INVITED REVIEW ARTICLE

Pediatric Myelodysplastic Syndromes: They Do Exist! Taly Glaubach, MD,*w Lisa J. Robinson, MD,z and Seth J. Corey, MD, MPH*wy

Summary: One of the most common hematologic malignancies in adults, myelodysplastic syndrome (MDS) is a heterogenous group of clonal disorders characterized by peripheral cytopenia(s) and normal or hypercellular bone marrow with dysplasia in Z1 blood cell lineages. MDS frequently evolves to secondary acute myeloid leukemia with poor prognosis. Although uncommon among pediatric hematologic malignancies, both de novo and secondary MDS occur in children and may be the first presentation of an inherited bone marrow failure syndrome. Unlike its adult counterpart, pediatric MDS is more frequently associated with hypocellular bone marrow and monosomy 7. Refractory cytopenia is more typical than refractory anemia, as seen in the elderly. Its recognition and management can be quite challenging and requires the expertise of an experienced hematopathologist. In this review, we describe the epidemiology, genetics, and clinical spectrum of pediatric MDS along with its diagnostic and therapeutic challenges. We also compare and contrast pediatric and adult MDS. Key Words: myelodysplastic syndromes, bone marrow failure syndromes, aplastic anemia, myeloid leukemia

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yelodysplastic syndromes (MDS) are a heterogenous group of clonal disorders characterized by peripheral cytopenia(s) and normal or hypercellular bone marrow with dysplasia in Z1 blood cell lineages. Some are well-recognized distinct entities, for example, refractory anemia with ring sideroblasts, del (5q), and therapy related. MDS frequently evolves to secondary acute myeloid leukemia (AML) with poor prognosis. Its pathobiology is still not well understood, which has hampered the advancement of diagnostic and therapeutic strategies. Recent drug approvals for MDS include lenalidomide for del (5q) syndrome and the hypomethylating agents azacitidine and decitabine. Although MDS is one of the most common hematopoietic malignancies in older adults with a median age of 70 years at diagnosis, it is less frequently diagnosed in pediatrics (for a comparison of features see Table 1). In children and adolescents, MDS occurs in both de novo and secondary forms, but often presents a unique diagnostic challenge for the clinician. Secondary MDS follows either after genotoxic Received for publication August 13, 2013; accepted September 10, 2013. From the *Department of Pediatrics, Northwestern University Feinberg School of Medicine, Ann & Robert H. Lurie Children’s Hospital of Chicago; wRobert H. Lurie Comprehensive Cancer Center, Chicago, IL; zDepartment of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA; and yDepartment of Cell & Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, IL. T.G. is supported by the ASH Research Training Award and the MDS Foundation Young Investigator Grant. The remaining authors declare no conflict of interest. Reprints: Seth J. Corey, MD, MPH, Lurie 5-107, Robert H. Lurie Comprehensive Cancer Center, 303 E. Superior Street, Chicago, IL 60611 (e-mail: [email protected]). Copyright r 2013 by Lippincott Williams & Wilkins

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therapy or inherited bone marrow failure syndromes (IBMFS). Juvenile myelomonocytic leukemia (JMML) represents a special form of myelodysplastic and myeloproliferative disorder. Pediatric MDS may be underdiagnosed due to lack of validated, pediatric-specific diagnostic criteria or understanding of the natural history of refractory cytopenias. As little is known about the natural history of MDS in pediatrics, the decision when to transplant may be difficult.

EPIDEMIOLOGY Although the true incidence of pediatric MDS has been difficult to ascertain, best estimates come from large population-based studies in Europe and Canada. The estimated incidence is approximately 1.8 to 4 cases per million per year, with the lower end of the range estimated from exclusion of patients with Down syndrome.1,2 Data published from the United Kingdom suggest a lower annual incidence of 0.8 cases per million, but included only primary MDS.3 In contrast, the incidence of AML and ALL is approximately 6 and 42 cases per million, respectively. The median age at presentation of pediatric MDS is 6.8 years and seems to be equally distributed among males and females.1–7 In the only large published series of advanced or high-risk pediatric MDS, the median age was higher at 10.7 years with a 2:1 male predominance.8 Secondary pediatric MDS is strongly associated with IBMFS, such as Fanconi anemia, Shwachman-Diamond syndrome, severe congenital neutropenia, dyskeratosis congenita, and MonoMAC syndrome.1,9–20 Other genetic conditions associated with MDS include paroxysmal nocturnal hemoglobinuria (PNH), monosomy 7 syndrome, Down syndrome, neurofibromatosis, Bloom syndrome, and Li-Fraumeni syndrome.1,9–20 Some will display MDS as the first presenting sign of that disorder. As our recognition and genetic-based diagnosis of these rare genetic disorders advance, it is likely that this number will increase and the corresponding incidence of purported de novo pediatric MDS will decrease, respectively. In addition, acquired severe aplastic anemia (SAA) infrequently evolves into secondary MDS. However, resolving the distinction between SAA and MDS significantly reduces the number of secondary MDS and AML after immunosuppressive therapy (IST) for SAA.21,22

