AUTHOR INFORMATION

Section 1 of 10

Authored by Prasad Mathew, MBBS, DCH, Director, Ted R Montoya Hemophilia Center, Associate Professor, Department of Pediatrics, University of New Mexico

Coauthored by Franklin Smith, MD, Marjory J Johnson Endowed Chair, Professor of Pediatrics, Professor of Pediatrics, University of Cincinnati College of Medicine, Division of Hematology/Oncology, Cincinnati Children's Hospital Medical Center; Glenda H Grawe, MD, Fellow, Department of Pediatric Emergency Medicine, Children's Hospitals and Clinics of Minneapolis; 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

Prasad Mathew, MBBS, DCH, is a member of the following medical societies: American Society of Hematology

Edited by 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; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; 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; Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida, Clinical Professor, Department of Pediatrics, UNC, Adjunct Professor, Department of Pediatrics, Duke University; and Robert J Arceci, MD, PhD, King Fahd Professor, Division of Pediatric Oncology, Johns Hopkins University School of Medicine

Author's Email:	Prasad Mathew, MBBS, DCH
Editor's Email:	Kathleen Sakamoto, MD

eMedicine Journal, April 18 2006, VOLUME 7, Number 4

INTRODUCTION

Section 2 of 10

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 which results in ineffective hematopoiesis with dysplastic changes in the marrow. These disorders are characterized by one or more cytopenias, despite a relatively hypercellular bone marrow. They are referred to as preleukemia because of their tendency to transform into acute myeloid leukemia (AML).

MDS is rare in childhood, and most children have a rapidly progressive course with extremely poor prognosis. It can arise in a previously healthy child when it is referred to as "de novo" or primary MDS, or it may develop in a child with a known predisposition (secondary MDS). It is more common in adults, especially elderly people, and has a variable course ranging from an acute rapidly fatal illness to a chronic indolent illness.

MDS is classified into groups according to findings on peripheral blood smear, bone marrow histology, and clinical findings. Significant controversy exists over classification with systematic evaluation of frequency, outcomes, and treatment difficulty. Most accepted systems use a modified classification of adult MDS, proposed by French-American-British (FAB) group. Children with MDS who fit within these classifications are often referred to in current studies as having adult-type MDS. FAB types include 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)

An exception to the FAB system is classification of chronic myelomonocytic leukemia (CMML). A number of children fit this criteria; however, they often have findings on peripheral blood smears of greater than 5% blasts. In addition, most children who otherwise fulfill criteria of CMML share an extremely poor prognosis compared to adult patients with CMML who have a more prolonged course than with other forms of MDS.

CMML as it occurs in the adult population 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). Currently, the preferred term is JMML. Since JMML is a separate entity from MDS, it will not be discussed in detail in this section. Other differences exist between MDS in children and adults; for example, RARS is exceedingly rare in children, and constitutional abnormalities are observed in a large fraction of children but are very uncommon in adults.

One of the criticisms of the FAB system is that it does not include the prognostic implications of cytogenetic findings or other biological features. Of particular note are 5q-, monosomy 7 syndrome, and infantile monosomy 7. The presence of monosomy 7 is most often associated with JMML, and up to 30% of children with JMML have a deletion of all, or part, of chromosome 7. While this finding imparts some prognostic value concerning morbidity, it remains controversial as to any contribution to predicting mortality in these patients.

In an attempt to include some cytogenetic information, the World Health Organization (WHO) recently proposed an alternate classification scheme for MDS. As depicted below, the RAEBT category has been eliminated (prompting criticism for lumping RAEBT with frank AML) and an unclassified category has been added. The changing classification schemes and continuing controversies are indicative of the limited understanding of MDS. An adequate scheme is likely to be devised only after a much more detailed comprehension of MDS at the genetic, biologic, and clinical levels is attained. The WHO classification includes the following:

• RA with or without ringed sideroblasts (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 capable of giving rise to multiple lineages. This explains the presence of multiple derangements observed within the bone marrow, involving several cell lineages. As these cell lines continue to divide and provide the marrow with dysplastic cells, bone marrow dysfunction becomes apparent. This state may persist and continue until a clone undergoes further transformation to leukemia and the marrow becomes fibrotic and aplastic, or the clone may progressively deteriorate and the appearance of marrow returns to normal as healthy stem cells repopulate the marrow. Natural progression of MDS is thus a function of abnormal clone leading to progressive loss of marrow function, transformation to AML, or spontaneous remission.

