Pediatric Myelodysplastic Syndrome

Pediatric Myelodysplastic Syndrome
Overview
Presentation
DDx
Workup
Treatment
Medication
Updated: Oct 4, 2013
Background
Pathophysiology
Etiology
Epidemiology
Prognosis
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References
Background
Myelodysplastic syndrome (MDS) in childhood encompasses a diverse group of bone marrow
disorders that share a common clonal defect of stem cells and that result in ineffective
hematopoiesis with dysplastic changes in the marrow. These disorders are characterized by one
or more cytopenias despite a relatively hypercellular bone marrow. MDS disorders have been
referred to as preleukemias because of their tendency to transform into acute myeloid leukemia
(AML).
MDS is rare in childhood and may have a rapidly progressive course with an extremely poor
prognosis without hematopoietic stem cell transplantation (HSCT). The disease can arise in a
previously healthy child; in this case, it is referred to as de novo or primary MDS. MDS may
develop in a child with a known predisposition (eg, previous cytotoxic chemotherapy); this is
referred to as secondary MDS (see Etiology). The disease is most common in adults, especially
elderly people, and the course varies, ranging from an acute, rapidly fatal illness to a chronic,
indolent illness.
MDS is classified into groups according to findings on peripheral blood smears, bone marrow
histology, cytogenetics, and clinical examination. Notable controversy surrounds classification
based on a systematic evaluation of frequency, outcomes, and treatment difficulty. Most
accepted systems are modification of the classification of adult MDS proposed by the French-
American-British (FAB) group.[1] Children with MDS whose disease fit in these classes are often
considered to have adult-type MDS in current studies.
Types in the FAB system are the following:
Refractory anemia (RA)

RA with ringed sideroblasts (RARS)
RA with excess blasts (RAEB; 5-20% marrow blasts)
RAEB in transition to AML (RAEBT; 20-30% marrow blasts)
Chronic myelomonocytic leukemia (CMML)
MDS in children and adults differs in other ways. For example, CMML is extremely rare in
pediatric populations. RARS is exceedingly rare in children. Finally, constitutional abnormalities
are observed in many children but few adults.
One of the criticisms of the FAB system is that it does not include the prognostic implications of
cytogenetic findings or other biologic features. Of note are 5q- syndrome (5q deletion
syndrome), which is extremely rare in children; monosomy 7 syndrome; and infantile monosomy
7. Monosomy 7 is most often associated with juvenile myelomonocytic leukemia (JMML), and
as many as 30% of children with JMML have a deletion of all or part of chromosome 7.
Although this finding imparts some prognostic value concerning morbidity, its contribution in
predicting mortality is controversial.
In an attempt to better characterize these disorders and incorporate cytogenetic information, the
World Health Organization (WHO) described an alternate classification scheme for MDS.[2] As
described below, the WHO classification eliminated the RAEBT category and added an
unclassified category. The WHO current classification is as follows:
RA or RARS (erythroid dysplasia only, marrow blasts < 5%)

RA with multilineage dysplasia (blasts < 5%)
5q- syndrome (blasts < 5%, no other genetic abnormalities)
RAEB (blasts 5-20%)
MDS unclassified (does not fit into above groups)
Another classification schema directed toward MDS in childhood, mainly adapted by the
European community, included MDS (refractory cytopenia, RAEB and RAEBT), JMML, and
Down syndromespecific diseases. The changing classification schemes and continuing
controversies reflect a limited understanding of MDS. An adequate scheme is likely to be
devised only after detailed comprehension of MDS at its genetic, biologic, and clinical levels is
attained. Progress in classifying MDS and myeloproliferative disorders in children has been
slow. These diseases were included for the first time in the international classification of
childhood cancers in 2005.[3]
When a child presents with cytopenias associated with MDS, physicians should administer
supportive care until the diagnosis is established. Many patients present with profound cytopenia
and a notable risk for infection. Transfusions and broad-spectrum antibiotics may be required to
treat life-threatening anemia, thrombocytopenia, and infection until definitive therapy can be
started.
In MDS pediatric patients with refractory cytopenia, hematopoietic stem cell transplantation
(HSCT) from a matched related or unrelated donor early in the course of the disease is the
treatment of choice. (See Treatment.)
Pediatric Myelodysplastic Syndrome
Overview
Presentation
DDx
Workup
Treatment
Medication
Background
Pathophysiology
Etiology
Epidemiology
Prognosis
Show All
References
Background
Myelodysplastic syndrome (MDS) in childhood encompasses a diverse group of bone marrow
disorders that share a common clonal defect of stem cells and that result in ineffective
hematopoiesis with dysplastic changes in the marrow. These disorders are characterized by one
or more cytopenias despite a relatively hypercellular bone marrow. MDS disorders have been
referred to as preleukemias because of their tendency to transform into acute myeloid leukemia
(AML).
MDS is rare in childhood and may have a rapidly progressive course with an extremely poor
prognosis without hematopoietic stem cell transplantation (HSCT). The disease can arise in a
previously healthy child; in this case, it is referred to as de novo or primary MDS. MDS may
develop in a child with a known predisposition (eg, previous cytotoxic chemotherapy); this is
referred to as secondary MDS (see Etiology). The disease is most common in adults, especially
elderly people, and the course varies, ranging from an acute, rapidly fatal illness to a chronic,
indolent illness.
MDS is classified into groups according to findings on peripheral blood smears, bone marrow
histology, cytogenetics, and clinical examination. Notable controversy surrounds classification
based on a systematic evaluation of frequency, outcomes, and treatment difficulty. Most
accepted systems are modification of the classification of adult MDS proposed by the French-
American-British (FAB) group.[1] Children with MDS whose disease fit in these classes are often
considered to have adult-type MDS in current studies.
Types in the FAB system are the following:
Refractory anemia (RA)

RA with ringed sideroblasts (RARS)
RA with excess blasts (RAEB; 5-20% marrow blasts)
RAEB in transition to AML (RAEBT; 20-30% marrow blasts)
Chronic myelomonocytic leukemia (CMML)
MDS in children and adults differs in other ways. For example, CMML is extremely rare in
pediatric populations. RARS is exceedingly rare in children. Finally, constitutional abnormalities
are observed in many children but few adults.
One of the criticisms of the FAB system is that it does not include the prognostic implications of
cytogenetic findings or other biologic features. Of note are 5q- syndrome (5q deletion
syndrome), which is extremely rare in children; monosomy 7 syndrome; and infantile monosomy
7. Monosomy 7 is most often associated with juvenile myelomonocytic leukemia (JMML), and
as many as 30% of children with JMML have a deletion of all or part of chromosome 7.
Although this finding imparts some prognostic value concerning morbidity, its contribution in
predicting mortality is controversial.
In an attempt to better characterize these disorders and incorporate cytogenetic information, the
World Health Organization (WHO) described an alternate classification scheme for MDS.[2] As
described below, the WHO classification eliminated the RAEBT category and added an
unclassified category. The WHO current classification is as follows:
RA or RARS (erythroid dysplasia only, marrow blasts < 5%)

