Pediatric Myelodysplastic Syndrome 

Updated: Oct 03, 2019
Author: Meena Kadapakkam, MD; Chief Editor: Jennifer Reikes Willert, MD 



Myelodysplastic syndrome (MDS) in childhood is a diverse group of clonal bone marrow disorders characterized by peripheral cytopenia, dysplastic changes in the bone marrow, and ineffective hematopoiesis. MDS disorders have been referred to as “preleukemias” because of their tendency to transform into acute myeloid leukemia (AML). Because of this risk, they are most commonly treated with bone marrow transplantation.

MDS is rare in childhood, with an incidence of 1-4 cases per 1 million children affected. The disease is more common in adults, especially elderly people, and the course varies, ranging from an acute, rapidly fatal illness to a chronic, indolent disease. MDS in children is a distinct entity from that seen in adults. Childhood MDS is more commonly associated with inherited bone marrow failure syndromes and other genetic disorders.  

Diagnosis of MDS is made based upon evaluation of blood and bone marrow, cytogenetic abnormalities, and blast percentage. MDS is considered transformed to AML once the bone marrow blast percentage rises above 20-30%. Diagnostic criteria for MDS include two of the following four criteria:

  • Sustained unexplained cytopenia
  • Bilineage morphological myelodysplasia (10% of at least one myeloid cell line with confirmed dysplasia)
  • Acquired clonal cytogenetic abnormality
  • Increased blasts (>5%)

Childhood MDS rarely presents with anemia alone; often, neutropenia or thrombocytopenia accompanies anemia.[1]

Childhood MDS is categorized based on the 2008 WHO Classification of Childhood Myelodysplastic Syndromes, as described below.

MDSs are characterized as follows:

  • Refractory cytopenia of childhood (RCC): Blood blasts less than 2%, bone marrow blasts less than 5%
  • Refractory anemia with excessive blasts (RAEB): Blood blasts greater than 2%, bone marrow blasts 5-19%
  • Refractory anemia with excess blasts in transformation (RAEB-T): Bone marrow blasts 20-29%, or acute myelogenous leukemia with MDS-related changes (peripheral blood or blood blast >20%)

Myelodysplastic/myeloproliferative disease is characterized as follow:

  • Juvenile myelomonocytic leukemia (JMML)

Down syndrome disease is characterized as follows:

  • Transient abnormal myelopoiesis
  • Myeloid leukemia of Down syndrome

Classification of adult MDS is based upon the French-American-British (FAB) classification of MDS (1982) and consists of five categories: (1) refractory anemia, (2) refractory anemia with ring sideroblasts (RARS), (3) RAEB, (4) RAEB-T, and (5) and myelomonocytic leukemia. RARS is exceedingly rare in childhood, leading to its omission from the childhood WHO classification. Other cytogenetic differences between adult and childhood MDS include very low occurrence of 5q- aberration in childhood MDS and increased occurrence of monosomy 7 in childhood MDS (30% vs 10%). Driver mutations have also been noted to be distinct between adult and childhood MDS (see Pathophysiology).[2]

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.

For pediatric patients with refractory cytopenia, certain cytogenetic abnormalities, or malignant transformation, 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.


MDS is a clonal disorder of myeloid stem cells. 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.[2]

Monosomy 7 occurs in approximately 30% of primary childhood MDS cases and in about 50% of therapy-related MDS cases.[3]

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 (Revlimid). Although 5q- is occasionally reported in children, the typical 5q- syndrome has not been reported.

In a 2013 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.[4] Monosomy 7/deletion 7q was the most frequent clonal abnormality (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 refractory cytopenis (27.2%). The median overall survival 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.

A 2017 publication on the genomic landscape of pediatric MDS showed that the genomic landscape is distinct from adult MDS.[2] Mutations in the Ras/MAPK pathway are more common in pediatric MDS (45%). SAMD9/SAMD9L mutations were detected in 17% of primary MDS samples and represented a new MDS predisposing mutation. Mutations in RNA splicing genes and epigenetic pathways are commonly seen in adult MDS, but are rare (< 2%) in childhood. Mutations in transcription factors such as GATA2, RUNX1, ETV6, SRP72, and CEBPA have been shown to lead to familial MDS/AML. GATA2 mutations are found in 7% of childhood MDS cases and are associated with a higher risk of malignant transformation. Similarly, patients with monosomy 7 also have a higher risk of developing MDS/AML.