Cytogenetic abnormalities, most specifically monosomy 7 and neurofibromatosis type 1 (NF-1) gene mutations, provide support for the theory of cell dysregulation occurring in a multi-hit fashion. In the case of monosomy 7, a genetic predisposition and a later loss of a critical region on chromosome 7 that codes for a suspected tumor suppressor gene is suggested to set the stage for proliferation of an abnormal clone. Loss of chromosome may occur during an embryonic period within hematopoietic stem cells or it may occur as result of cytotoxic therapy.

In patients with neurofibromatosis (NF), loss of NF-1 gene product occurs, which results in loss of negative feedback via guanosine triphosphatase (GTPase) of oncogene N-ras. Without negative feedback, cell proliferation becomes disrupted. Another event occurring in children with NF then sets the stage for proliferation of abnormal clone. Genetic predisposition or a second event in either one of these scenarios may be complete or partial loss of a gene product. Both of these concepts are theoretical, based on known frequency of monosomy 7 found in patients with MDS and increased risk of MDS in children with NF. Either event may occur at several levels of differentiation, leading to variable involvement of multiple cell lines such as erythroid and myeloid lines observed with RAEB.

The 5q- syndrome is considered a unique MDS entity characterized by 5q- as the sole abnormality, BM blasts <5%, normal or elevated platelets, and long survival. 5q- has occasionally been reported in children, but no reports exist on the typical 5q- syndrome in children.

Frequency:

• In the US: The epidemiologic literature on childhood MDS is very sparse. This is due to the following:
  • A lack of widely accepted classification

  • More indolent forms of the disease may not be referred to a tertiary center, resulting in a bias of institution-based studies toward the more aggressive forms.

  • Cancer registries do not generally register MDS.

  • No incidence data exist. In one of the earliest reports, MDS or preleukemia was reported in 17% of childhood AML, corresponding to 2.9% of all children with leukemia. Other studies have confirmed that 12-20% of childhood AML are preceded by a preleukemic phase. These studies are based upon referrals for suspected AML, leaving out the less advanced cases of MDS.

• Internationally: The few population-based studies have given conflicting data on the incidence. Population-based data from Denmark and Canada (British Columbia) found MDS and JMML to represent 6% of all hematologic malignancies in children, corresponding to an annual incidence of MDS and JMML of 1.8 and 1.2 per million children aged 0-14 years, respectively.

  A similar proportion of MDS and JMML (in combination 7.7% of childhood leukemia) was found in Japan, where therapy-related MDS represents a relatively large proportion (23%). In England, incidence is reported to be 0.5 in 1 million population, which accounts for 1.1% of childhood hematologic malignancies. The exclusion of secondary MDS may only partly explain the lower incidence in the United Kingdom study. Incidence in elderly people is 89 in 100,000 population.

Mortality/Morbidity:

• Prognosis in MDS for pediatric patients is poor. The most common cause of death is secondary to cytopenia, resulting from dysplastic marrow. A recent study that also included adult patients showed that the prognosis for Japanese patients with RA was significantly more favorable than that of German patients (median survival 175 months vs 40 months, p <0.01), suggesting an ethnic variation in survival between Asian and Caucasian populations. Furthermore, the Japanese patients also had a significantly lower cumulative risk of acute leukemia evolution than did German patients.

• Most long-term complications are related to myeloablative therapy with stem cell rescue, including short stature, obesity, gonadal failure, hypothyroidism, and cataracts.