RA with multilineage dysplasia (blasts < 5%)
5q- syndrome (blasts < 5%, no other genetic abnormalities)
RAEB (blasts 5-20%)
MDS unclassified (does not fit into above groups)
Another classification schema directed toward MDS in childhood, mainly adapted by the
European community, included MDS (refractory cytopenia, RAEB and RAEBT), JMML, and
Down syndromespecific diseases. The changing classification schemes and continuing
controversies reflect a limited understanding of MDS. An adequate scheme is likely to be
devised only after detailed comprehension of MDS at its genetic, biologic, and clinical levels is
attained. Progress in classifying MDS and myeloproliferative disorders in children has been
slow. These diseases were included for the first time in the international classification of
childhood cancers in 2005.[3]
When a child presents with cytopenias associated with MDS, physicians should administer
supportive care until the diagnosis is established. Many patients present with profound cytopenia
and a notable risk for infection. Transfusions and broad-spectrum antibiotics may be required to
treat life-threatening anemia, thrombocytopenia, and infection until definitive therapy can be
started.
In MDS pediatric patients with refractory cytopenia, hematopoietic stem cell transplantation
(HSCT) from a matched related or unrelated donor early in the course of the disease is the
treatment of choice. (See Treatment.)
Pathophysiology
MDS is a clonal disorder. Aberration occurs in a stem cell that can give rise to multiple lineages.
This event explains the presence of multiple derangements observed in the bone marrow that
involve several cell lineages. Genetic abnormalities associated with MDS block differentiation of
hematopoietic stem and progenitor cells.
As the affected cell lines continue to divide and to provide the marrow with dysplastic cells,
bone marrow dysfunction becomes apparent. This state may persist until a clone undergoes
further transformation to leukemia and the marrow becomes fibrotic and aplastic.
As an alternative, the clone may progressively deteriorate, and the appearance of marrow may
return to normal as healthy stem cells repopulate it. The natural progression of MDS is, thus, a
function of an abnormal clone leading to progressive loss of marrow function, transformation to
AML, or spontaneous remission.
The observation of cytogenetic abnormalities, most specifically monosomy 7 and

neurofibromatosis type 1 (NF1) genetic mutations, support the theory that cell dysregulation
occurs in a multi-hit fashion. In monosomy 7, a genetic predisposition and a later loss of a
critical region on chromosome 7 that encodes a suspected tumor suppressor gene is suggested to
set the stage for proliferation of an abnormal clone. Loss of the chromosome may occur during
an embryonic period in hematopoietic stem cells or may result from cytotoxic therapy.
In patients with NF1, function of the NF1 gene product, neurofibronin (a glutamyl transpeptidase
[GTPase]) is decreased, resulting in the loss of negative feedback on the RAS gene. Therefore,
RAS is constitutively active in NF1. Farnesyltransferase inhibitors are able to inhibit activated
RAS by preventing the required farnesylation reaction from occurring. Murine experiments
suggest that RAS mutations disturb hemopoietic differentiation and lead to a proliferative
advantage of hematopoietic precursor cells, ineffective erythropoiesis, and anemia.
Monosomy 7 occurs in approximately 30% of primary childhood MDS cases and in about 50%
of therapy-related MDS cases.
The 5q- syndrome is considered a distinct MDS subtype, characterized by deletion of 5q-, less
than 5% bone marrow blasts, normal or elevated platelet counts, longer survival, and an
increased response to therapy with lenalidomide (Revelmid). Although 5q- is occasionally
reported in children, the typical 5q- syndrome has not been reported.
In a recent study from the Brazilian Cytogenetic Subcommittee of the Pediatric Myelodysplastic
Syndromes Cooperative Group, clonal abnormalities were found in 36.9% of the 84 pediatric
MDS cases. Monosomy 7/deletion 7q was the most frequent clonal abnormalaity (13.9% of
cases), followed by trisomy 8 and 21. Clonal abnormalities were more frequent in RAEB/T
(37.5%), JMML (36.4%) and secondary MDS (33.3%) than in RC (27.2%). The median OS was
31 months for the MDS group, 122 months for the subgroup with chromosome 7 abnormality, 35
months for the subgroup with abnormal karyotype without chromosomal 7 abnormality and 29
months with those with a normal karyotype.[4]
Etiology
MDS may be primary or secondary. Children with primary MDS may have an underlying but
unknown genetic defect that predisposes them to develop MDS at a young age. Approximately
20% of children have an underlying congenital anomaly or syndrome associated with
chromosomal abnormalities.
Secondary MDS occurs in patients after chemotherapy or radiation therapy (therapy-related

MDS) or in patients with inherited bone marrow failure disorders, acquired aplastic anemia, or
familial MDS. Therefore, the distinction between primary MDS and secondary MDS may
become arbitrary.
Not all bone marrow failure syndromes are associated with the development of MDS. For
example, patients with dyskeratosis congenita develop bone marrow failure in 95% of cases, but
MDS has only been reported in a few cases.[5]
MDS and acute myeloid leukemia (AML) in Down syndrome are closely linked; the biologic and
clinical features are distinct from the diseases observed in children without Down syndrome. In
the proposed WHO classification, MDS and AML in Down syndrome are recognized as a single
specific entity, myeloid leukemia of Down syndrome (ML-DS).[2] Antecedent MDS is common
in those who develop AML in this population, affecting as many as 70% of children with ML-
DS.[6]
Neurofibromatosis type 1 (NF1) is associated with the development of JMML. Patients with NF1
have a 350-fold increased risk of JMML. Shwachman-Diamond syndrome is characterized by
pancreatic insufficiency with neutropenia. MDS occurs in 10-25% of individuals with this
syndrome.[7]
Fanconi anemia (4-7%) increases the risk of MDS and AML[8] ; 48% of patients with Fanconi
anemia develop leukemia or MDS by age 40 years. It is often associated with monosomy 7 and
duplication of 1q. Diagnosing refractory cytopenia in a patient with Fanconi anemia may be
difficult.
Kostmann syndrome (0.6%) is also known as congenital agranulocytosis. The survival of

patients with this syndrome has significantly improved with the introduction of granulocyte
colony-stimulating factor (G-CSF) treatment. Studies from the severe congenital neutropenia
registry have shown a 9% crude rate of MDS development and an annual progression rate of
3%.[9] Partial or complete loss of chromosome 7 is found in more than half of the patients who
develop MDS, and the development of MDS is almost always preceded by acquired mutation of
the G-CSF receptor gene.
MDS has occasionally been described in patients with Diamond-Blackfan anemia. However, no
estimates are available, and it may be rare, given the lack of MDS cases in a study of 229
patients.[10]
As a causative factor, previous therapy with alkylating agents (2-5%) is associated with
monosomy 7 and chromosome 5 deletions. These patients have poor response rates. Previous
administration of a topoisomerase inhibitor is a rare contributing factor. In the rare cases
involving a topoisomerase inhibitor, patients usually develop AML.
MDS develops in 10-15% of patients with acquired aplastic anemia who are not treated with
stem cell transplantation; this appears to occur at the same rate in idiopathic and hepatitis-
associated aplastic anemia.[11] MDS may occur in these cases within 3 years of presentation;
whether prolonged treatment with G-CSF and cyclosporine is associated with MDS development
is controversial.[12]
Kim et al showed that pediatric MDS patients showed a higher methylation level of CDKN2B
than pediatric controls, but a lower level than adult MDS patients. Methylation level was higher
in cases with greater than 5% blasts than in pediatric controls, and the level was also higher in
cases with abnormal karyotype. The CDKN2B gene encodes a tumor suppressor that normally
prevents uncontrolled cell proliferation by arresting the cell cycle at the G1 phase. This gene is
the most commonly silenced tumor suppressor gene in MDS, mainly by promoter
hypermethylation, which contributes to disease progression in adult MDS. Thus, these authors
were able to show that methylation of CDKN2B is associated with the pathogenesis and
prognosis in pediatric MDS.[13]
Epidemiology
United States statistics
The distribution of FAB classifications of MDS in adult populations is as follows:
RA - 38.4%
RARS - 11.5%
RAEB - 15%
RAEBT - 3.9%
CMML - 31.2%
In the pediatric population, aggressive forms such as RAEB and RAEBT are more common than
RA or RARS.
The epidemiologic literature on childhood MDS is sparse. Factors for this lack of information
include the following:
A widely accepted classification is lacking