Myelodysplastic syndrome (MDS) may be primary or secondary. Children with primary MDS may have an underlying genetic defect that predisposes them to develop MDS at a young age. Approximately 30-50% of children with MDS have an underlying congenital anomaly or syndrome associated with chromosomal abnormalities. Monosomy 7 is the most common of these chromosomal abnormalities, occurring in 30% of childhood MDS cases.

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).[6]  Antecedent MDS is common in those who develop AML in this population, affecting as many as 70% of children with ML-DS.[7]

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.[8]

Fanconi anemia (4-7%) increases the risk of MDS and AML[9] ; 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%.[10]  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.[11]

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.[12]  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.[13]

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.[14]


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).[15] Other studies confirmed that a preleukemic phase precedes AML in about 12-20% of children with AML.[16] 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.[17]

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.[18] 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.


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).[19] 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.[20]

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.[7] 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-Münster (BFM), Nordic Society of Paediatric Haematology and Oncology (NOPHO), and Medical Research Council studies.

The Center of International Blood and Marrow Transplant Research showed an 8-year disease-free survival rate of 40–65% for RCC and 28-48% for RAEB/RAEB-T. In another study, the European Working Group of Myelodysplastic Syndromes in Childhood reported outcomes for children with advanced MDS, with a 5-year overall survival of 63%. Outcome rates are worse for patients with treatment-related MDS, ranging from 10-35%.[21]




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

Physical Examination

Children with myelodysplastic syndrome (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. Bruising and petechiae may be noted from thrombocytopenia. 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 MDS. About 30% of patients with JMML have a diffuse erythematous, maculopapular rash.



Diagnostic Considerations

The two major diagnostic challenges are distinguishing myelodysplastic syndrome (MDS) with a low blast count due to aplastic anemia and other nonclonal bone marrow disorders and differentiating MDS with excess blasts from acute myeloid leukemia (AML). Additional diagnoses to consider include autoimmune cytopenias, Diamond-Blackfan anemia, vitamin and mineral deficiencies, zinc toxicity, viral infections, and other inherited bone marrow failure syndromes.

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. The bone marrow morphology in RCC has a characteristic appearance, with patchy, left-shifted erythropoiesis with increased mitosis, markedly decreased and left-shifted myelopoiesis, and markedly decreased megakaryocytes with dysplastic micromegakaryocytes.[21]

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



Approach Considerations

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 count, patients often have anemia with high mean cellular volume and red blood cell distribution width. Neutropenia and thrombocytopenia may be found. Pediatric patients more commonly present with thrombocytopenia or neutropenia along with anemia.

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:

  • Bone marrow failure workup: Chromosome breakage studies for Fanconi anemia, telomere length for dyskeratosis congenita, PNH clone by flow cytometry, SBDS gene testing for Shwachman-Diamond syndrome, and a bone marrow failure panel genetic testing
  • Hemoglobin electrophoresis (elevated Hgb F)
  • Studies for cytomegalovirus (CMV),  Epstein-Barr virus (EBV), herpes simplex virus (HSV), and parvovirus 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 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.

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 two different myeloid cell lines or dysplasia that exceeds 10% in one single cell line, with evidence of a clonal cytogenetic abnormality in hematopoietic cells. Hypocellular marrow or dysplastic cells of various stages of differentiation with hypercellular findings may be evident.

Bone marrow should be sent for flow cytometry, karyotype, fluorescence in situ hybridization (FISH) for MDS panel (-7, 7q-, +8, -5, -5q, 20q-), and molecular testing for GATA2 for all samples and CBBPA, ETV6, RUNX1, SAMD9/SAMD9L, and CEBPA for patients with concern for familial MDS.[21]

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.[22]

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. Pseudo–Pelger-Huët 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.[23] Loss of the long arm of chromosome 5 (5q-), the most frequent chromosomal aberration in adults with RA, is rare in childhood.