Race:

• Data from the Children's Cancer Group showed that 75% of patients are white, 8.5% are Hispanic, 8% are African American, 3.5% are Asian, and 5% are unknown.

• Most studies have been conducted in countries with predominately white populations; results may not be a true reflection of racial distribution.

• Incidence within each race has not yet been reported.

Sex:

• Combined data on 290 mainly primary MDS patients shows an equal sex distribution (144/146).

• In patients with adult-type MDS, such as RA, RAEB, and RAEBT, the male-to-female ratio is 1.2:1.

Age:

• This condition 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.

• Distribution of FAB classifications in adult populations is as follows: RA, 38.4%; RARS, 11.5%; RAEB, 15%; RAEBT, 3.9%; and CMML, 31.2%. In the pediatric population, more aggressive forms, such as RAEB and RAEBT, are more common than RA or RARS.

CLINICAL

Section 3 of 10

History:

• Children present with a history consistent with bone marrow failure. History and presentation are similar to children with leukemia.



• The interval between the onset of symptoms and diagnosis ranges from 0-23 months, with a median time of 2 months.



• Patients may be asymptomatic and the condition may be discovered on routine CBC count.



• 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 mimic children with acute leukemia.



• General appearance ranges from well-appearing to constitutional wasting.



• Pallor and fatigue from anemia may be present.



• Hepatosplenomegaly predominates in JMML.



• Lymphadenopathy is present in 40-76% of JMML cases but in fewer than 10% of adult-type MDS cases.



• In 30% of JMML cases, a diffuse erythematous maculopapular rash is present.

Causes: MDS may be primary or secondary. Secondary MDS is seen in patients after chemotherapy or radiation therapy (therapy-related MDS), with inherited bone marrow failure disorders, with acquired aplastic anemia, and with familial MDS. It should be recognized that children with primary MDS may have an underlying yet unknown genetic defect predisposing them to MDS at a young age. Thus, 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.



• Down syndrome: MDS and AML in DS are closely linked with biological and clinical features distinct from the diseases in non-DS children, and they are now recognized as a single specific entity, myeloid leukemia of Down syndrome (ML-DS) in the proposed WHO classification (Hasle, Leukemia, 2003). Antecedent MDS is common, affecting up to 70% of children diagnosed with ML-DS (Lange, 1998).



• NF (1%) occurs mainly in JMML. Patients with NF-1 have a 350-fold increased risk of JMML.



• Shwachman syndrome (7%) is pancreatic insufficiency with neutropenia.



• Fanconi anemia (4-7%) may be a factor, with 48% of patients developing leukemia or MDS by age 40 years.



• Familial leukemia (2-6%) may be a factor; monosomy 7 families tend to have JMML.



• Kostmann syndrome (0.6%) is congenital agranulocytosis.



• Previous therapy with alkylating agents (2-5%) as a causative factor is associated with monosomy 7 and chromosome 5 deletions. These patients have poor response rates.



• Previous topoisomerase inhibitor (rare) administration may be a factor. In these rare cases, patients usually develop AML.

DIFFERENTIALS

Section 4 of 10

Acute Lymphoblastic Leukemia
Acute Myelocytic Leukemia
Anemia, Acute
Anemia, Chronic
Blastomycosis
Chromosomal Breakage Syndromes
Cytomegalovirus Infection
Herpesvirus 6 Infection
Histoplasmosis
Kostmann Disease
Myelodysplasia
Myelofibrosis
Parvovirus B19 Infection
Transient Erythroblastopenia of Childhood

Other Problems to be Considered:

Autoimmune cytopenias
Diamond-Blackfan anemia

The two major diagnostic challenges are to distinguish MDS with a low blast count from aplastic anemia and other nonclonal bone marrow disorders and to differentiate MDS with excess blasts from AML.

WORKUP

Section 5 of 10

Lab Studies:

• Complete blood cell count with differential and smear


• • Patients are often anemic with high mean cellular volume (MCV) and red blood cell distribution width (RDW).
  
  
  
  • They may be neutropenic and thrombocytopenic.
  