Patients with indolent forms of the disease may not be referred to a tertiary center; this
practice may result in a bias among institution-based studies toward the aggressive forms
Cancer registries do not generally register patients with MDS
In one of the earliest reports, MDS or preleukemia was reported in 17% of childhood AMLs
(2.9% of all children with leukemia).[14] Other studies confirmed that a preleukemic phase
precedes AML in about 12-20% of children with AML.[15] These studies were based on referrals
for suspected AML and did not include the less advanced cases of MDS.
International statistics
The few population-based studies have given conflicting data about the incidence of MDS.
Population-based data from Denmark and Canada (British Columbia) showed that MDS and
JMML represented 6% of all hematologic malignancies in children, corresponding to annual
incidences of 1.8 and 1.2 cases per million children and adolescents aged 0-14 years,
respectively.[16]
A similar rate of MDS and JMML (7.7% in combination with childhood leukemia) was found in
Japan, where therapy-related MDS represents 23% of all cases.
In the United Kingdom, the incidence is reported to be 0.5 case per million population, which
accounts for 1.1% of childhood hematologic malignancies. The exclusion of secondary MDS
may only partly explain the relatively low incidence in the United Kingdom. The incidence in
elderly people is 89 per 100,000 population.
Race-, sex-, and age-related demographics
Data from the Children's Cancer Group showed that 75% of patients are white, 8.5% are
Hispanic, 8% are African American, 3.5% are Asian, and 5% are of unknown race or
ethnicity.[17] Most studies have been conducted in countries with predominantly white
populations. Therefore, results may not reflection the true racial distribution. The incidence for
each race has not been reported.
Combined data from 290 patients with mainly primary MDS showed a nearly-equal sex
distribution. In patients with adult-type MDS such as RA, RAEB, and RAEBT, the male-to-
female ratio is 1.2:1.
MDS occurs in people of all ages. For adult-type MDS, the median age is 5-8 years. Data from
about 290 children with primary MDS showed a median age of 6.8 years.
Prognosis
The prognosis for pediatric patients with MDS is poor without HSCT. The most common cause
of death is cytopenia. Infection, rather than progression to AML, ultimately results in the demise
of most patients with MDS.
One study that included adults showed that the prognosis for Japanese patients with RA was
significantly more favorable than that of German patients (median survival, 175 vs 40 mo).[18]
This result suggests an ethnic variation in survival between Asian and Caucasian populations.
Furthermore, the cumulative risk of acute leukemia evolution was significantly lower in Japanese
patients than in German patients.
Patients with Down syndrome and MDS respond best to treatment, whereas those with MDS due
to previous therapy with alkylating agents fare the worst. Patients without Down syndrome who
undergo allogeneic HSCT have the best outcome, despite transplant-related mortality.
Until recently, most of the prognostic factors in MDS, such as those used in the International
Prognostic Scoring System (IPSS), the Bournemouth score, and others, were based on data from
adult patients. In adults, factors that have had prognostic significance for survival and
progression to AML include bone marrow morphology, myeloblast percentage in the bone
marrow, the appearance of the bone marrow on biopsy findings, number of cytopenias,
cytogenetic abnormalities in bone marrow, age, and blood lactate dehydrogenase levels.
An analysis of candidate gene mutations in adults with MDS has demonstrated that 51% of all
patients had mutations in at least 1 of 18 genes, with mutations in TP53, EZH2, ETV6, RUNX1,
and ASXL1 significantly associated with a poor prognosis. Such studies have not yet been
completed in children with MDS.[19]
The only factor that has consistently had prognostic significance in children with MDS is
cytogenetic abnormality, notably monosomy 7.
Researchers from Japan, the United Kingdom, and the European Working Group on MDS in
Childhood have all concluded that the IPSS is of limited value in children. Investigators from
Japan and the United Kingdom found that only the IPSS karyotype group had significant
prognostic value in terms of overall survival.
In the United States, a prospective study (CCG 2891) of AML-based therapy in children with
MDS found that overall survival at 6 years was 29% 12% for patients with MDS and 31%
26% for those with JMML.[6] These outcomes were worse than those of patients who had
antecedent MDS and who were treated in the AML phase (50% 25%) or those of patients with
de novo AML (45% 3%). Nonsignificant differences in 6-year survival were observed between
patients with JMML and MDS.
In recent reports, 5-year event-free survival (EFS) rates in patients with Down syndrome and
MDS and/or AML were in excess of 80%. These rates were largely because of reductions in
treatment-related deaths from 30-40% in the early 1990s to around 10% in recent Berlin-
Frankfurt-Mnster (BFM), Nordic Society of Paediatric Haematology and Oncology (NOPHO),
and Medical Research Council studies.
Proceed to Clinical Presentation
Pediatric Myelodysplastic Syndrome Clinical

Presentation
Overview
Presentation
DDx
Workup
Treatment
Medication
History
Physical Examination
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History
Children with myelodysplastic syndrome (MDS) have a history consistent with bone marrow
failure. Their history and presentation are similar to those of children with leukemia.
The interval between the onset of symptoms and diagnosis is 0-23 months, with a median of 2
months. Patients may be asymptomatic, and the condition may be discovered when a routine
complete blood count is obtained.
Other symptoms include the following:

Fatigue
Systemic infection (bacterial or fungal)
Prolonged fever
Bruising, bleeding
Pediatric Myelodysplastic Syndrome Clinical

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History
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Children with MDS have findings consistent with bone marrow failure. The presentation may
resemble that of acute leukemia.
General appearances range from well to constitutional wasting. Pallor and fatigue due to anemia
may be present. Hepatosplenomegaly predominates in juvenile myelomonocytic leukemia
(JMML). Lymphadenopathy is present in 40-76% of patients with JMML but is present in less
than 10% of patients with adult-type myelodysplastic syndrome (MDS). About 30% of patients
with JMML have a diffuse erythematous, maculopapular rash.
Previous
Proceed to Differential Diagnose
Pediatric Myelodysplastic
Syndrome Differential Diagnoses
Overview
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DDx
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Treatment
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References
Diagnostic Considerations
The 2 major diagnostic challenges are distinguishing myelodysplastic syndrome (MDS) with a
low blast count from aplastic anemia and other nonclonal bone marrow disorders and
differentiating MDS with excess blasts from acute myeloid leukemia (AML). Also consider
autoimmune cytopenias and Diamond-Blackfan anemia.
Refractory cytopenia may be difficult to diagnose because bone marrow cellularity is often
reduced (as in aplastic anemia), impeding the identification of the often subtle dysplastic changes
that may be present. In the absence of a cytogenetic marker, the clinical course must be carefully
monitored with repeated bone marrow examinations and biopsies at least 2-3 weeks apart.
Differentiating MDS with increased blast count from de novo AML remains challenging, and
thresholds of blast counts (set at 20% or 30%) are arbitrary and may not reflect the biology of
these transitional states. De novo AML is chemotherapy-sensitive and is characterized by
balanced translocations, such as t(8;21), t(15;17), t(9;11). The usual genetic changes in MDS,
typically markers of chemoresistance, are aneuploidy and aberrations in chromosome numbers
(eg, monosomy 7).
Thus, individuals with typical cytogenetic abnormalities should be treated as having de novo
AML, regardless of the blast count. Note that most patients with MDS have a blast count of less
than 20%, whereas the vast majority of children with de novo AML have frankly leukemic
marrow. For patients with borderline blast counts, other clinical signs (eg, organomegaly,
chloroma, spinal fluid blasts) suggest a diagnosis of de novo AML.
Differential Diagnoses
Acute Lymphoblastic Leukemia
Acute Myelocytic Leukemia
Anemia, Chronic
Chromosomal Breakage Syndromes
Cytomegalovirus Infection
Herpesvirus 6 Infection
Myelodysplasia
Myelofibrosis
Parvovirus B19 Infection
Transient Erythroblastopenia of Childhood
Proceed to Workup
Pediatric Myelodysplastic Syndrome Workup
Overview
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DDx
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Treatment
Medication
Approach Considerations
Histologic Findings
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References
Diagnostic studies for myelodysplastic syndrome center on a complete blood count (CBC) with
differential, peripheral blood smears, bone marrow aspiration and biopsy. On the CBC, patients
often have anemia with high mean cellular volume and RBC distribution width. Neutropenia and
thrombocytopenia may be found.
In juvenile myelomonocytic leukemia (JMML), marked monocytosis may be present. Other

