AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• 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 are 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; this is secondary MDS. 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, 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 the French-American-British (FAB) group proposed.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)

CMML, as it occurs in adults, is extremely rare in pediatric populations. Because of differences between adults and children, this entity has been referred to as juvenile myelomonocytic leukemia (JMML) or juvenile chronic myelogenous leukemia (JCML). The currently preferred term is JMML. Because JMML is a separate entity from MDS, it is not discussed in detail in this article. MDS in children and adults differs in other ways; for example, RARS is exceedingly rare in children, and 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), monosomy 7 syndrome, and infantile monosomy 7. Monosomy 7 is most often associated with 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 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) 

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. 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 multihit 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 RAS. 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.

Frequency

United States

The distribution of FAB classifications in adult populations is as follows:

• RA - 38.4%
• RARS - 11.5%
• RAEB - 15%
• RAEBT - 3.9%
• CMML - 31.2%

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.
• The incidence is not well known. In one of the earliest reports, MDS or preleukemia was reported in 17% of childhood AMLs (2.9% of all children with leukemia).⁴ Other studies confirmed that a preleukemic phase precedes AML in about 12-20% of children with AML.⁵ These studies were based on referrals for suspected AML and did not include the less advanced cases of MDS.

International

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.⁶ 

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 England, 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.

Mortality/Morbidity

• The prognosis for pediatric patients with MDS is poor without HSCT. The most common cause of death is cytopenia.
• 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 mo vs 40 mo, P <.01).⁷ 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.
• Most long-term complications are related to myeloablative therapy with stem cell rescue. Sequelae include short stature, obesity, gonadal failure, hypothyroidism, and cataracts.

Race

• Data from the Children's Cancer Group showed that 75% of patients are Caucasian, 8.5% are Hispanic, 8% are African American, 3.5% are Asian, and 5% are of unknown race or ethnicity.⁸ 
• Most studies have been conducted in countries with predominately Caucasian populations. Therefore, results may not reflection the true racial distribution.
• The incidence for each race has not been reported.

Sex

• 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.

Age

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.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

History

• Children 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 CBC count is obtained.
• Other symptoms include the following:
• • Fatigue
• • Systemic infection (bacterial or fungal)
• • Prolonged fever
• • Bruising, bleeding

Physical

• Children 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.

Causes

MDS may be primary or secondary. Children with primary MDS may have an underlying but unknown genetic defect that predispose them to develop MDS at a young age. 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.

• Approximately 20% of children have an underlying congenital anomaly or syndrome associated with chromosomal abnormalities.
• 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.⁹ 
• 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.¹⁰
• Fanconi anemia (4-7%) may be a factor;¹¹ 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.
• Familial leukemia (2-6%) may be a factor; JMML is observed in families with monosomy.
• Kostmann syndrome (0.6%) is 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%.¹² 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.¹³
• Not all bone marrow failure syndromes are associated with the development of MDS (eg, patients with dyskeratosis congenita develop bone marrow failure in 95% of cases, but MDS has only been reported in a few cases).¹⁴
• 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 transplant; this appears to occur at the same rate in idiopathic and hepatitis-associated aplastic anemia.¹⁵ 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.¹⁶

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Other Problems to be Considered

Also consider autoimmune cytopenias and Diamond-Blackfan anemia.

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).

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.

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Lab Studies

• CBC count with differential and smear
• • Patients often have anemia with high mean cellular volume and RBC distribution width.
• • Patients may be neutropenic and thrombocytopenic.
• • In juvenile myelomonocytic leukemia (JMML), marked monocytosis may be present. The monocyte count in peripheral blood may exceed 1 million cells. 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.
• Hemoglobin electrophoresis: Elevated levels of fetal hemoglobin are associated with a poor prognosis and with JMML. 
• Chromosomal analysis
• • Look for constitutional abnormalities if the patient has symptoms 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 and mitomycin C 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: Morphologic myelodysplasia involves dysplasia in 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.
• Viral studies: Perform viral studies for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) to exclude marrow suppression due to a viral etiology.
• Folate and vitamin B-12 studies: Obtain folate and vitamin B-12 levels to evaluate for possible defects or deficiencies.