  
  
  • In JMML, a marked monocytosis may be present (Peripheral blood monocyte count may exceed 1 million).
  
  
  
• Hemoglobin electrophoresis: Elevated levels of fetal hemoglobin are associated with poor prognosis and JMML.



• Chromosomal analysis


• • Look for constitutional abnormalities if the patient has stigmata of Down syndrome.
  
  
  
  • Obtain chromosomal fragility studies, including diepoxybutane and mitomycin C for Fanconi anemia.
  
  
  
  • Children with more complex chromosomal aberrations when combined with a low platelet count and/or elevated hemoglobin F had a significantly poorer outcome.
  
  
  
  • The presence of monosomy 7 should prompt investigation of family members.
  
  
  
• Perform viral studies for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) to exclude marrow suppression due to a viral etiology.



• Obtain folate and vitamin B-12 levels to evaluate for possible defects or deficiencies.

Other Tests:

• Perform tissue typing of patient and family in anticipation of hematopoietic stem cell rescue.



• Granulocyte-macrophage colony-stimulating factor (GM-CSF) hypersensitivity

Procedures:

• Bone marrow aspirate and biopsy


• • These are essential in establishing diagnosis and classification.
  
  
  
  • Biopsy may reveal dysplastic cells of various stages of differentiation with hypercellular findings.
  
  
  

Depending on classification, variable granulocytic abnormalities are present. Pseudo–Pelger-Huët anomalies (eg, hyposegmented mature neutrophils, hypogranulation of cytoplasm) are characteristic of dysgranulopoiesis observed with MDS. As more immature elements are observed in periphery, these elements often appear bizarre, with abnormal nucleus-to-cytoplasm ratios and are often oddly shaped. In addition, an increased number of eosinophils and basophils may be present in patients with adult-type MDS. Platelets show marked variability in size within a smear.

Myelodysplasia predominates in hypercellular marrow. In refractory anemia, an abnormal ratio of erythroid to myeloid cells is present and marrow appears similar to the marrow 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 RAEB, the myeloid component of marrow increases. Small myeloblasts and promyelocytes predominate within marrow. These cells are often dysmorphic with abnormal nucleus-to-cytoplasm ratios.

Abnormal megakaryocytes may appear small (ie, micromegakaryocytes) or large, displaying a variable number of nuclei, all within the same marrow sample.

TREATMENT

Section 6 of 10

Medical Care:

• Initially, administer supportive care until the diagnosis is established. Many patients present with profound cytopenias and significant risk for infection. Transfusion support and broad-spectrum antibiotics to treat life-threatening anemia, thrombocytopenia, and infection may be required until more definitive therapy can be initiated.



• Intensive chemotherapy is successful for induction of bone marrow remission, but this is usually short-lived, and patients often relapse within 2 years of initial remission. In addition, some studies suggest that those patients who receive chemotherapy (with its associated toxicities) prior to myeloablative therapy do poorly as compared to patients who are directly placed on transplant regimens. Studies of chemotherapeutic regimens are difficult to interpret because of the small numbers of patients and inclusion of children with MDS in adult studies or those of children with AML.

• Medications used in adult patients with MDS: Based on the IPSS scoring system, adults with low-risk MDS often can be monitored for an extended period without specific therapy, whereas those with intermediate- or high-risk MDS benefit from treatment. Currently, only azacitidine is approved for the treatment of MDS. Several new agents are being tested, including inhibitors of angiogenesis (thalidomide, lenalidomide), farnesyl transferase inhibitors (lonafarnib, tipifarnib), and DNA methyltransferase inhibitors (azacitidine, decitabine). Lenalidomide (Revlimid) appears particularly effective in patients with low-risk MDS with the deletion of chromosome band 5q31 and has been approved for this indication. Allogeneic stem cell transplantation is an alternative for high-risk MDS. With advances in transplantation techniques, this treatment can be offered to an increasing number of patients.