diagnostic criteria for JMML include myeloid precursors in blood smears, clonal abnormality,
granulocyte-macrophage colony-stimulating factor (GM-CSF) hypersensitivity of myeloid
progenitors, and hemoglobin F levels above the reference range for age.
Other studies include the following:
Hemoglobin electrophoresis
Studies for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) to exclude marrow
suppression due to a viral etiology
Folate and vitamin B-12 studies to evaluate for possible defects or deficiencies
Tissue typing of the patient and the family in anticipation of hematopoietic stem cell
rescue
Testing for hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-
CSF)
Chromosomal analysis
Look for constitutional abnormalities if the patient has manifestations of Down syndrome
(trisomy 21). Trisomy 21 with mosaicism occurs in 2-3% of cases in which 2 populations of cell
types are present: a normal cell line with 46 chromosomes and a second cell line with trisomy 21.
These children may appear phenotypically normal.
Order chromosomal fragility studies, including diepoxybutane (DEB) and mitomycin C (MCC)
tests for Fanconi anemia.
Children with complex chromosomal aberrations combined with a low platelet count and/or
elevated hemoglobin F levels have a notably worsened outcome.
The presence of monosomy 7 should prompt an evaluation of family members.
Bone marrow studies
Performing a bone marrow aspiration and biopsy is essential in establishing diagnosis and
classification. In MDS, bone marrow findings reveal evidence of morphologic myelodysplasia in
at least 2 different myeloid cell lines or dysplasia that exceeds 10% in one single cell line, with
evidence of a clonal cytogenetic abnormality in hematopoietic cells. Dysplastic cells of various
stages of differentiation with hypercellular findings may be evident.
Gene expression profile (GEP) analysis of bone marrow specimens has proved to be a powerful
tool for the identification of gene signatures associated with distinct leukemia subtypes and has
helped to stratify patients into different risk classes, as well as to identify deregulated genes
involved in leukemia development. In 32 pediatric bone marrow specimens from MDS patients,
GEP analysis was able to identify at diagnosis, patients with high risk to progress into AML. All
MDS patients who evolved into AML showed AML-like signatures, while none of the MDS
patients with a non AML-like signature showed evolution to AML.[20]
Pediatric Myelodysplastic Syndrome Workup
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Histologic Findings
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Histologic Findings
On peripheral smears, dysplastic shapes and cells with odd-appearing nuclear and cytoplasmic
ratios (eg, anisocytosis, macrocytosis, microcytosis, poikilocytosis) are apparent. Although
macrocytosis can indicate megaloblastic anemia (vitamin B-12 or folate deficiency), it is often
observed in most bone marrow failure syndromes, including MDS. RBCs are often dimorphic
(both hypochromic and normochromic). The number of reticulocytes is reduced in relation to the
degree of anemia.
Depending on the class, variable granulocytic abnormalities are present. PseudoPelger-Hut

anomalies (eg, hyposegmented mature neutrophils, hypogranulation of cytoplasm) are
characteristic of dysgranulopoiesis observed with MDS.
As additional immature elements are observed in periphery, these elements often appear bizarre
with abnormal nucleus-to-cytoplasm ratios and are often oddly shaped. In addition, the number
of eosinophils and basophils may increase in patients with adult-type MDS. On smears, platelets
markedly vary in size.
Myelodysplasia most commonly presents with a hypercellular marrow. In refractory anemia

(RA), the ratio of erythroid to myeloid cells is abnormal, and the marrow appears similar to that
of patients with megaloblastic anemia due to folate or vitamin B-12 deficiency. Erythroblasts are
often large, with clumped chromatin and a large nucleolus.
In refractory anemia with excess blasts (RAEB), the myeloid component of marrow increases.
Small myeloblasts and promyelocytes predominate in the marrow. These cells are often
dysmorphic with abnormal nucleus-to-cytoplasm ratios.
Abnormal megakaryocytes may appear small (micromegakaryocytes) or large. They may have a
variable number of nuclei in the same marrow sample.
The minimal diagnostic criteria for MDS includes at least 2 of the following:
Sustained, unexplained cytopenia (neutropenia, thrombocytopenia, or anemia)
At least bilineage morphologic dysplasia
Acquired clonal cytogenetic abnormality in hematopoietic cells
In the prospective study of the European Working Group on MDS in Childhood, more than half
of the patients with refractory cytopenia had a normal karyotype, followed in frequency by
monosomy 7, trisomy 8, and other abnormalities.[21] Loss of the long arm of chromosome 5 (5q-),
the most frequent chromosomal aberration in adults with RA, is rare in childhood.
Previous
Proceed to Treatment & Management
Syndrome Treatment & Management
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Medication
Hematopoietic Stem Cell Transplantation
Agents Used in Adults
Growth Factor Therapy
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Administer supportive care until the diagnosis is established. Many patients present with
profound cytopenia and a notable risk for infection. Transfusions and broad-spectrum antibiotics
may be required to treat life-threatening anemia, thrombocytopenia, and infection until definitive
therapy can be started.
In patients with refractory cytopenia, hematopoietic stem cell transplantation (HSCT) from a
matched related or well-matched unrelated donor early in the course of the disease is the
treatment of choice, especially in those with monosomy 7, 7q-, or complex karyotype. Family
members of children with monosomy 7 cytogenetics should be evaluated for familial monosomy
7.
Children with refractory cytopenia and a normal karyotype or chromosomal abnormalities other
than aberrations of chromosome 7 and absence of transfusion dependency or severe neutropenia
may be carefully observed over time. If the cytopenias necessitate treatment, then options
include HSCT with either myeloablative or reduced intensity preparative therapies.
Treatment with hematopoietic growth factors may be indicated.
Splenectomy may prove helpful in patients with marked splenomegaly or hypersplenia. The
great risk is infection, as is the case with any patient who is asplenic. No significant change in
the event-free survival rate is noted in splenectomized patients who undergo hematopoietic stem
cell rescue.
Some patients may respond to immunosuppressive therapy with cyclosporine and antithymocyte
globulin. Yoshimi et al reported a pilot study involving 29 children who received therapy with
these agents.[22] At 6 months, 22 children had a complete or partial response. Six patients were
subsequently transplanted for nonresponse, progression, or evolution of monosomy 7. Overall
and failure-free survivals were 89% and 55%, respectively.
No dietary restrictions are needed. Patients should take adequate amounts of folate and vitamin
B-12. Limitation of iron intake may be necessary in patients who are transfusion dependent.
Activity should be undertaken as tolerated. Restriction of activity when platelet counts are low is
necessary to prevent hemorrhagic complications from minor trauma.
Consultation may be indicated with a pediatric hematologist/oncologist. A clinical geneticist may

provide an invaluable opinion for many children because of the notable association of MSD with
other anomalies. Patients should be referred to centers affiliated with major multicenter pediatric
oncologic groups.
Children should be monitored often because of the propensity of these disorders to transform to
AML. Patients often require frequent transfusions, and their blood cell counts must be monitored
at least monthly. Repeated transfusions may result in iron overload, requiring chelation therapy.
However, iron overload is observed most often in adults with MDS related to transfusions over a
prolonged course.
Patients who have undergone myeloablative therapy with stem cell rescue should be monitored
for long-term sequelae, including short stature, obesity, gonadal failure, hypothyroidism, and
cataracts.
Next Section: Hematopoietic Stem Cell Transplantation