Approach Considerations

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.

HSCT is also indicated for patients with increasing blast counts concerning for malignant transformation, especially in those with GATA2 mutations. 

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.[24] 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.

Hematopoietic Stem Cell Transplantation

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.[25]

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.[26] 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%.[27]

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%.[28]

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.[29]

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%.[30, 31] 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.

Agents Used in Adults

The US Food and Drug Administration (FDA) has approved three agents for treatment of adult MDS since 2004: azacitidine (Vidaza), decitabine (Dacogen) and lenalidomide (Revlimid). None of these compounds have been approved for the pediatric population. Studies should be undertaken to elucidate the efficacy of these agents in the pediatric population; however, pediatric MDS does not seen to have driver epigenetic mutations unlike adult MDS.

In adults, lenalidomide is approved for the treatment of transfusion-dependent anemia in patients with MDS and chromosome 5q deletion. In the pivotal trial, 76% of patients had a 50% or greater reduction in transfusions, with 67% achieving transfusion independence.[32] Achievement of transfusion independence strictly correlated with cytogenetic response. In addition, cytogenetic response had the highest predictive value for prolonged survival in a multivariate analysis, as well as a statistically significant decreased risk for AML progression.

Azacitidine and decitabine have become established as part of the standard medications in the treatment of MDS in adults. In a phase III study of azacitidine, Silverman et al reported an overall response rate of 60% in 191 patients, with 7% complete response, 16% partial response, and 37% hematological response.[33] In a phase III study using decitabine, Kantarian et al reported an overall response rate of 17% in 170 patients, with 9% complete response, 8% partial response, and 13% hematologic response.[34]

Data from a study by Bernal et al showed that despite widespread use of azacitidine, there is a lack of improvement in long-term survival of patients with high-risk myelodysplastic syndromes.[35, 36]

A randomized controlled trial by Garcia-Manero et al compared rigosertib to the best supportive care in patients with myelodysplastic syndromes with excess blasts after failure of azacitidine or decitabine treatment. The study reported that rigosertib did not significantly improve overall survival compared with best supportive care.[37]

Growth Factor Therapy

The use of erythropoietin is helpful in patients who have low erythropoietin levels. Recent data from a phase III adult trial by the Eastern Cooperative group (ECOG) showed that erythropoietin treatment improved overall survival in patients responding to the erythropoiesis-stimulating agents compared with the best supportive care management.[38] This has also been confirmed by the Nordic and French MDS Study Groups.

Granulocyte colony-stimulating factor (G-CSF) has also been used, with a transient improvement in neutropenia.

Hesitation in using growth factors has been based on the known increased response of myelodysplastic clones to granulocyte-macrophage colony-stimulating factor (GM-CSF) and on reports that the use of G-CSF in children with severe aplastic anemia is associated with the later development of MDS or AML.



Medication Summary

Children with myelodysplastic syndrome (MDS) have been treated with a wide variety of drugs. For children with an increased number of blasts, treatment like AML is commonly used. The most frequently used chemotherapeutic agents include idarubicin, dexamethasone, cytarabine arabinoside, fludarabine, etoposide, daunorubicin, L-asparaginase, and thioguanine.

Antineoplastic agents

Class Summary

Cancer chemotherapy is based on an understanding of tumor cell growth and of how drugs affect this growth. After cells divide, they enter a period of growth (G1 phase), followed by DNA synthesis (S phase). The next phase is a premitotic phase (G2 phase). Finally, a phase of mitotic cell division (M phase) occurs.

The rate of cell division varies for different tumors. Most common cancers grow slowly compared with normal tissues, and the rate may decrease further in large tumors. This difference allows normal cells to recover from chemotherapy more quickly than malignant cells, and it is in part the rationale for current cyclic dosage schedules.

Antineoplastic agents interfere with cell reproduction. Some agents are cell cycle specific, whereas others (eg, alkylating agents, anthracyclines, cisplatin) are not phase specific. Cellular apoptosis (ie, programmed cell death) is another potential mechanism of many antineoplastic agents.