• Because of the rarity of studies addressing MDS as a unique disease entity, the Children's Oncology Group (COG) has initiated a phase II study (AAML0121) that is currently open to accrual. Details of this study are found on the COG Web site. Additionally, an open phase I study is enrolling patients with relapsed/refractory MDS (ADVL0319), the details of which are also found on the COG Web site.



• Hematopoietic stem cell rescue regimens show a 30-50% event-free survival rate at 3 years. Better outcomes are observed in children who receive hematopoietic stem cell rescue soon after diagnosis and who are younger. For those children who do not have an eligible sibling donor, seek alternative donors, although outcome is even less favorable.



• Acute and chronic graft versus host disease (GVHD) have been shown to be associated with a lower incidence of relapse in patients who experience either acute or chronic moderate-to-marked GVHD.



• Growth factors


• • Hesitation with use of these therapies has been based on (1) known increased response of myelodysplastic clone to GM-CSF and (2) reports on association of use of G-CSF in children with severe aplastic anemia and later development of myelodysplastic syndromes or AML.

  • Use of erythropoietin has been shown to be helpful in those patients who have low erythropoietin levels, and G-CSF has also been used, with transient improvement in neutropenia.
  
  
  

Surgical Care:

• Central line access is often needed for chemotherapy and transfusion.



• Splenectomy may prove helpful in patients with marked splenomegaly or hypersplenia. No significant change in the event-free survival rate has been noted in patients undergoing hematopoietic stem cell rescue. The biggest risk is infection, as with any patient who is asplenic.

Consultations:

• Pediatric hematologist/oncologist



• Clinical geneticist


• • A clinical geneticist may also provide an invaluable opinion for many children because of the significant association with other anomalies.
  
  
  
  • In addition, children with monosomy 7 cytogenetics should have family members evaluated for familial monosomy 7.
  
  
  

Diet:

• No dietary restrictions are needed.



• Patients should receive adequate intake of folate and vitamin B-12.



• In patients who are transfusion dependent, limitation of iron intake may be necessary.

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 10

Children are treated with a wide variety of medications. Among the most frequently used chemotherapeutic agents are 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 how drugs affect this growth. After cells divide, they enter a period of growth (phase G1), followed by DNA synthesis (phase S). The next phase is a premitotic phase (G2), then finally a mitotic cell division (phase M).

Cell division rate varies for different tumors. Most common cancers increase very slowly in size compared to normal tissues, and the rate may decrease further in large tumors. This difference allows normal cells to recover more quickly than malignant ones from chemotherapy and is in part the rationale behind current cyclic dosage schedules.

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

Drug Name	Cytarabine (Cytosar-U) -- Antimetabolite antineoplastic agent. Converted intracellularly to active compound, cytarabine-5'-triphosphate, which inhibits DNA polymerase. It is metabolized in the liver with a half-life of 1-3 h. It is widely distributed, including in the CNS and tears after IV administration. It is not orally active.
Adult Dose	100-200 mg/m2/d IV qd for 5-7 d; not to exceed 3 g/m2 IV infusion q12h
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; liver failure
Interactions	Decreases effects of gentamicin and flucytosine; other alkylating agents and radiation increase cytarabine toxicity
Pregnancy	D - Unsafe in pregnancy
Precautions	If significant increase in bone marrow suppression occurs, reduce the number of treatment days; patients with hepatic or renal insufficiencies are at higher risk for CNS toxicity after a high dose of cytarabine (reduce dose)

Drug Name	Fludarabine (Fludara) -- 2-Fluoro, 5-phosphate derivative of vidarabine. Converted to 2-fluoro-ara-A that enters the cell and is phosphorylated to form active metabolite 2-fluoro-ara-ATP, which inhibits DNA synthesis. Half-life of active metabolite is 9 h.
Adult Dose	25-30 mg/m2 qd for 5 d repeated q28d
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Pentostatin increases risk of pulmonary toxicity; cytarabine administered with or prior to fludarabine decreases conversion to active drug
Pregnancy	D - Unsafe in pregnancy
Precautions	Perform frequent peripheral blood cell counts to detect development of anemia, thrombocytopenia, and neutropenia; monitor for tumor lysis syndrome; adjust dose for renal impairment, severe bone marrow suppression, severe neurologic effects, or life-threatening and fatal autoimmune hemolytic anemia