Syndrome Treatment & Management
Overview
Presentation
DDx
Workup
Treatment
Medication
Agents Used in Adults
Growth Factor Therapy
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References

Because MDS is a clonal early stem-cell disorder with very limited residual nonclonal stem cells,
myeloablative therapy is the only treatment option with a realistic curative potential. Regimens
for hematopoietic stem cell rescue result in a 30-50% event-free survival (EFS) rate at 3 years.
Outcomes improve in children who are relatively young and who receive hematopoietic stem cell
rescue soon after diagnosis.
Myeloablative therapy with hematopoietic stem cell rescue from a human leukocyte antigen
(HLA)matched sibling is the best therapy for MDS. For children who do not have an eligible
sibling donor, alternative donors should be sought, although outcome is even less favorable than
it is with a sibling donor. A study by Lang et al reported 5-year EFS rates of 60% and 47% for
HSCT using matched sibling donors or compatible unrelated donors, respectively.[23]
In a cohort of 27 children with refractory cytopenia, Yusuf et al reported an estimated survival

probability of 0.74 following various high-intensity conditioning regimens.[24] In an Italian study
involving 49 children, using the busulfan/cyclophosphamide regimen, the 5-year estimate of EFS
rate was 77%, whereas the 5-year cumulative incidence of transplantation-related mortality and
disease recurrence were 19% and 2%, respectively.
A cohort of 16 children, 14 of whom met the criteria for MDS, received allogeneic stem cell
transplants. Median age was 4.8 years (range 1-14 y). The median time from diagnosis to
transplant was 6 months. Eleven of 14 patients were conditioned with a busulphan-based
myeloablative regimen, with the addition of low-dose etoposide, and all but one received a bone
marrow graft. Nine patients achieved complete remission. At a median follow-up of 3 years
(range 2-14 y), the overall survival and EFS was 57% (95% confidence interval, 0.28-0.78).
Cumulative EFS at 10 y was 43% (95% confidence interval, 0.14-0.70). Relapse-related
mortality was 21.4%.[25]
In a single-center experience with 37 consecutive pediatric MDS patients (20 had primary MDS,
and 17 had secondary MDS) who received myeloablative HSCT (majority received
cyclophosphamide/total body irradiation conditioning regimen),the overall survival and disease-
free survival at 10 years was 53% and 45%, respectively. Monosomy 7 was present in 21,
trisomy 8 in 7, and normal cytogenetics in 8. According to the modified WHO criteria, 30 had
RC and 7 had RAEB. The 3-year disease-free survival in patients who did not receive pre-HSCT
chemotherapy and those who had a shorter interval to transplantation (< 140 d) was 80%.[26]
These data indicate that transplant-related mortality represents the main cause of treatment
failure. Using a reduced-intensity conditioning regimen with fludarabine, Strahm et al reported
that in 19 children with refractory cytopenia, the 3-year overall survival and EFS were 0.84 and
0.74, respectively.[27]
In patients with myelodysplastic syndrome (MDS) who have an increased blast count, allogeneic
HSCT is the treatment of choice. Toxicity of the procedure and relapse rate contribute equally to
the number of adverse events.
Whether intensive chemotherapy should be routinely administered prior to HSCT is highly

controversial. In the United States and United Kingdom, children with refractory anemia with
excess blasts (RAEB) and RAEB in transition to acute myeloid leukemia (AML) are generally
included in pediatric AML trials.
Most AML studies have reported significant morbidity and mortality in patients with MDS, and
an overall survival of less than 30%.[28, 29] Zecca et al reported that AML-type therapy prior to
HSCT did not prolong survival in 101 children with MDS and an increased blast count.
Previous
Next Section: Agents Used in Adults
Pediatric Myelodysplastic Syndromes

Pathology
Updated: Dec 2, 2013
Overview
Epidemiology
Clinical Features
Morphologic Features
Immunophenotypic Features and Methods
Molecular/Genetic Features and Methods
Diagnosis and Classification
Differential Diagnosis
Prognosis and Predictive Factors
Myeloid Diseases in Down Syndrome
Additional Resources
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References
Overview
Myelodysplastic syndrome (MDS) is a set of disorders characterized by marrow failure with
peripheral blood cytopenias, a peculiar set of morphologic abnormalities in hematopoietic cells,
increased marrow blasts in some cases, frequent characteristic cytogenetic abnormalities, and
frequent progression to a subset of acute myeloid leukemia (AML).[1, 2] The incidence of MDS
increases exponentially with increasing age; the median age is estimated to be in the 70s.[2, 3, 4]
The image below depicts typical morphologic features that may be seen in MDS.
A = binucleate megaloblastoid erythroid precursor; B = megaloblastoid erythroid precursor;

C = small megakaryocyte with monolobate nucleus.
Adult MDS includes both low-grade, slowly progressive or nonprogressive subtypes (eg,
refractory cytopenia with unilineage dysplasia [RCUD], refractory anemia with ringed
sideroblasts [RARS], and 5q- syndrome), and high-grade potentially progressive and life-
threatening subtypes (eg, refractory cytopenia with multilineage dysplasia [RCMD] and RA with
excess blasts [RAEB]).[1, 2]
AML with background MDS (MDS-related AML or MDR-AML) is difficult to treat, being
resistant to cytotoxic chemotherapy, whereas background myelodysplastic hematopoiesis is
abnormally sensitive to chemotherapy. If patients with MDR-AML respond to chemotherapy,
they typically revert to clonal hematopoiesis (MDS) rather than a polyclonal complete remission.
MDR-AML may be preceded by overt MDS or may simply exhibit the cytogenetic changes and
hematopoietic dysplasia typical of MDS. At present, MDR-AML, like MDS, is curable only with
an allogeneic stem cell transplant.
MDS and MDR-AML are less common in children and young adults than in older adults and
elderly persons. Nevertheless, a significant subset of pediatric myeloid disease (estimated at 10-
15%) consists of MDS and MDR-AML.[5, 6, 7, 8] The low-grade nonprogressive subtypes of MDS
found in older patients (especially 5q- syndrome and RARS) are rare to nonexistent in pediatric
patients.
Diagnosis and correct subclassification of MDS-related entities are often difficult, but because
both their treatment and their prognoses differ substantially from those of the more common de
novo AML [eg, AML with t(15;17), t(8;21), inv(16), or t(9;11)], recognition of MDS and MDR-
AML is critical for treatment, prognostication, and analysis of biologic and clinical studies.
While these entities typically occur with no antecedent causative event, there are a known set of
precipitating causes, which include alkylating agents, platinum derivatives, nitrosoureas, ionizing
radiation, and benzene derivatives.
Disorders included in MDS-related diseases of childhood are:
MDS (refractory cytopenia of childhood [RCC], RAEB)

MDR-AML
Therapy-related MDS and AML
Historically MDS and AML in Down syndrome patients have been included in classification
with MDR-disease, and they are discussed below, but given their excellent outcome with
chemotherapy, their apparent single gene (GATA-1) founder mutation, and their differing
morphology from other MDS disease, they should now be considered a separate entity distinct
from MDS. See also Pathology of Myeloid Proliferations Related to Down Syndrome.
This discussion does not address juvenile myelomonocytic leukemia, a related disorder with
mixed features of MDS and myeloproliferation.
See also the following:
Pathology of Acute Myeloid Leukemia With Myelodysplasia-Related Features