Other Tests

• Perform tissue typing of the patient and the family in anticipation of hematopoietic stem cell rescue.
• Test for hypersensitivity to GM-CSF.

Procedures

• Performing a bone marrow aspiration and biopsy is essential in establishing diagnosis and classification.
• Bone marrow findings reveal evidence of morphologic myelodysplasia in at least 2 cell lines.
• Biopsy may reveal dysplastic cells of various stages of differentiation with hypercellular findings.

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. 

• 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.¹⁷ Loss of the long arm of chromosome 5 (5q-), the most frequent chromosomal aberration in adults with RA, is rare in childhood.

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Medical Care

• Initially, administer supportive care until the diagnosis is established. Many patients present with profound cytopenia and a notable risk for infection. Initial care may include transfusion support, and the administration of broad-spectrum antibiotics to treat life-threatening anemia, thrombocytopenia, and infection may be required until definitive therapy can be started.
• In patients with refractory cytopenia, HSCT from a matched related or unrelated donor early in the course of the disease is the treatment of choice, especially in those with monosomy 7, 7q-, or complex karyotype. 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.¹⁸ In an Italian study involving 49 children, using the busulfan/cyclophosphamide regimen, the 5-year estimate of event-free survival (EFS) rate was 77%, whereas the 5-year cumulative incidence of transplant-related mortality and disease recurrence were 19% and 2%, respectively. 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 a pilot study involving 19 children with refractory cytopenia. The 3-year overall survival and EFS were 0.84 and 0.74, respectively.¹⁹
• 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 cytopenia necessitates treatment, then options include HSCT with either myeloablative or reduced intensity preparative therapies. 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.²⁰ 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.
• 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. A recent study reported 5-year EFS rates of 60% and 47% for HSCT using matched sibling donors or compatible unrelated donors, respectively.²¹ Whether intensive chemotherapy prior to HSCT should be routinely administered 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 reported significant morbidity and mortality in patients with MDS, and an overall survival of less than 30%.^{22, 23} Zecca et al reported AML-type therapy prior to HSCT did not prolong survival in 101 children with MDS and an increased blast count.
• In contrast to children, using the International Prognostic Scoring System (IPSS), adults with low-risk MDS can often be monitored for extended periods without specific therapy; however, those with intermediate-risk or high-risk MDS benefit from treatment.
• • Currently, the US Food and Drug Administration (FDA) has approved 3 agents for treatment of adult MDS in the past 3 years: azacitidine (Vidaza), decitabine (Dacogen) and lenalidomide (Revlimid). None of these compounds have been approved for the pediatric population.
  • 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.²⁴ Furthermore, the response 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.
  • In the early-phase clinical trials, both azacitidine and decitabine demonstrated impressive response rates (20-40%), including some complete remissions. Results from these studies resulted in large, randomized trials for both agents, which ultimately established these agents as part of the standard medications in the treatment of MDS. 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.²⁵ 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% hematological response.²⁶
• Because of the rarity of studies that address MDS as a unique disease entity, the Children's Oncology Group (COG) began a phase II study (AAML0121) that is currently closed due to lack of accrual, which reveals the rarity of de novo MDS in children. In addition, investigators in an open phase I study (ADVL0319) are enrolling patients with relapsed or refractory MDS. Details of these studies can be found on the COG Web site.
• 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% 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, seek alternative donors, although outcome is even less favorable than it is with a sibling donor.
• Growth factors may be indicated.
• • Hesitation in using growth factors has been based on the known increased response of myelodysplastic clone to GM-CSF and on the reported associated of the use of G-CSF in children with severe aplastic anemia with the later development of MDS or AML.  
  • 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.²⁷ This has also been confirmed by the Nordic and French MDS Study Groups.
  • G-CSF has also been used, with a transient improvement in neutropenia.

Surgical Care

• A central line is often needed to administer chemotherapy and transfusions.
• Splenectomy may prove helpful in patients with marked splenomegaly or hypersplenia. No significant change in the EFS rate is noted in patients who are undergoing hematopoietic stem cell rescue.
• The biggest risk is infection, as is the case with any patient who is asplenic.