Drug Name	Idarubicin (Idamycin) -- Anthracycline antineoplastic agent. Inhibits cell proliferation by inhibiting DNA and RNA polymerase. It is metabolized in the liver to active idarubicinol. Half-life is 14-35 h (PO) or 12-27 h (IV). It is a vesicant.
Adult Dose	12 mg/m2 IV qd for 3 d 30-45 mg/m2 PO q3wk (breast cancer) 20-25 mg/m2 qd for 3 d (AML)
Pediatric Dose	12 mg/m2 IV qd for 3 d
Contraindications	Documented hypersensitivity; severe CHF; cardiomyopathy; arrhythmias; previous treatment with maximal cumulative doses of other anthracyclines
Interactions	Trastuzumab increases risk of cardiotoxicity
Pregnancy	D - Unsafe in pregnancy
Precautions	Extravasation can result in severe tissue necrosis; caution in preexisting cardiac disease, impaired hepatic or renal function, or myelosuppression; cardiac toxicity is the most serious complication of idarubicin therapy

Drug Name	Daunorubicin (Cerubidine) -- Anthracycline antineoplastic agent. Inhibits DNA and RNA synthesis by intercalating between DNA base pairs. Half-life is 14-20 h (23-40 h for active metabolite).
Adult Dose	25-100 mg/m2 IV qd for 3-5 d via intermittent or continuous infusion
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; severe CHF; cardiomyopathy; arrhythmias; previous treatment with maximal cumulative doses of other anthracyclines
Interactions	Trastuzumab increases risk of cardiotoxicity
Pregnancy	D - Unsafe in pregnancy
Precautions	Extravasation may occur, resulting in severe tissue necrosis; caution in patients with impaired hepatic, renal, or biliary function; monitor for myelosuppression and, if necessary, decrease dose; may cause urine discoloration (ie, red)

Drug Name	Dexamethasone (Decadron) -- Long-acting fluorinated corticosteroid. It induces apoptosis of leukemia cells via glucocorticoid receptors. A dose of 0.75 mg is equivalent to 4 mg methylprednisolone, 5 mg prednisolone, 30 mg hydrocortisone, or 25 mg cortisone.
Adult Dose	0.75-9 mg/d PO q2-4d 0.5-9 mg/d IV qd or divided q6h
Pediatric Dose	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
Contraindications	Documented hypersensitivity; active bacterial or fungal infection
Interactions	Phenobarbital, phenytoin, ephedrine, and rifampin may enhance clearance of corticosteroids; coadministration with potassium-depleting diuretics increases the risk of hypokalemia; may alter the response to Coumadin anticoagulants (usually inhibitory but unsubstantiated reports of potentiation exist); dexamethasone decreases effect of salicylates and vaccines used for immunization
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Increases risk of multiple complications, including severe infections; monitor adrenal insufficiency when tapering drug; abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections are possible complications of glucocorticoid use

Drug Name	Thioguanine -- Purine analogue with antineoplastic and antimetabolite properties.
Adult Dose	40-100 mg/m2 PO qd
Pediatric Dose	2 mg/kg PO qd
Contraindications	Documented hypersensitivity; prior resistance to antitumor effects
Interactions	Increases busulfan toxicity
Pregnancy	D - Unsafe in pregnancy
Precautions	Adjust dose to compensate for myelosuppression, renal disease, or hepatic disease; may cause neurotoxicity, hyperuricemia, or myelosuppression