Azacytidine, decitabine, and lenalidomide (for those with 5q- MDS) are approved for use in adults with myelodysplastic syndrome (MDS). There is currently no data on the safety and efficacy of these drugs in children with MDS.


An antimetabolite antineoplastic agent, cytarabine is converted intracellularly to the active compound cytarabine-5'-triphosphate, which inhibits DNA polymerase. It is metabolized in the liver, with a half-life of 1-3 h. The agent is widely distributed, including in the central nervous system and tears, after IV administration. It is not active via the oral route.

Pegaspargase (Oncaspar)

Pegaspargase is polyethylene glycol-L-asparaginase. It catabolizes asparagine, which is an essential amino acid for lymphoblast growth. This agent has a half-life of 2-3 wk.

Fludarabine (Fludara, Oforta)

Fludarabine is a 2-Fluoro, 5-phosphate derivative of vidarabine. It is converted to 2-fluoro-ara-A that enters cells; it is phosphorylated to form active metabolite 2-fluoro-ara-ATP, which inhibits DNA synthesis. The half-life of the active metabolite is 9 h.

Idarubicin (Idamycin)

Idarubicin is an anthracycline antineoplastic agent. It inhibits cell proliferation by inhibiting DNA and RNA polymerase. It is metabolized in the liver to active idarubicinol. It has half-life of 14-35 h (PO) or 12-27 h (IV). This agent is a vesicant.

Daunorubicin (Cerubidine)

An anthracycline antineoplastic agent, daunorubicin inhibits DNA and RNA synthesis by intercalating between DNA base pairs. It has a half-life of 14-20 h (23-40 h for active metabolite).

Dexamethasone (Baycadron)

A long-acting fluorinated corticosteroid, dexamethasone induces apoptosis of leukemia cells by means of glucocorticoid receptors. Dexamethasone 0.75 mg is equivalent to 4 mg methylprednisolone, 5 mg prednisolone, 30 mg hydrocortisone, or 25 mg cortisone.

Thioguanine (Tabloid)

Thioguanine is a purine analog with antineoplastic and antimetabolite properties.

Etoposide (Toposar)

Etoposide is a semisynthetic podophyllotoxin with poor penetration of the cerebrospinal fluid (CSF). It inhibits topoisomerase II and causes DNA strand breakage, which arrests cell proliferation in the late S or early G2 portion of cell cycle. It has a half-life of 4-11 h.

Azacitidine (Vidaza)

Azacitidine is approved for use in adults with myelodysplastic syndrome (MDS). It is a pyrimidine nucleoside analog of cytidine. It interferes with nucleic acid metabolism. This agent exerts its antineoplastic effects by DNA hypomethylation and direct cytotoxicity on abnormal hematopoietic bone marrow cells. Hypomethylation may restore normal function to genes critical for cell differentiation and proliferation. Nonproliferative cells are largely insensitive to azacitidine.

Azacitidine is approved for adults by the US Food and Drug Administration for treatment of all 5 MDS subtypes.

Decitabine (Dacogen)

Decitabine is approved for use in adults with myelodysplastic syndrome (MDS). It is a hypomethylating agent believed to exert antineoplastic effects by incorporating into DNA and inhibiting methyltransferase, resulting in hypomethylation. Hypomethylation in neoplastic cells may restore normal function to genes critical for cellular control of differentiation and proliferation.

This agent is indicated for treatment of MDSs, including previously treated and untreated, de novo, and secondary MDSs of all French-American-British (FAB) Cooperative Group MDS subtypes and International Prognostic Scoring System (IPSS) groups intermediate-1 risk, intermediate-2 risk, and high risk.

Lenalidomide (Revlimid)

Lenalidomide is approved for use in adults with myelodysplastic syndrome (MDS). It is indicated for transfusion-dependent MDS subtype of 5q- cytogenetic abnormality. It is structurally similar to thalidomide. This agent has immunomodulatory and antiangiogenic properties. It inhibits proinflammatory cytokine secretion and increases anti-inflammatory cytokines from peripheral blood mononuclear cells. The dose used in MDS is much lower than that used for multiple myeloma.