Consultations

• Pediatric hematologist/oncologist
• Clinical geneticist
• • A clinical geneticist may provide an invaluable opinion for many children because of the notable association of MSD with other anomalies.
• • Family members of children with monosomy 7 cytogenetics should be evaluated for familial monosomy 7.

Diet

• 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

• Activity should be undertaken as tolerated.
• Restriction of activity when platelet counts are low is necessary to prevent hemorrhagic complications from minor trauma.

MEDICATION

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Children are treated with a wide variety of drugs. The most frequently used chemotherapeutic agents include idarubicin, dexamethasone, cytarabine arabinoside, fludarabine, etoposide, daunorubicin, L-asparaginase, and thioguanine.

Drug Category: Antineoplastic agents

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.

Drug Category: New antineoplastic agents

As noted in the Treatment section, the following drugs are approved for use in adults with myelodysplastic syndrome (MDS): azacytidine, decitabine, and lenalidomide (for those with 5q- MDS).

FOLLOW-UP

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Further Inpatient Care

• Hospitalization is required to administer some chemotherapeutic agents.
• Inpatient treatment is required if the patient is undergoing bone marrow transplantation.
• Children with myelodysplastic syndrome (MDS) should be treated like other patients with neutropenia. They require hospitalization, observation, and intravenous (IV) antibiotics to manage fever.
• Inpatient admission is required in some locations for transfusion support.

Further Outpatient Care

• Children should be monitored often because of the propensity of these disorders to transform to acute myeloid leukemia (AML).
• Patients often require frequent transfusions, and their blood cell counts must be monitored at least monthly.

In/Out Patient Meds

• Trimethoprim-sulfamethoxazole should be administered for prophylaxis against Pneumocystis carinii (opportunistic infection).
• Fluconazole is often administered for prophylaxis against Candida species.
• Chlorhexidine is recommended to prevent mouth infections.

Transfer

• Patients should be referred to centers affiliated with major multicenter pediatric oncologic groups.

Complications

• Infection
• • Severe neutropenia results in life-threatening infection secondary to overgrowth of skin and bowel flora and increased susceptibility to community and hospital pathogens.
  • Patients are extremely susceptible to life-threatening fungal infections.
  • Patients with cytogenetic findings of monosomy 7 or refractory anemia with excess blasts in transition to AML also have poor overall neutrophil function, despite adequate absolute neutrophil counts (ANCs) of more than 1000/µL.
  • Infection, rather than progression to AML, ultimately results in the demise of most patients with MDS.
• Bleeding
• • Patients often have thrombocytopenia and resultant hemorrhage.
  • Patients require frequent transfusions as marrow is increasingly involved.
• Anemia and iron overload
• • The inability of marrow to keep up with normal turnover of RBCs results in a frequent need for transfusion. Repeated transfusions may result in iron overload, requiring chelation therapy.
  • In rare circumstances, patients respond to splenectomy.
  • Iron overload is observed most often in adults with MDS related to transfusions over a prolonged course.

Prognosis

• Patients with Down syndrome and MDS respond best to treatment, whereas those with MDS due to previous therapy with alkylating agents fare the worst. As noted above, patients without Down syndrome who undergo allogeneic HSCT have the best outcome, despite transplant-related mortality.  
• Continued multicenter trials are needed with further elucidation of biologic markers to best classify MDS in childhood. Studies of medications such as azacitidine, decitabine, and lenalidomide should be undertaken to elucidate the efficacy in the pediatric population.
• Until recently, most of the prognostic factors in MDS, such as those used in the 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.
  • 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, one prospective study (CCG 2891) provided results about the effects of AML-based therapy in children with MDS.⁹ Of 1096 patients enrolled, 90 had MDS classified according to the FAB classification. Overall survival at 6 years was 29% ±12 for patients with MDS and 31% ±26 for those with JMML treated in the CCG 2891. 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 juvenile myelomonocytic leukemia (JMML) and MDS.
• In recent reports, 5-year 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.

Patient Education

• Families must be educated about signs and symptoms of infection, anemia, and thrombocytopenia.
• Many patients require placement of a central venous catheter, and their families need to learn how to care for the line.