Drug Name	Etoposide (VePesid, VP-16) -- Semisynthetic podophyllotoxin with poor penetration to CSF. Inhibits topoisomerase II and causes DNA strand breakage, which causes cell proliferation to arrest in late S or early G2 portion of the cell cycle. Half-life is 4-11 h.
Adult Dose	Low dose: 20-100 mg/m2/d IV for 5 d High dose: up to 3 g/m2 IV qd
Pediatric Dose	Low dose: 20-100 mg/m2/d IV for 5 d High dose: up to 3 g/m2 IV qd
Contraindications	Documented hypersensitivity; intrathecal administration (may cause death)
Interactions	May prolong the effects of warfarin and increase the clearance of methotrexate; cyclosporine and etoposide have additive effects in the cytotoxicity of tumor cells
Pregnancy	D - Unsafe in pregnancy
Precautions	Bleeding and severe myelosuppression may occur; monitor for hypotension during administration

Drug Name	Pegaspargase (Oncaspar) -- Polyethylene glycol-L-asparaginase. Catabolizes asparagine, an essential amino acid for lymphoblast growth. Half-life is 2-3 wk.
Adult Dose	2500 IU/m2 IM q14d
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; pancreatitis; prior thrombosis associated with pegasparaginase
Interactions	Increase toxicity with vincristine; may displace highly protein-bound drugs (eg, warfarin); increased bleeding with warfarin, heparin, aspirin, NSAIDs, or dipyridamole
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in hypofibrinogenemia, confusion, diabetes mellitus, or hepatic impairment

FOLLOW-UP

Section 8 of 10

Further Inpatient Care:

• Hospitalization is required for some chemotherapeutic agents.



• Inpatient treatment is required if the patient is undergoing bone marrow transplantation.



• Children with MDS should be treated as are other neutropenic patients. They require hospitalization, observation, and IV antibiotics for fevers.



• 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 AML.



• Patients often require frequent transfusions and must have their blood cell counts monitored on a minimum basis of 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 RAEBT also have poor overall neutrophil function, despite adequate absolute neutrophil counts (ANC) greater than 1000.

  • Ultimately, infection, rather than progression to AML, results in the demise of most patients with MDS.
  
  
  
• Bleeding



• Patients often have thrombocytopenia and resultant hemorrhage.

• Patients require frequent transfusions as more marrow becomes involved.



• Anemia and iron overload


• • The inability of marrow to keep up with normal turnover of red blood cells results in a frequent need for transfusion. This may result in iron overload requiring chelation therapy.

  • In rare circumstances, patients respond to splenectomy.

  • Iron overload is observed more often in adults with MDS from transfusions over a more prolonged course.
  
  
  

Prognosis:

• Outcomes for children with MDS are poor. Continued multicenter trials, with further elucidation of the meaning of biological markers to better classify MDS in childhood, are needed.



• Currently, the best treatment option available is hematopoietic stem cell rescue, offering at best a 40% event-free survival rate at 5 years.

• Until recently, most of the prognostic factors in MDS have been developed from data collected from adult patients, eg, International Prognostic Scoring System (IPSS), the Bournemouth Score, and others.
  • The factors shown to have prognostic significance for survival and progression to AML in adult patients have included bone marrow morphology, BM myeloblast percentage, BM biopsy appearance, number of cytopenias, BM cytogenetic abnormalities, age, and blood lactate dehydrogenase level. In contrast, the only factor that has consistently been shown to have prognostic significance in pediatric cases of MDS is cytogenetic abnormalities, notably monosomy 7.

  • Studies from Japan, the UK, and the European Working group on MDS in childhood (EWOG-MDS) have all concluded that the IPSS scoring system is of limited value in children. The Japanese and UK studies found only the IPSS karyotype group to be of significant prognostic value for overall survival.



• In the United States, there has been only one large prospective study (CCG 2891) that reported on the effects of AML-based therapy in children with MDS. Of the total 1096 patients enrolled on this study, there were 90 patients with MDS classified according to the FAB classification. Overall survival at 6 years was 29% ± 12% (95% confidence intervals) for patients with MDS and 31% ± 26% for those with JMML treated on CCG 2891. These outcomes were worse than those with antecedent MDS and treated in the AML phase (50% ± 25%) or those with de novo AML (45% ± 3%). Nonsignificant differences in survival at 6 years from the beginning of the study were seen between patients with JMML and MDS.