CLINICAL PRESENTATION About 20% of pediatric MDS is found incidentally on routine laboratory evaluation7 or during evaluation for a suspected bone marrow failure syndrome. More commonly, it presents with symptoms related to the cytopenias(s), such as fatigue, fever, infection, and bleeding.7 In contrast to adults, pediatric MDS often presents with bilineage cytopenias and very rarely with isolated anemia (ie, neutropenia and/or thrombocytopenia, with/without macrocytic anemia).7,23 Isolated 5q  or del (5q) syndrome common in

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TABLE 1. Comparison of Common Features of Adult and Pediatric MDS

Adult MDS

Pediatric MDS

3-5/105 > 20/105 in those >70 y 70 Isolated, transfusion-dependent anemia, with/ without neutropenia and/or thrombocytopenia

Incidence Median age (y) Presentation Etiology Morphologic subtype BM cellularity

Primary (de novo) most common RARS and 5q  most common Hypercellular or normocellular; hypocellular is rare 5/5q > 7/7q , 3q, 20q anomalies Mutations in DNMT3a, ASXL1, TET2, SF3B1, U2AF35; methylation changes

Cytogenetics Genetics Physical findings

None

Therapeutic options

RBC and platelet transfusions Lenalidomide for del (5q) Azacitidine, decitabine HSCT for those with low risk for morbidity and mortality

1.8-4/106 7 Bilineage cytopenias most common; refractory thrombocytopenia >neutropenia and/or anemia Secondary or therapy related most common RCC most common; RARS or 5q  rare Variable; hypocellular is most common Monosomy 7/7q  > trisomy 8 FANC members, SBDS, DKC, TERT, TERC, ELANE, HAX1, WAS, GATA-2 (related to IBMFS) Skeletal, cutaneous, genitourinary, cardiovascular, and gastrointestinal anomalies (related to IBMFS) Monitoring RBC and platelet transfusions HSCT ?Lenalidomide ?Hypomethylating agents ?IST

HSCT indicates hematopoietic stem cell transplant; IBMFS, inherited bone marrow failure syndromes; IST, immunosuppressive therapy; MDS, myelodysplastic syndrome; RARS, refractory anemia with ring sideroblasts; RBC, red blood cells; RCC, refractory cytopenia of childhood; ?, unknown efficacy.

adults, is almost never seen in children.24,25 These findings are collectively reflected in the current World Health Organization (WHO) nomenclature of “refractory cytopenia of childhood” (RCC), as opposed to “refractory anemia.” RCC is the most common subtype of pediatric MDS, accounting for approximately 50% of cases, with the remainder being indistinguishable from “adult-type” refractory anemia with excess blast (RAEB) or RAEBT.3,26,27

GENETICS Clonal analyses of karyotype and gene mutations revealed that pediatric MDS differs from adult MDS. Karyotype abnormalities are common, occurring in 30% to 50% of pediatric MDS,28 with the majority consisting of copy number variations in all or part of the chromosome. In contrast to abnormalities involving chromosome 5 in adult MDS, monosomy 7 is the most common cytogenetic abnormality in pediatric MDS and occurs in about 30% of patients.28 Other less common but recurrent cytogenetic abnormalities are trisomies 8 and 21 (which may be constitutional, mosaic, or somatically acquired), and the loss of part of chromosome 20 (eg, 20q). Complex karyotypes tend to signify a high-risk population.28 Development and refinement of single-nucleotide polymorphism arrays have allowed the identification of additional microdeletions below the resolution of standard cytogenetic assays, and can reveal previously undetectable regions of copy number—neutral loss of heterozygosity, or uniparental disomy. Understanding noncoding regions of DNA, identification of noncoding RNA, and description of global methylation and histone modification changes (epigenetics) are adding to the complexity of an emerging story for MDS in adults. Recurrent mutations affecting genes that regulate

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DNA methylation (DNMT3A, IDH1/IDH2, and TET2), histone function (EZH2 and ASXL1), and splicing machinery (U2AF35, ZRSR2, SRSF2, and SF3B1) have been identified in adult patients with MDS.29–31 Interestingly, these mutations are rare in pediatric de novo or secondary MDS. Several studies have found splicing factor mutations in only 1 of 187 pediatric MDS patients who had RAEBT,32 and in none of 28 patients with MDS,33 after excluding JMML which accounted for an additional 3 of 142 total JMML patients (combined data). However, even in the identified cases, the SRSF2 mutation did not seem to serve as a driver.33 It was always accompanied by other known oncogenic driver mutations (PTPN11 or NRAS), disappeared during disease progression, and was not present at the time of multiple relapses. To date, mutations in genes that regulate DNA methylation and histone function have not yet been established in pediatric MDS. Exactly how these genetic and epigenetic changes lead to disease have yet to be elucidated, but is an area of active research.