Pathology of Acute Myeloid Leukemia Not Otherwise Categorized
Pathology of Myelodysplastic Syndromes Associated With Isolated Del (5q)
Pathology of Myeloid Proliferations Related to Down Syndrome
Pathology of Other Myeloid Related Precursor Neoplasms
Pathology of Therapy-Related Acute Myeloid Leukemia, Myelodysplastic Syndromes,
and Myelodysplastic/Myeloproliferative Neoplasms
Pathology of Unclassifiable Myelodysplastic Syndromes
Next Section: Epidemiology

Pathology
Overview
Epidemiology
Clinical Features
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While some cases of pediatric myelodysplastic syndrome (MDS) may follow a stable or slowly
progressive course, the long-term prognosis is generally poor, whether due to cytopenias or
progression to AML. The International Prognostic Scoring System (IPSS) for MDS has not
proven useful in pediatric MDS.[6, 22, 23] Some evidence suggests that the rate of disease
progression in pediatric disease may vary with specific cytogenetic abnormalities.[24] The most
frequent abnormalities, monosomy 7 and complex abnormalities, follow an aggressive course
with poor survival without treatment. Patients with trisomy 8 are infrequent, but some data
suggest they may experience slower progression of disease.[24] Some patients may benefit from
immunosuppression, similar to aplastic anemia.
Nevertheless, the only current curative option is allogeneic stem cell transplantation. Aggressive
cytotoxic chemotherapy is virtually never curative in this setting and may induce prolonged, life-
threatening cytopenias. Alternative approaches, such as demethylating agents (azacytidine,
decitabine) and the thalidomide analogue lenalidomide, are not curative, the side effects of long-
term treatment (which must be determined before use in a child) are unknown, and extended
therapy may be prohibitively expensive.
Even allogeneic stem cell transplantation, with its attendant treatment-related morbidity and
mortality, has a high relapse rate. If MDS progresses to MDR-AML, the leukemia tends to be
resistant to chemotherapy; primary drug resistance, prolonged therapy-related cytopenias, and
short clonal remissions are seen. As with MDS, the only curative treatment is allogeneic stem
cell transplantation.
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Next Section: Myeloid Diseases in Down Syndrome

Pathology
Overview
Epidemiology
Clinical Features
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Parameters routinely used to diagnose myelodysplastic syndrome (MDS) are peripheral blood
cytopenias, dysplasia, genetic/cytogenetic abnormalities, and blasts in peripheral blood or
increased blasts in marrow.[6]
Diagnosis is frequently problematic in that none of these parameters is completely sensitive or

specific for this purpose. Peripheral blood cytopenias have myriad causes, as do peripheral blood
and marrow dysplasia. Cytogenetic abnormalities similar to those of MDS may appear
transiently in other settings, including megaloblastic processes, aplastic anemia, and Fanconi
anemia. Monosomy 7 unrelated to any of these settings may be present transiently, regressing
spontaneously or with treatment (eg, folate or vitamin B-12 replacement). At least in patients
with therapy-related MDSand presumably, by extension, in other MDS patientsany of these
parameters may be lacking, including dysplastic morphology and cytopenias.
Because of these limitations, better methods of diagnosis are needed, but until such methods
become available, at least 2 of the 4 cited parameters (unexplained cytopenias, multilineage
dysplasia, cytogenetic abnormalities, and increased blasts) should be present to provide some
certainty of the diagnosis of MDS.[6]
Parameters used for diagnosis should be unrelated to any underlying preexisting condition (eg,
cytopenias in aplastic anemia or Fanconi anemia). A careful analysis to rule out other possible
causes of abnormalities is always warranted. As a rule, definitive diagnosis should be deferred
until abnormalities are shown to be sustained over several months.
Pediatric MDS comprises a more limited set of diseases than MDS in older patients.[2, 6, 16] In
older patients, multiple subtypes of MDS are divisible into 2 broad groups: (1) low-grade disease
with little tendency to progress to higher-grade disease (MDS or AML) and (2) high-grade
disease with a strong tendency to progress. Low-grade MDS in older patients includes refractory
cytopenia with unilineage dysplasia (RCUD), refractory anemia with ringed sideroblasts
(RARS), and 5q- syndrome. High-grade MDS in older patients includes refractory cytopenia
with multilineage dysplasia (RCMD), RA with excess blasts (RAEB) (subgroups -1 and -2), and
therapy-related MDS.
The low-grade MDS subtypes of adults are rare in pediatric patients, and the clinical utility of
separating adult RAEB into subgroups on the basis of blast percentages has not been established
for pediatric disease. Thus, in practice, only 3 MDS categories are used in pediatric patients:
Refractory cytopenia of childhood (RCC, corresponding approximately to RCMD in adults),
RAEB, and therapy-related MDS.
Criteria for these 3 subtypes are essentially the same as for the corresponding conditions in
adults. RCC should have unexplained cytopenias (anemia, neutropenia, and/or
thrombocytopenia), with no increase in blasts in marrow and only rare blasts in peripheral blood.
RAEB is similar but with increased blasts in marrow or blood. Therapy-related MDS requires a
history of appropriate chemotherapy or ionizing radiation.
Both RCC and RAEB in childhood may follow prolonged courses with little progression of
cytopenias or blast percentage over months (RAEB) to years (RCC); therefore, a period of
follow up with repeat marrow examination may be prudent before undertaking aggressive
treatment such as stem cell transplantation in these patients. Similarly, patients diagnosed as
MDR-AML with a relatively low blast percentage (20-30%) may follow a relatively indolent
course, similar to RAEB; as with RAEB, a period of follow up may be helpful to define the
patient's disease course.
Refractory anemia with excess blasts vs MDS-related AML
Distinguishing between RAEB and MDS-related AML (MDR-AML) is often problematic, and,
as noted in the previous paragraph, may be more semantic than biological.[2] This distinction has
been based on the progression of blasts beyond a threshold of 20% (historically 30%) of marrow
elements, but this approach is simplistic. The intent of a diagnosis of AML is to inform the
clinician that the patient has a proliferative disease that may respond to aggressive cytotoxic
chemotherapy. However, blasts per se do not prove proliferation, only a lack of differentiation.
Blastic chromatin indicates DNA dissociation from histones. For example, blastic chromatin is
found in cells with nucleocytoplasmic asynchrony, in which nuclei look blastic but cytoplasmic
maturation disproves a significant mitotic rate. Knockout of an appropriate histone deacetylase
also results in blastic dissociated chromatin without proliferation.
As noted previously, patients with blasts in the 20-30% range or even higher may have a clinical
picture of marrow failure (MDS) rather than progressive tumor burden (AML). Either situation is
potentially life threatening, but optimal treatment may differ. Marrow failure patients tend to
respond poorly to cytotoxic chemotherapy, which is also virtually never curative. In contrast,
proliferating blasts in this setting may respond to chemotherapy, albeit with prolonged
cytopenias in many cases because of the sensitivity of background hematopoiesis (MDS); if the
chemotherapy is effective, patients typically revert to clonal hematopoiesis (MDS) rather than
normal hematopoiesis.
Which pattern of disease a given patient will follow (ie, predominant marrow failure or
proliferation) cannot usually be discerned with a single marrow examination. If possible,
definitive diagnosis should be delayed for several weeks, with a repeat marrow examination to
clarify the patient's course. In patients with a high blast percentage at presentation, diagnosis of
MDR-AML is justified.
Therapy-related MDS/MDR-AML versus other therapy-related leukemia