• In recent reports, 5-year event-free survival rates in patients with Down syndrome with MDS/AML have been in excess of 80%, largely because of reductions in treatment-related deaths with a fall from 30-40% in the early 1990s to around 10% in recent BFM, NOPHO, and Medical Research Council studies.

Patient Education:

• Families must be educated about signs and symptoms of infection, anemia, and thrombocytopenia.



• In addition, many patients require placement of a central venous catheter and families need to learn care of line.

TEST QUESTIONS

Section 9 of 10

CME Question 1: A 7-year-old child presents with a 1-year history of fatigue and pallor. The CBC count shows hemoglobin of 6 g/dL. Which of the following laboratory results is most concerning for primary bone marrow dysplasia?

A: Mean corpuscular hemoglobin (MCH) 22 pg
B: Mean cellular volume (MCV) 105 fL
C: Red blood cell distribution width (RDW) 19%
D: Reticulocytes 1%
E: Hypersegmented neutrophils

The correct answer is B: Although macrocytosis can indicate megaloblastic anemia (vitamin B-12 or folate deficiency), it is often observed in most bone marrow failure syndromes, including myelodysplastic syndrome (MDS).

CME Question 2: Myelodysplastic syndrome (MDS) is diagnosed in a 5-year-old child. Of the following underlying causes, which is associated with the best prognosis?

A: Idiopathic (no underlying cause)
B: Neurofibromatosis
C: Secondary to previous chemotherapy
D: Down syndrome
E: Fanconi anemia

The correct answer is D: Patients with Down syndrome and MDS respond best to treatment, whereas those with MDS due to previous therapy with alkylating agents fare the worst.

Pearl Question 1 (T/F): Monosomy 7 is the most common cytogenetic finding in the bone marrow of children with myelodysplastic syndrome (MDS).

The correct answer is True: Monosomy 7 is the most common cytogenetic finding. Cytogenetic abnormalities, most specifically monosomy 7 and NF-1 gene mutations, provide support for the theory of cell dysregulation occurring in a multi-hit fashion. In the case of monosomy 7, a genetic predisposition and a later loss of a critical region on chromosome 7 that codes for a suspected tumor suppressor gene is suggested to set the stage for proliferation of an abnormal clone. Loss of chromosome may occur during an embryonic period within hematopoietic stem cells or it may occur as result of cytotoxic therapy.

Pearl Question 2 (T/F): Patients with neurofibromatosis type 1 (NF-1) have a higher incidence of myelodysplastic syndrome (MDS). This suggests that farnesyltransferase inhibitors might be efficacious in its treatment.

The correct answer is True: In patients with NF-1, loss of NF-1 gene product occurs, which results in loss of negative feedback via guanosine triphosphatase (GTPase) of oncogene N-ras. Without negative feedback, cell proliferation becomes disrupted. Therefore, Ras is constitutively active in NF-1. Farnesyltransferase inhibitors deactivate ras signaling; consequently, farnesyltransferase inhibitors might provide successful therapy.

Pearl Question 3 (T/F): Myelosuppression is the most serious complication of idarubicin therapy for myelodysplastic syndrome (MDS).

The correct answer is False: Cardiac toxicity is the most serious complication of idarubicin therapy. Idarubicin is an anthracycline.

Pearl Question 4 (T/F): Intensive chemotherapy is the best therapy for myelodysplastic syndrome (MDS).

The correct answer is False: Myeloablative therapy with hematopoietic stem cell rescue from a human leukocyte antigen (HLA)–matched sibling is the best therapy for MDS. Intensive chemotherapy is successful for induction of bone marrow remission, but this is usually short-lived, and patients often relapse within 2 years of initial remission. In addition, some studies suggest that those patients who receive chemotherapy (with its associated toxicities) prior to myeloablative therapy do poorly as compared to patients who are directly placed on transplant regimens.

BIBLIOGRAPHY

Section 10 of 10

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