HLA-matched sibling donors is associated
with lower relapse risk and superior overall
survival (OS) compared with other types of
postremission therapy, including consolidation
therapy, maintenance chemotherapy, and
autologous BMT. Drug resistance is a major
Majalah Kedokteran Nusantara Volume 41 y No. 2 y Juni 2008
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Insidence of Acute Myeloid…
obstacle to effective AML treatment. The
rates of early death (ED) and treatmentrelated mortality (TRM) are unacceptably
high in children undergoing intensive
chemotherapy for acute myeloid leukemia
(AML). Better strategies of supportive care
might help to improve overall survival in
7-13
these children.
METHODS
This was a retrospective study, we review
all the children who came to Division
Hematology-Oncology Haji Adam Malik
Hospital during January 2001 - December
2006 with diagnosis Acute Myeloid Leukemia
(AML) were enrolled to this study. The
diagnosis of AML was established based on
morphology. There were 45 children meet the
criteria.
RESULTS
Table 1. Characteristic of study subject
N=45
Sex
Boys
25
Girls
20
Age group (years)
10
17
Nutritional State
Normal
5
Mild
13
Moderate
13
Severe
14
Table 2. Distribution sample based on FAB Classification
N=45
FAB Classification
M1
28
M2
2
M3
0
M4
10
M5
1
M6
4
M7
0
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106
Karangan Asli
Table 3. Chemotherapy
N=45
Chemotherapy phase
Induction
17
Consolidation
12
Maintenance
10
Discontinued
6
Table 4. Treatment outcome
N=45
Survival
6
Induction
10
Death
Consolidation
7
Maintenance
3
Before chemotherapy
6
During chemotherapy
13
Drop out
Table 1 showed that in our study there
were 25 boys and 20 girls. Most patient were
in group age more than 10 years old, followed
by group age 1-5 and 5-10 years as much as
13 cases
each. There were 14 children
suffered from severe malnutrition, 13 mild
malnutrition and 13 moderate malnutrition.
From table 3, found that there were total
of 39 patient had chemotherapy, and 6
patient refused to have chemotherapy with
one and another reason
Only 6 from 45 were survival, death in
20 cases mostly in induction phase 10 cases,
consolidation 7 cases and maintenance 3 cases.
There were 19 cases who refused to follow
the chemotherapy protocol.
107
DISCUSSION
The effect of BMI on outcome in
pediatric AML is not a trivial problem: the
reduced survival in underweight and
overweight patients is roughly equal to the
improved survival accomplished by 10 years
of progress in pediatric AML. Treatmentrelated mortality is the worst possible
outcome for an individual enrolled in a clinical
trial, and if treatment-related mortality is not
countered by a net gain in survival, excess
treatment related mortality is also the worst
possible outcome for a clinical trial. These
results have implications for clinicians and
clinical investigators. This is the first example
of immediate rather than impending lifeshortening effects of excess weight in the
young and a confirmation of the risks of
Majalah Kedokteran Nusantara Volume 41 y No. 2 y Juni 2008
Selvi Nafianti dkk.
undernutrition in other pediatric cancers.
Interventions currently available that could
reduce the treatment related mortality in
underweight and overweight groups include
formal
nutritional
and
immunologic
assessment at diagnosis. Underweight patients
could benefit from preemptive nutritional
intervention or intravenousglobulin. In
overweight patients, correction of persistent
moderate hyperglycemia and hypertension
may remediate 2 important comorbidities.
15
Lange et al , in their study to compare
survival rates in children with AML who at
diagnosis are underweight (body mass index
[BMI] _10th percentile), overweight (BMI
_95th percentile), or middleweight (BMI =
11th-94th percentiles). Eighty-four of 768
patients (10.9%) were underweight and 114
(14.8%) were overweight. After adjustment
for potentially confounding variables of age,
race, leukocyte count, cytogenetics, and bone
marrow transplantation, compared with
middleweight patients, underweight patients
were less likely to survive and more likely to
experience treatment related mortality.
Similarly, overweight patients were less likely
to survive and more likely to have treatmentrelated mortality than middleweight patients.
Infections incurred during the first 2 courses
of chemotherapy caused most treatmentrelated deaths. The study noted that
treatment-related complications significantly
reduce
survival
in
overweight
and
underweight children with AML. Becton et
16
al , reported that intensifying induction with
high-dose DAT and the addition of CsA to
consolidation chemotherapy did not prolong
the durations of remission or improve overall
survival for children with AML. O’Brian et
17
al , found that improvements in remissioninduction rates, decreased treatment related
toxicity, and improved outcomes with
allogeneic
sibling
transplantation
have
contributed to higher survival rates.
Nevertheless, further improvements are
needed. Unlike AML trials in adults, AML in
children results do not support an advantage
of idarubicin over daunorubicin in the
treatment of pediatric AML in terms of
remission induction or overall survival rates.
In addition, it’s found greater toxicity with
idarubicin than with daunorubicin.
Insidence of Acute Myeloid…
Creutzig et al, found that idarubicin
when used for remission induction in
childhood AML was associated with more
bone marrow toxicity, with a greater number
of days to neutrophil recovery, than patients
treated with daunorubicin. The study shown
that greater renal, gastrointestinal, and
pulmonary toxicity occurred in patients
receiving
idarubicin
during
remission
induction. Gastrointestinal toxicity in our
patient group was dose related and entailed
significantly more toxicity in patients
receiving the higher dosage of idarubicin. This
may
reflect
different
pharmacokinetic
parameters in pediatric patients than those
used in previously published studies in adults.
