eMedicine Specialties > Pediatrics: General Medicine > Oncology

Myelodysplastic Syndrome

Prasad Mathew, MB, BS, DCH, Director, Hemostasis and Hematology Program, Professor of Pediatrics, University of New Mexico
Franklin Smith, MD, Marjory J Johnson Endowed Chair, Professor of Pediatrics, Division of Hematology/Oncology, Professor of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Children's Hospital Medical Center; Glenda H Grawe, MD, Assistant Professor, Baylor College of Medicine Department of Pediatrics, Section of Emergency Medicine; Attending Physician, Texas Children's Hospital

Updated: May 22, 2008

Introduction

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

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

Differential Diagnoses

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

Laboratory 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

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

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.

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.

Cytarabine (Cytosar-U)

Antimetabolite antineoplastic agent. Converted intracellularly to active compound, cytarabine-5'-triphosphate, which inhibits DNA polymerase. Metabolized in liver with half-life of 1-3 h. Widely distributed, including in CNS and tears after IV administration. Not PO active.

Dosing

Adult

100-200 mg/m²/d IV qd for 5-7 d; not to exceed 3 g/m² IV infusion q12h

Pediatric

Administer as in adults

Interactions

Decreases effects of gentamicin and flucytosine; other alkylating agents and radiation increase toxicity

Contraindications

Documented hypersensitivity; liver failure

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

If bone marrow suppression notably worsens, reduce number of treatment days; patients with hepatic or renal insufficiencies at increased risk for CNS toxicity after high dose (reduce dose)

Pegaspargase (Oncaspar)

Polyethylene glycol-L-asparaginase. Catabolizes asparagine, essential amino acid for lymphoblast growth. Half-life 2-3 wk.

Dosing

Adult

2500 IU/m² IM q14d

Pediatric

Administer as in adults

Interactions

Increase toxicity with vincristine; may displace highly protein-bound drugs (eg, warfarin); increased bleeding with warfarin, heparin, aspirin, NSAIDs, or dipyridamole

Contraindications

Documented hypersensitivity; pancreatitis; previous thrombosis associated with pegaspargase

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in hypofibrinogenemia, confusion, diabetes mellitus, or hepatic impairment

Fludarabine (Fludara)

2-Fluoro, 5-phosphate derivative of vidarabine. Converted to 2-fluoro-ara-A that enters cell; phosphorylated to form active metabolite 2-fluoro-ara-ATP, which inhibits DNA synthesis. Half-life of active metabolite is 9 h.

Dosing

Adult

25-30 mg/m² qd for 5 d q28d

Pediatric

Administer as in adults

Interactions

Pentostatin increases risk of pulmonary toxicity; cytarabine administered with or before decreases conversion to active drug

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Frequently monitor peripheral blood cell counts to detect anemia, thrombocytopenia, and neutropenia; monitor for tumor lysis syndrome; adjust dose in renal impairment, severe bone marrow suppression, severe neurologic effects, or life-threatening or fatal autoimmune hemolytic anemia

Idarubicin (Idamycin)

Anthracycline antineoplastic agent. Inhibits cell proliferation by inhibiting DNA and RNA polymerase. Metabolized in liver to active idarubicinol. Half-life 14-35 h (PO) or 12-27 h (IV). Vesicant.

Dosing

Adult

12 mg/m² IV qd for 3 d
Breast cancer: 30-45 mg/m² PO q3wk
AML: 20-25 mg/m² qd for 3 d

Pediatric

12 mg/m² IV qd for 3 d

Interactions

Trastuzumab increases risk of cardiotoxicity

Contraindications

Documented hypersensitivity; severe CHF; cardiomyopathy; arrhythmias; previous treatment with maximal cumulative doses of other anthracyclines

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Extravasation can result in severe tissue necrosis; caution in preexisting cardiac disease, impaired hepatic or renal function, or myelosuppression; cardiac toxicity is most serious complication

Daunorubicin (Cerubidine)

Anthracycline antineoplastic agent. Inhibits DNA and RNA synthesis by intercalating between DNA base pairs. Half-life 14-20 h (23-40 h for active metabolite).

Dosing

Adult

25-100 mg/m² IV qd for 3-5 d intermittent or continuous infusion

Pediatric

Administer as in adults

Interactions

Trastuzumab increases risk of cardiotoxicity

Contraindications

Documented hypersensitivity; severe CHF; cardiomyopathy; arrhythmias; previous treatment with maximal cumulative doses of other anthracyclines

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Extravasation may occur, resulting in severe tissue necrosis; caution in impaired hepatic, renal, or biliary function; monitor for myelosuppression and, if necessary, decrease dose; may discolor urine (red)

Dexamethasone (Decadron)

Long-acting fluorinated corticosteroid. Induces apoptosis of leukemia cells by means of glucocorticoid receptors. 0.75 mg equivalent to 4 mg methylprednisolone, 5 mg prednisolone, 30 mg hydrocortisone, or 25 mg cortisone.