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

1. Bennett JM, Catovsky D, Daniel MT, et al. The chronic myeloid leukaemias: guidelines for distinguishing chronic granulocytic, atypical chronic myeloid, and chronic myelomonocytic leukaemia. Proposals by the French-American-British Cooperative Leukaemia Group. Br J Haematol. 87(4):746-54. [Medline].
2. Hasle H, Niemeyer CM, Chessells JM, Baumann I, Bennett JM, Kerndrup G. A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases. Leukemia. Feb 2003;17(2):277-82. [Medline].
3. Steliarova-Foucher E, Stiller C, Lacour B, Kaatsch P. International Classification of Childhood Cancer, third edition. Cancer. Apr 1 2005;103(7):1457-67. [Medline].
4. Blank J, Lange B. Preleukemia in children. J Pediatr. Apr 1981;98(4):565-8. [Medline].
5. Greenberg PL, Mara B. The preleukemic syndrome: correlation of in vitro parameters of granulopoiesis with clinical features. Am J Med. Jun 1979;66(6):951-8. [Medline].
6. Hasle H, Kerndrup G, Jacobsen BB. Childhood myelodysplastic syndrome in Denmark: incidence and predisposing conditions. Leukemia. Sep 1995;9(9):1569-72. [Medline].
7. Malcovati L, Della Porta MG, Cazzola M. Predicting survival and leukemic evolution in patients with myelodysplastic syndrome. Haematologica. Dec 2006;91(12):1588-90. [Medline].
8. Luna-Fineman S, Shannon KM, Atwater SK, et al. Myelodysplastic and myeloproliferative disorders of childhood: a study of 167 patients. Blood. 93(2):459-66. [Medline].
9. Lange BJ, Kobrinsky N, Barnard DR, et al. Distinctive demography, biology, and outcome of acute myeloid leukemia and myelodysplastic syndrome in children with Down syndrome: Children's Cancer Group Studies 2861 and 2891. Blood. Jan 15 1998;91(2):608-15. [Medline].
10. Smith OP. Shwachman-Diamond syndrome. Semin Hematol. Apr 2002;39(2):95-102. [Medline].
11. Butturini A, Gale RP, Verlander PC, et al. Hematologic abnormalities in Fanconi anemia: an International Fanconi Anemia Registry study. Blood. 84(5):1650-5. [Medline].
12. Freedman MH, Bonilla MA, Fier C, et al. Myelodysplasia syndrome and acute myeloid leukemia in patients with congenital neutropenia receiving G-CSF therapy. Blood. Jul 15 2000;96(2):429-36. [Medline].
13. Willig TN, Niemeyer CM, Leblanc T, et al. Identification of new prognosis factors from the clinical and epidemiologic analysis of a registry of 229 Diamond-Blackfan anemia patients. Pediatr Res. Nov 1999;46(5):553-61. [Medline].
14. Dokal I. Dyskeratosis congenita in all its forms. Br J Haematol. Sep 2000;110(4):768-79. [Medline].
15. Ohara A, Kojima S, Okamura J, et al. Evolution of myelodysplastic syndrome and acute myelogenous leukaemia in children with hepatitis-associated aplastic anaemia. Br J Haematol. Jan 2002;116(1):151-4. [Medline].
16. Ohara A, Kojima S, Hamajima N, et al. Myelodysplastic syndrome and acute myelogenous leukemia as a late clonal complication in children with acquired aplastic anemia. Blood. Aug 1 1997;90(3):1009-13. [Medline].
17. Hasle H, Arico M, Basso G, et al. Myelodysplastic syndrome, juvenile myelomonocytic leukemia, and acute myeloid leukemia associated with complete or partial monosomy 7. European Working Group on MDS in Childhood (EWOG-MDS). Leukemia. 13(3):376-85. [Medline].
18. Yusuf U, Frangoul HA, Gooley TA, et al. Allogeneic bone marrow transplantation in children with myelodysplastic syndrome or juvenile myelomonocytic leukemia: the Seattle experience. Bone Marrow Transplant. Apr 2004;33(8):805-14. [Medline].