Rare Yet Novel MDS Genes and Associated Syndromes (RUNX1, CEBPA, and GATA2) Although very rare, familial forms of nonsyndromic MDS and AML have been described and 2 genes identified: RUNX1/AML1 in familial platelet disorder with a predisposition to acute myelogenous leukemia and CEBPA in familial AML.34,35 Recently, germline missense mutations in GATA2 were identified in 4 distinct families with multigenerational early-onset MDS/AML in an autosomal dominant manner.36 These mutations result in a dominantnegative loss of function through disruption of protein interactions necessary for DNA binding and activation of target genes. In these patients, the MDS subtype and clinical course were variable. r

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In addition, recurrent germline mutations in GATA2 have also been described in syndromic forms of familial and sporadic MDS. The MonoMAC syndrome is an immunodeficiency syndrome characterized by marked monocytopenia, and B-cell and NK-cell lymphopenia, with resultant susceptibility to mycobacterial infections, human papillomavirus, and other opportunistic viral and fungal infections. The constellation of features also includes a predisposition to MDS/AML, and/or pulmonary alveolar proteinosis.14,37,38 In Emberger syndrome, GATA2 mutations are associated with lymphedema and MDS/AML.39 As more patients are sequenced for GATA2 mutations, we will learn more about the range of GATA2 mutations and their associated MDS phenotypes.

DIAGNOSTIC CHALLENGE Consideration of pediatric MDS should occur when thrombocytopenia, neutropenia, and/or anemia has persisted for 3 months in an otherwise healthy child or adolescent. Closer inspection might reveal the physical anomalies associated with Fanconi anemia, ShwachmanDiamond syndrome, or dyskeratosis congenita. The presence of warts might suggest Mono-Mac syndrome. Subtle clues also include the presence of macrocytic anemia with normal vitamin B12 and folate levels. Dysplastic granules or abnormal nuclear segmentation in circulating neutrophils would also raise suspicion. Diagnosis depends greatly on bone marrow aspirate and biopsy. MDS is largely a diagnosis of morphology and thus subject to interpretation, interobserver variability in diagnosis, and sampling error if significant hypocellularity exists. Morphologic evaluations of peripheral blood and of bone marrow are important components in the evaluation of pediatric myelodysplasia. The overall spectrum of morphologic change found in pediatric MDS is similar to that of adult MDS, but the frequency and clinical significance of specific abnormalities can differ. Blast cell numbers are a critical morphologic parameter for identifying and classifying MDS. For both adults and children, a blast percentage of at least 5% (but 6

1

1.5

2-5 Good 8-10 50-99 < 800

< 50

Good

Intermediate

2

3

5-10

> 10

Intermediate

4

Poor Very poor

3 double including -7/ abnormalities del(7q), complex: 3 abnormalities

Risk Category Very low Low Intermediate High Very high

This table is meant purely as a point of reference for the discussions in the text of this manuscript. We caution its use in pediatric therapeutic or management strategies. From Greenberg et al.55 Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.

However, more studies are needed to better characterize these patterns in pediatric MDS to assess the clinical utility of these agents as a therapeutic strategy. Furthermore, the likelihood of these agents providing lifelong durability of response will need to be weighed against the curative intent of HSCT.

CONCLUSIONS The incidence of pediatric MDS is underestimated and diagnosis requires index of suspicion and an experienced hematopathologist. All pediatric patients with suspected MDS or aplastic anemia should have a bone marrow evaluation with routine cytogenetics, in addition to FISH for common MDS-associated cytogenetic anomalies as these 2 modalities are complimentary. In addition, these patients should have a workup to rule out occult PNH or IBMFS (Fanconi anemia, Shwachman-Diamond syndrome, dyskeratosis congenita, etc.) that may have MDS or aplastic anemia as its first presentation. The high rates of MDS/AML in associated congenital syndromes, including pediatric IBMFS, may provide meaningful insights into MDS pathogenesis and mechanisms of disease. However, for primary pediatric MDS, because of their infrequency, the lack of consensus on their classification, and the incomplete understanding of their biology and natural history, therapeutic advances have been stymied. We call upon the Children’s Oncology Group, the European Working Group on MDS, and the Japan Aplastic Anemia Study Group to convene and form an international pediatric consortium to study the biology and therapy of primary MDS. REFERENCES 1. Hasle H, Kerndrup G, Jacobsen BB. Childhood myelodysplastic syndrome in Denmark: incidence and predisposing conditions. Leukemia. 1995;9:1569–1572. r

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