syndromes
In the appropriate clinical setting (history of alkylating agent, platinum derivative, or ionizing
radiation exposure), diagnosis of therapy-related MDS is based on the presence of prolonged
cytopenias after chemotherapy or the onset of cytopenias unrelated to chemotherapy, the
appearance of MDS-related cytogenetic abnormalities, dysplastic changes in hematopoietic cells,
and/or increased myeloid blasts.[2] If the blast count exceeds 20%, diagnosis of therapy-related
MDR-AML is warranted. Patients initially may have only a single feature (eg, monosomy 7 in a
marrow sample or unexpectedly prolonged cytopenias after chemotherapy). Dysplastic
morphology or increased blasts may be lacking.
Distinction should be made between therapy-related MDS/MDR-AML and 2 other therapy-

related leukemia syndromes. Epipodophyllotoxin chemotherapy causes translocations involving
the MLL gene at 11q23 and, to a lesser extent, the AML1 gene at 21q22.[20] Therapy-related
leukemia with an MLL translocation includes acute lymphoid leukemia (ALL) and AML.
Complex therapy including all of the above noted agents plus other chemotherapy (eg,
anthracyclines) also causes an increased incidence of AML, with each of the balanced
translocations found in AML [eg, t(15;17), t(8;21) or inv(16)]; although the incidence of this
complication is not as high as those of the previous 2 syndromes, it is several logs higher than
that in the general population.[21] Neither of these latter 2 syndromes is related to MDS.
Previous
Next Section: Differential Diagnosis
Myelodysplastic Syndromes Treatment
Protocols
Updated: Aug 2, 2013
References
Treatment Protocols
Treatment recommendations for myelodysplastic syndromes (MDS) are based on a patients
International Prognostic Scoring System (IPSS or IPSS-R) score in addition to evaluation of a
patients performance status. Currently, there are limited FDA-approved therapies for MDS,
which include hypomethylating agents such as azacitidine and decitabine, iron chelators such as
deferasirox, and lenalidomide.[1] Special considerations and supportive care are also provided
below.[2]
IPSS low-risk or intermediate (INT)-1risk patients
Selected patients with IPSS low-risk or INT-1risk MDS who have not required
transfusion and have modest, asymptomatic cytopenias may be observed initially
IPSS low-risk or INT-1risk patients with symptomatic anemia; < 2 units (U) of red blood cell
(RBC) transfusion required per month; and low ( 500 mU/mL) serum erythropoietin levels:
Consider therapy with erythropoiesis-stimulating agents (ESAs), with or without myeloid

growth factors [3, 4]
Epoetin alfa 40,000-60,000 U SC weekly, with or without filgrastim [4] or
Darbepoetin alfa 150-300 g SC weekly [5, 6] or
Darbepoetin alfa 300 g SC weekly plus filgrastim 300 g SC 3 times weekly, doses
adjusted to hemoglobin (Hb) level of 11-13 g/dL, and total white blood cell (WBC) count
10 10 9/L [7]
IPSS low-risk or INT-1risk patients with symptomatic anemia (without symptomatic
thrombocytopenia or neutropenia); < 2 U of RBC required per month; and low ( 500 mU/mL)
serum erythropoietin levels that are not responsive to ESAs or lose response to ESAs, or those
who are deemed unlikely to benefit from immunosuppressive therapy (see below):
Consider azacitidine/decitabine or lenalidomide [8]

Recommended azacitidine dose is 75 mg/m 2 SC or IV on days 1-7; every 28d [9, 10, 11] or
Alternative azacitidine schedule, associated with similar response rates: 75 mg/m 2 SC or
IV on days 1-5, 8, and 9; every 28d [12] or
Decitabine on FDA-approved schedule: 15 mg/m 2 IV over 3h every 8h (or 45 mg/m
2
/day) for 3d; every 6wk [13] or
Decitabine on outpatient schedule, now widely adopted: 20 mg/m 2 IV over 1h daily on
days 1-5; every 28d [13, 14, 15] or
Lenalidomide 10 mg PO daily, either continuous dosing or on days 1-21 every 28d; this
is the preferred therapy for patients with del(5q31), either isolated or accompanied by
other cytogenetic abnormalities, [16] but it can result in hematologic improvement in low-
risk or INT-1risk MDS without this deletion as well [17]
IPSS low-risk or INT-1risk patients with symptomatic anemia (without symptomatic

thrombocytopenia or neutropenia); < 2 U of RBC transfusion required per month; and high (>
500 mU/mL) serum erythropoietin levels:
Evaluate likelihood of response to immunosuppressive therapy

Patients who are < 60y, are human leukocyte antigen (HLA)DR15 positive, and have
had a short duration (approximately < 1y) of transfusion dependence [18, 19] may be
candidates for equine antithymocyte globulin (ATG) 40 mg/kg/day IV over 4-6h for 4d
plus cyclosporine starting at 5-12 mg/kg/day IV beginning on day 14, dosed to maintain
therapeutic levels between 200 and 400 ng/mL [8]
Recent trials have reinforced previous data that demonstrated a statistically significant
benefit in hematologic response rates with ATG and cyclosporine when compared with
best supportive care [1, 20]
IPSS high-risk or INT-2risk patients
IPSS high-risk or INT-2risk patients regardless of transfusion frequency or INT-1risk patients

with high transfusion needs (> 2 U RBC per month):
Evaluate patients for candidacy for high-intensity therapy

Good candidates for high-intensity therapy include young patients with few or no
comorbidities, good performance status, and adequate psychosocial support
Patients who are not good candidates for high-intensity therapy:
Azacitidine has been associated with improvements in transfusion dependence, quality of