Dosing

Adult

0.75-9 mg/d PO q2-4d
0.5-9 mg/d IV qd or divided q6h

Pediatric

0.03-0.15 mg/kg/d PO or 1-5 mg/m²/d PO divided q6-12h; not to exceed 25 mg/m² IV qd

Interactions

Phenobarbital, phenytoin, ephedrine, and rifampin may enhance clearance of corticosteroids; coadministration with potassium-depleting diuretics increases risk of hypokalemia; may alter response to warfarin anticoagulants (usually inhibitory but unsubstantiated reports of potentiation have been made); decreases effect of salicylates and vaccines for immunization

Contraindications

Documented hypersensitivity; active bacterial or fungal infection

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Increases risk of several complications, including severe infections; monitor adrenal insufficiency when tapering; abrupt discontinuation of glucocorticoids may cause adrenal crisis; possible complications of glucocorticoid use are hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections

Thioguanine

Purine analog with antineoplastic and antimetabolite properties.

Dosing

Adult

40-100 mg/m² PO qd

Pediatric

2 mg/kg PO qd

Interactions

Increases busulfan toxicity

Contraindications

Documented hypersensitivity; previous resistance to antitumoral effects

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Adjust dose to compensate for myelosuppression, renal disease, or hepatic disease; may cause neurotoxicity, hyperuricemia, or myelosuppression

Etoposide (VePesid, VP-16)

Semisynthetic podophyllotoxin with poor penetration of CSF. Inhibits topoisomerase II and causes DNA strand breakage, which arrests cell proliferation in late S or early G2 portion of cell cycle. Half-life 4-11 h.

Dosing

Adult

Low dosage: 20-100 mg/m²/d IV for 5 d
High dosage: up to 3 g/m² IV qd

Pediatric

Low dosage: 20-100 mg/m²/d IV for 5 d
High dosage: up to 3 g/m² IV qd

Interactions

May prolong effects of warfarin and increase clearance of methotrexate; has additive effects with cyclosporine in cytotoxicity of tumor cells

Contraindications

Documented hypersensitivity; intrathecal administration (may cause death)

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Bleeding and severe myelosuppression may occur; monitor for hypotension during administration

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).

Azacitidine (Vidaza)

Pyrimidine nucleoside analog of cytidine. Interferes with nucleic acid metabolism. Exerts 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. Indicated to treat MDS in adults. FDA approved for all 5 MDS subtypes.

Dosing

Adult

75 mg/m² IV/SC qd for 7 days initially, repeat cycle q4wk; may increase to 100 mg/m² if no beneficial effect after 2 cycles; treat for a minimum of 4 cycles; treatment may be continued as long as response continues and treatment tolerated

Pediatric

Not established

Interactions

Limited data exist, none reported

Contraindications

Documented hypersensitivity to azacitidine or mannitol; advanced malignant hepatic tumors

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

While receiving azacitidine, males should avoid fathering children; do not use in breastfeeding women; may cause neutropenia and thrombocytopenia (following first cycle, may require dose adjustment or delay based on nadir counts and hematologic response); caution with hepatic or renal impairment; common adverse effects following SC administration include nausea, vomiting (premedicate for nausea and vomiting before administration), diarrhea, constipation, anemia, thrombocytopenia, leukopenia, neutropenia, pyrexia, fatigue, infection site erythema, and ecchymosis; administer IV over 10-40 min in clinic or hospital setting; common adverse effects following IV administration include petechiae, rigors, weakness, and hypokalemia

Decitabine (Dacogen)

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. Indicated for treatment of MDSs, including previously treated and untreated, de novo, and secondary MDSs of all FAB subtypes (ie, RA, RARS, RAEB, RAEBT, CMML) and IPSS groups intermediate-1 risk, intermediate-2 risk, and high risk.

Dosing

Adult

15 mg/m² IV q8h for 3 d; infuse over 3 h; repeat q6wk for at least 4 cycles and as long as continued benefit observed

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Common adverse effects include neutropenia (90%), thrombocytopenia (89%), anemia (82%), pyrexia (53%), fatigue (48%), nausea (42%), cough (40%), petechiae (39%), constipation (35%), and diarrhea (34%); males must avoid fathering children while receiving decitabine and for 2 mo following discontinuation; decrease or delay dose if hematologic recovery requires >6 wk

Lenalidomide (Revlimid)

Indicated for transfusion-dependent MDS subtype of 5q- cytogenetic abnormality. Structurally similar to thalidomide. Elicits immunomodulatory and antiangiogenic properties. Inhibits proinflammatory cytokine secretion and increases anti-inflammatory cytokines from peripheral blood mononuclear cells.