19. Strahm B, Locatelli F, Bader P, et al. Reduced intensity conditioning in unrelated donor transplantation for refractory cytopenia in childhood. Bone Marrow Transplant. Aug 2007;40(4):329-33. [Medline].
20. Yoshimi A, Baumann I, Fuhrer M, et al. Immunosuppressive therapy with anti-thymocyte globulin and cyclosporine A in selected children with hypoplastic refractory cytopenia. Haematologica. Mar 2007;92(3):397-400. [Medline].
21. Lang P, Greil J, Bader P, et al. Long-term outcome after haploidentical stem cell transplantation in children. Blood Cells Mol Dis. Nov-Dec 2004;33(3):281-7. [Medline].
22. Williamson PJ, Kruger AR, Reynolds PJ, et al. Establishing the incidence of myelodysplastic syndrome. Br J Haematol. 87(4):743-5. [Medline].
23. Hasle H, Kerndrup G, Yssing M, et al. Intensive chemotherapy in childhood myelodysplastic syndrome. A comparison with results in acute myeloid leukemia. Leukemia. Aug 1996;10(8):1269-73. [Medline].
24. List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. Oct 5 2006;355(14):1456-65. [Medline].
25. Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. May 15 2002;20(10):2429-40. [Medline].
26. Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. Apr 15 2006;106(8):1794-803. [Medline].
27. Miller K, Haesook K, Greenberg P, et al. Phase III prospective randomized trial of EPO with or without G-CSF versus supportive care in the treatment of MDS: results of the ECOG-CLSG trial. Blood. 2004;104:70.
28. Arico M, Biondi A, Pui CH. Juvenile myelomonocytic leukemia. Blood. Jul 15 1997;90(2):479-88. [Medline].
29. Aul C, Gattermann N, Schneider W. Age-related incidence and other epidemiological aspects of myelodysplastic syndromes. Br J Haematol. Oct 1992;82(2):358-67. [Medline].
30. Brandwein JM, Horsman DE, Eaves AC, et al. Childhood myelodysplasia: suggested classification as myelodysplastic syndromes based on laboratory and clinical findings. Am J Pediatr Hematol Oncol. 12(1):63-70. [Medline].
31. Carroll WL, Morgan R, Glader BE. Childhood bone marrow monosomy 7 syndrome: a familial disorder?. J Pediatr. Oct 1985;107(4):578-80. [Medline].
32. Chan GC, Wang WC, Raimondi SC, et al. Myelodysplastic syndrome in children: differentiation from acute myeloid leukemia with a low blast count. Leukemia. 11(2):206-11. [Medline].
33. Duffner PK, Krischer JP, Horowitz ME, et al. Second malignancies in young children with primary brain tumors following treatment with prolonged postoperative chemotherapy and delayed irradiation: a Pediatric Oncology Group study. Ann Neurol. 44(3):313-6. [Medline].
34. Haas OA, Gadner H. Pathogenesis, biology, and management of myelodysplastic syndromes in children. Semin Hematol. Jul 1996;33(3):225-35. [Medline].
35. Hann IM. Myelodysplastic syndromes. Arch Dis Child. Jul 1992;67(7):962-6. [Medline].
36. Hasle H. Classification of MDS and myeloproliferative disorders in children. In: Lopes LF, Hasle H, eds. Myelodysplastic and Myeloproliferative Disorders in Children. Sao Paulo, Brazil: Livraria Editora Marina; 2003:21-35.
37. Hasle H, Kerndrup G, Jacobsen BB, et al. Chronic parvovirus infection mimicking myelodysplastic syndrome in a child with subclinical immunodeficiency. Am J Pediatr Hematol Oncol. 16(4):329-33. [Medline].
38. Hasle H, Passmore SJ. Epidemiology of MDS and myeloproliferative disorders in children. In: Lopes LF, Hasle H, eds. Myelodysplastic and Myeloproliferative Disorders in Children. Sao Paulo, Brazil: Livraria Editora Marina; 2003:49-66.