life (QOL), and overall survival (OS) in phase III trials
Azacitidine 75 mg/m 2 SC or IV on days 1-7; every 28d; this regimen has been associated
with improvements in transfusion dependence, QOS, and OS in phase III trials [9, 10, 11] or
Alternative schedule of azacitidine, associated with similar response rates: 75 mg/m 2 SC
or IV on days 1-5, 8, and 9; every 28d [12] or
Decitabine on FDA-approved schedule: 15 mg/m 2 IV over 3h every 8h (or 45 mg/m
2
/day) for 3d; every 6wk [13] or
Decitabine on outpatient schedule, now widely adopted: 20 mg/m 2 IV over 1h daily on
days 1-5; every 28d [13, 14, 15]
Patients who are good candidates for high-intensity therapy:
AML-type induction therapy, such as 7+3 ( idarubicin 12 mg/m 2 IV push on days 1-3
plus cytarabine 100-200 mg/m 2/day continuous IV infusion on days 1-7) [21] or
azacitidine or decitabine, as outlined above
Allogeneic stem cell transplantation consultation should also be recommended
Allogeneic stem cell transplantation may be performed as initial therapy or following
cytoreduction with any of the other therapies for MDS
Special considerations
Allogeneic stem cell transplantation is the only potentially curative therapy for MDS
Appropriate patients should be referred early for consultation with a transplant specialist,
before extensive transfusion support, infectious complications, or transformation to AML
Generally, early transplantation is advocated for young patients who are IPSS INT-2risk
and high-risk patients [22]
Consider referral for clinical trial participation at any stage of therapy
The regimens above have been tested in the frontline setting, and there is no standard of
care at the inevitable time of frontline therapeutic failure
Clinical trial participation in this situation is highly recommended
When considering the choice of a particular therapeutic regimen, it is important to
consider the time to best response; the duration of time to response is also critical in
evaluating the success of therapies
Therapeutic regimens should generally not be changed in the absence of progression or
toxicity unless an adequate trial of the current regimen has been undertaken
The median time to response for the therapies listed above is as follows:
ESAs with or without granulocyte-colony stimulating factor (G-CSF): 8-12wk [4, 14]
Lenalidomide: 4.6wk [16]
ATG + cyclosporine: 4mo [19]
Azacitidine or decitabine: 1.7 mo [15] to 3 mo [23]
7+3 induction therapy: 4-6wk
Supportive care
Prophylactic antibiotics are recommended during supportive care; patients with
prolonged, severe neutropenia (< 0.5 10 9/L 7d) due to either disease or therapy are at
risk for opportunistic infections and febrile neutropenia; in such cases, antimicrobial
prophylaxis during periods of neutropenia should be considered with a fluoroquinolone,
[24]
a second-generation azole antifungal, [25] and an antiherpetic agent [26]
Transfusion support: RBC transfusions (leuko-reduced) for patients who have
symptomatic anemia; platelet transfusions for thrombocytopenia bleeding; irradiated
packed RBCs are suggested for transplant candidates and necessary to improve anemia-
related fatigue and prevent bleeding
Management of transfusion iron overload: For patients who survive long enough to
receive over 20-30 U of packed RBCs, transfusion iron overload is probable
End-organ iron deposition may cause cardiac, hepatic, or endocrine dysfunction
Iron-chelating agents ( deferoxamine, deferasirox) are available, but they have not been
shown to decrease complications in MDS patients in prospective randomized trials. For
this reason, many experts limit the use of these agents to patients likely to survive several
years with transfusion dependence (eg, IPSS low and intermediate-1 risk patients).
Each iron-chelating agent has the following drawbacks: Deferoxamine is associated with
inconvenient subcutaneous infusions, infusion-site reactions, and cataracts; deferasirox is
an oral agent, but it is costly, requires monitoring of vision and renal and hepatic
function, and is contraindicated in severe thrombocytopenia
Mmmmmmmmmmmmmm
Anemia fanconi (4-7%) meningkatkan risiko MDS dan AML; 48% pasien dengan anemia fanconi memiliki
leukemia atau MDS pada usia 40 tahun. Hal ini sering berhubungan dengan monosomi 7 dan duplikasi
1q. Cukup sulit mendiagnosis sitopenia refraktori pada pasien dengan anemia fanconi.
Sindroma Kostmann (0.6%) juga disebut sebagai agranulositosis congenital. Harapan hidup pasien
dengan sindroma ini membaik secara signifikan dengan adanya terapi gralunocyte colony-stimulating
factor (G-CSF). Penelitian-penelitian mengenai neutropenia congenital berat menunjukkan angka kasar
sebesar 9% mengenai perkembangan MDS dan kecepatan progesivitas per tahunnya sebesar 3%.
Kromosom 7 yang hilang sebagian atau total ditemukan pada lebih dari separuh pasien yang memiliki
MDS, dan perkembangan MDS hampir selalu didahului oleh mutasi didapat dari gen reseptor G-CSF.
Kadang-kadang MDS terdapat pada pasien dengan anemia Diamond-Blackfan. Akan tetapi, tidak ada
estimasi yang tersedia, dan bisa jadi termasuk langka, karena sedikitnya kasus MDS dalam sebuah
penelitian dengan 229 pasien.
Sebagai faktor penyebab, terapi dengan agen alkylating (2-5%) yang dilakukan sebelumnya berhubungan
dengan monosomi 7 dan penghapusan kromosom 5. Pasien-pasien tersebut memiliki respon yang
buruk. Pemberian inhibitor topoisomerase sebelumnya merupakan faktor penyumbang yang jarang.
Pada kasus langka yang melibatkan inhibitor topoisomerase, pasien biasanya memiliki AML.
MDS terdapat pada 10-15% pasien dengan anemia aplastik didapat yang tidak diterapi dengan
transplantasi sel stem; hal ini tampaknya terjadi pada angka yang sama pada anemia aplastik yang
berhubungan dengan hepatitis dan idiopatik. Mds dapat terjadi pada kasus-kasus tersebut dalam 3
tahun; apakah terapi dengan G-CSF dan cyclosporine yang diperpanjang berhubungan dengan
perkembangan MDS masih hal yang kontroversial.
Kim et al menunjukkan bahwa pasien MDS pediatric memiliki tingkat metilasi CDKN2B yang lebih tinggi
dibandingkan kelompok kontrol pediatric, tetapi lebih rendah dibandingkan pasien MDS dewasa. tingkat
metilasi tinggi pada kasus dengan sel blas > 5% dibandingkan pada kelompok kontrol pediatrik, dan
tingaktnya juga lebih tinggi pada kasus dengan kariotipe abnormal. Gen CDKN2B menyandi supresor
tumor yang biasanya mencegah prolifesasi sel yang tidak terkontrol dengan cara menahan siklus sel
pada fase G1. Gen ini biasanya membungkam gen supresor tumor pada MDS, terutama oleh
hipermetilasi promoter, yang dimana memberi kontribusi kemajuan penyakit pada MDS dewasa. maka
dari itu, peneliti-peneliti tersebut dapat menunjukkan bahwa metilasi CDKN2B berhubungan dengan
patogenesis dan prognosis pada MDS pediatric.
EPIDEMIOLOGI
Statistic Amerika Serikat

Distribusi klasifikasi FAB mengenai MDS pada populasi dewasa adalah sebagai berikut:
RA - 38.4%
RARS - 11.5%
RAEB - 15%
RAEBT - 3.9%
CMML - 31.2%
Pada populasi pediatrik, bentuk agresif seperti RAEB dan RAEBT lebih umum ditemui dibandingkan RA
atau RARS.
Masih jarang terdapat literature mengenai epidemiologi MDS pada anak-anak. Faktor-faktor mengenai
kurangnya informasi ini termasuk sebagai berikut:
- Klasifikasi yang diterima secara luas masih kurang

- Pasien dengan penyakit bentuk indolens bisa jadi tidak dirujuk ke pusat tersier; praktik
ini dapat menyebabkan bias di antara penelitian-penelitian berbasis institusi terhadap
bentuk progresif
- Daftar penyakit kanker biasanya tidak mandaftar pasien dengan MDS
Pada salah satu laporan paling awal, MDS atau preleukimia dilaporkan pada 17% AML anak-anak (2.9%
dari semua anak-anak dengan leukemia). Penelitian-penelitian lainnya mengkonfirmasi bahwa fase
preleukemi mendahului AML pada sekitar 12-20% anak-anak dengan AML. Penelitian-penelitian ini
berdasarkan pada rujukan dugaan AML dan tidak memasukkan kasus MDS yang kurang menonjol.
Statistik internasional
Beberapa penelitian berbasis populasi memberikan data yang bertentangan mengenai insidensi MDS.
Data berbasis populasi dari Denmark dan Canada (British Columbia) menunjukkan bahwa MDS dan
JMML terdapat pada 6% semua keganasan hematologi anak-anak, sesuai dengan insidensi tahunan 1.8-
1.2 kasus per 1 juta anak-anak dan remaja berusia 0-14 tahun.
Angka MDS dan JMML yang sama (7.7% pada kombinasi dengan leukemia anak-anak) ditemukan di
Jepang, di mana MDS yang berhubungan dengan terapi terdapat pada 23% dari semua kasus.
Di United Kingdom, dilaporkan insidensi sebesar 0.5 per 1 juta populasi, di mana terdapat 1.1%
keganasan hematologi anak-anak. Eksklusi MDS sekunder hanya menjelaskan sebagian mengenai
insidensi yang relatif rendah di United Kingdom. Insidensi pada orang lanjut usia sebesar 89 tiap 100.000
populasi.

Pediatric Myelodysplastic Syndrome

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Pediatric Myelodysplastic Syndrome

Updated: Oct 4, 2013

Types in the FAB system are the following:

Refractory anemia (RA)

RA or RARS (erythroid dysplasia only, marrow blasts < 5%)