No difference in acute cardiotoxicity was
noted, but long-term follow-up is needed to
establish any evidence of benefit that
idarubicin may provide in that regard.
Bone marrow transplantation from a
matched sibling donor for patients in first
complete remission is now established as the
treatment of choice for high-risk AML. The
cytogenetic profile of the leukaemic cells at
diagnosis is important in defining high- and
low-risk subgroups. For most children with
standard-risk AML in first remission without a
fully matched sibling donor, either autologous
transplantation or further intensive postremission chemotherapy is used. Some studies
have shown a survival advantage for patients
undergoing
autologous
transplantation.
However, several recent studies have shown
that intensive chemotherapy is just as
effective, with the issue remaining unresolved.
Unrelated allogeneic transplants result in
lower relapse rates but higher treatmentrelated mortality, making this option suitable
for high-risk patients only. Since only 15% to
20% of children with AML have suitable
related donors, other strategies are necessary
to improve overall survival. Several adult and
pediatric studies explored the benefits of
modifying induction therapy in AML. Some
included
substituting
idarubicin
or
mitoxantrone for daunorubicin, increasing the
dose or duration of cytarabine, and
administering the second course of induction
chemotherapy on days 10 to 14.13,14. The
latter approach is referred to as timed
sequential therapy and theoretically may
recruit residual leukemic cells into cell cycle,
Majalah Kedokteran Nusantara Volume 41 y No. 2 y Juni 2008
108
Karangan Asli
making them more susceptible to cytarabine
and other cell-cycle–specific agents.
AML is the most common leukaemia
seen in children with Down’s syndrome. The
risk of increased deaths from infection during
induction and remission means that there has
to be very good supportive and nursing care.
There must also be extreme vigilance as these
children are vulnerable to life-threatening
infections during their treatment although
they do have a very good chance of cure and a
very low risk of relapse. AML in children with
Down’s syndrome is quite an indolent disease.
Clinical problems may be slow to children
with Down’s syndrome and AML respond
unusually well to intensive treatment. The
need for aggressive cytotoxic chemotherapy
has been questioned and debated worldwide.
Some do well on less intensive regimens but
some die. An international trial would be
necessary to establish whether it is indeed safe
to use less intensive protocols. In the early
days of the AML trials, four children with
Down’s syndrome had bone marrow
transplants (BMT). However the excellent
response to intensive cytotoxic therapy which
is now reported suggests that BMT should no
longer be necessary for any child with Down’s
syndrome. Children with Down’s syndrome
get a unique form of myeloid leukaemia –
megakaryoblastic leukaemia – which is
extremely rare in other children. It is very
sensitive to agressive chemotherapy, which
gives a high chance of cure. BMT is not
needed as these children do very well on
18
chemotherapy. Gujral et al , concluded that
diagnostic work-up of proptosis must include
a full haemogram, meticulous peripheral
blood smear examination, repeated if
necessary, and bone marrow examination
where relevant. Refractory anaemia with
excess blasts in transformation (RAEB-t )
cases with extramedullary myeloid cell
tumour should be classified as acute myeloid
leukaemia.
19
Ziegler et al , suggested that much has
changed over the past decade in front-line
treatment, identifying relapse risk and in our
understanding of leukaemogenesis in AML.
The genome revolution, molecular drug
targeting and computer-aided drug design
techniques will reshape this field yet again
over the next decade in ways which may allow
109
for further individualisation of therapy to
enhance efficacy and reduce toxicity. Perel et
20
al , reported that more than 50% of patients
can be cured of AML in childhood. Either
drug intensity or each of the induction and
postremission phases may have contributed to
the outstanding improvement in outcome.
Lowdose MT is not recommended. Exposure
to this lowdose MT may contribute to clinical
drug resistance and treatment failure in
patients
who
experience
relapse.
21
Abrahamsson et al found the survival was
62±6% in 64 children given stem cell
transplantation (SCT) as part of their relapse
therapy. A significant proportion of children
with relapsed AML can be cured, even those
with early relapse. Children who receive reinduction therapy, enter remission and
proceed to SCT can achieve a cure rate of
60%.
22
Creutzig et al , found that late
subclinical
cardiomyopathy
occurred
temporarily in seven patients. The risk of
developing late clinical cardiotoxicity was
highest in patients with early cardiotoxicity
and in patients with secondary malignancy.
The investigators concluded that the
frequency
of
anthracyclineassociated
cardiomyopathy was low in patients treated
23
on the AML-BFM protocols. Leung et al
concluded that late sequelae are common in
long-term survivors of childhood AML. Our
findings should be useful in defining areas for
surveillance of and intervention for late
sequelae and in assessing the risk of individual
late effects on the basis of age and history of
treatment. To reduce the high incidence of
ED and TRM in children with AML, early
diagnosis and adequate treatment of
complications are needed. Children with
AML should be treated in specialized
pediatric cancer centres only. Prophylactic and
therapeutic regimens for better treatment
management of bleeding disorders and
infectious complications have to be assessed in
future trials to ultimately improve overall
survival in children with AML.
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