39. Ho PJ, Gibson J, Vincent P, Joshua D. The myelodysplastic syndromes: diagnostic criteria and laboratory evaluation. Pathology. Jul 1993;25(3):297-304. [Medline].
40. Jackson GH, Carey PJ, Cant AJ, et al. Myelodysplastic syndromes in children [letter]. Br J Haematol. 84(1):185-6. [Medline].
41. Kirby MA, Weitzman S, Freedman MH. Juvenile chronic myelogenous leukemia: differentiation from infantile cytomegalovirus infection. Am J Pediatr Hematol Oncol. Fall 1990;12(3):292-6. [Medline].
42. List A, Wride K, Dewald G, et al. Cytogenetic response to Lenalidomide is associated with improved survival in patients with chromosome 5q deletion. Leuk Res. 2007;31 (Suppl 1):S38.
43. Luna-Fineman S, Shannon KM, Lange BJ. Childhood monosomy 7: epidemiology, biology, and mechanistic implications. Blood. Apr 15 1995;85(8):1985-99. [Medline].
44. Mathew P, Woods WG. Experiences on MDS from the United States. In: Lopes LF, Hasle H, eds. Myelodysplastic and Myeloproliferative Disorders in Children. 2003. Sao Paulo, Brazil: Livraria Editora Marina; 340-60.
45. Nevill TJ, Fung HC, Shepherd JD, et al. Cytogenetic abnormalities in primary myelodysplastic syndrome are highly predictive of outcome after allogeneic bone marrow transplantation. Blood. 92(6):1910-7. [Medline].
46. Niemeyer CM, Arico M, Basso G, et al. Chronic myelomonocytic leukemia in childhood: a retrospective analysis of 110 cases. European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS). Blood. 89(10):3534-43. [Medline].
47. Niemeyer CM, Baumann I. Myelodysplastic syndrome in children and adolescents. Semin Hematol. Jan 2008;45(1):60-70. [Medline].
48. Park DJ, Koeffler HP. Therapy-related myelodysplastic syndromes. Semin Hematol. Jul 1996;33(3):256-73. [Medline].
49. Park S, Graber S, Kelaidi C, et al. Has treatment with EPO +/- G-CSF an impact on progression to AML and survival in low/int-1-risk MDS. Leuk Res. 2007;31 (Suppl 1):S113.
50. Passmore SJ. Prognostic factors in MDS. In: Lopes LF, Hasle H, eds. Myelodysplastic and Myeloproliferative Disorders in Children. Sao Paulo, Brazil: Livraria Editora Marina; 2003:171-6.
51. Passmore SJ, Hann IM. Paediatric myelodysplasia. Br Med Bull. Oct 1996;52(4):778-86. [Medline].
52. Passmore SJ, Hann IM, Stiller CA, et al. Pediatric myelodysplasia: a study of 68 children and a new prognostic scoring system. Blood. 85(7):1742-50. [Medline].
53. Tuncer MA, Pagliuca A, Hicsonmez G, et al. Primary myelodysplastic syndrome in children: the clinical experience in 33 cases. Br J Haematol. 82(2):347-53. [Medline].
54. Uderzo C, Locasciulli A, Rajnoldi AC, et al. Allogeneic bone marrow transplantation for myelodysplastic syndromes of childhood: report of three children with refractory anemia with excess of blasts in transformation and review of the literature. Med Pediatr Oncol. 21(1):43-8. [Medline].
55. Webb DK, Harrison G, Stevens RF, et al. Relationships between age at diagnosis, clinical features, and outcome of therapy in children treated in the Medical Research Council AML 10 and 12 trials for acute myeloid leukemia. Blood. Sep 15 2001;98(6):1714-20. [Medline].
56. Woods WG, Barnard DR, Alonzo TA, et al. Prospective study of 90 children requiring treatment for juvenile myelomonocytic leukemia or myelodysplastic syndrome: a report from the Children's Cancer Group. J Clin Oncol. Jan 15 2002;20(2):434-40. [Medline].
57. Zeller B, Gustafsson G, Forestier E, et al. Acute leukaemia in children with Down syndrome: a population-based Nordic study. Br J Haematol. Mar 2005;128(6):797-804. [Medline].

Article Last Updated: May 22, 2008