Dosing

Adult

10 mg PO qd initially; dose adjustment required if renal impairment, thrombocytopenia, or neutropenia occurs

Pediatric

<18 years: Not established
>18 years: Administer as in adults

Interactions

Data limited; none reported

Contraindications

Documented hypersensitivity; pregnancy

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Available only through RevAssist, a risk management plan to prevent fetal exposure; only pharmacists and prescribers registered with the program may prescribe and dispense (program requires mandatory pregnancy testing and limits prescription to 1-mo supply via mail); male patients, including those with vasectomy, must use latex condom during sexual contact with female of childbearing potential; women must not become pregnant 4 wk before starting lenalidomide and 4 wk after discontinuing lenalidomide; may cause anemia, DVT, pulmonary embolism, thrombocytopenia, neutropenia, diarrhea, pruritus, rash, and fatigue; renal excretion substantial, caution in elderly patients or those with renal impairment (may need to decrease dose); not break, chew, or open cap

Follow-up

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.

Inpatient & Outpatient Medications

• 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.

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Keywords

myelodysplastic syndrome, MDS, MDS, chronic myelomonocytic leukemia, CMML, clonal hemopathy, juvenile chronic myeloid leukemia, JCML, juvenile myelomonocytic leukemia, JMML, monosomy 7, oligoblastic leukemia, preleukemia, refractory anemia, RA, smoldering acute leukemia, acute myelogenous leukemia, acute myeloid leukemia, AML, adult-type MDS, a-MDS, refractory anemia with ringed sideroblasts, RARS, refractory anemia with excess blasts, RAEB, refractory anemia with excess blasts in transition to AML, RAEBT

cytopenia, preleukemia, hematopoietic stem cell transplantation, HSCT, 5q- syndrome, 5q deletion syndrome, infantile monosomy 7, myeloproliferative disorders, bone marrow dysfunction, neurofibromatosis type 1, NF1, cytopenia, short stature, obesity, gonadal failure, hypothyroidism, cataracts, bone marrow failure, lymphadenopathy, therapy-related MDS, Down syndrome, myeloid leukemia of Down syndrome, ML-DS, pancreatic insufficiency, Fanconi anemia, Kostmann syndrome, Diamond-Blackfan anemia, dyskeratosis congenita

Contributor Information and Disclosures

Author

Prasad Mathew, MB, BS, DCH, Director, Hemostasis and Hematology Program, Professor of Pediatrics, University of New Mexico
Prasad Mathew, MB, BS, DCH is a member of the following medical societies: American Society of Hematology
Disclosure: Nothing to disclose.

Coauthor(s)

Franklin Smith, MD, Marjory J Johnson Endowed Chair, Professor of Pediatrics, Division of Hematology/Oncology, Professor of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Children's Hospital Medical Center
Disclosure: Nothing to disclose.

Glenda H Grawe, MD, Assistant Professor, Baylor College of Medicine Department of Pediatrics, Section of Emergency Medicine; Attending Physician, Texas Children's Hospital
Glenda H Grawe, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Emergency Physicians, Harris County Medical Society, Minnesota Medical Association, National Association of EMS Physicians, and Texas Pediatric Society
Disclosure: Draeger Honoraria Review panel membership

Medical Editor

Kathleen Sakamoto, MD, Professor, Department of Pediatrics, Division of Hematology-Oncology and Pathology and Laboratory Medicine, Mattel Children's Hospital, David Geffen School of Medicine, University of California at Los Angeles
Kathleen Sakamoto, MD is a member of the following medical societies: American Society of Hematology, American Society of Pediatric Hematology/Oncology, New York Academy of Sciences, Society for Pediatric Research, and Western Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

Timothy P Cripe, MD, PhD, Associate Professor of Pediatric Hematology/Oncology, University of Cincinnati; Director, Translational Research Trials Office, Department of Pediatrics, Cincinnati Children's Hospital Medical Center
Timothy P Cripe, MD, PhD is a member of the following medical societies: American Association for the Advancement of Science, American Society of Hematology, and American Society of Pediatric Hematology/Oncology
Disclosure: Nothing to disclose.

CME Editor

Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida, Clinical Professor, Department of Pediatrics, UNC, Adjunct Professor, Department of Pediatrics, Duke University
Samuel Gross, MD is a member of the following medical societies: American Association for Cancer Research, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, American Society of Hematology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Chief Editor

Robert J Arceci, MD, PhD, King Fahd Professor of Pediatric Oncology, Department of Oncology, Division of Pediatric Oncology, Johns Hopkins University School of Medicine
Robert J Arceci, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Pediatric Society, American Society of Clinical Oncology, American Society of Hematology, and American Society of Pediatric Hematology/Oncology
Disclosure: Nothing to disclose.

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