Info

Isolated del (5q)

Note:± denotes that Auer rods may or may not be present.

From Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 2002;100:2292-302, with permission.

Note:± denotes that Auer rods may or may not be present.

From Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 2002;100:2292-302, with permission.

1. The concept of monosomy 7 as a distinct syndrome has been abandoned.

2. Myeloid leukemia in children with Down syndrome (DS) is distinct from the disease in non-DS children. MDS often precedes acute myeloid leukemia (AML) in DS. In some children with DS, AML is preceded by a transient myelo-proliferative disorder. MDS and AML in DS are highly chemosensitive and have an excellent prognosis when treated on a modified AML protocol.

3. Nonclonal disorders with dysplastic morphology should not be considered to be MDS.

Epidemiology

Incidence: 1.8 per million children per year in age group 0-14 years.

Constitutes 4% of all hematologic malignancies.

Table 13-13. Diagnostic Categories of Myelodysplastic and Myeloproliferative Diseases in Children

I. Myelodysplastic/myeloproliferative disease

• Juvenile myelomonocytic leukemia (JMML)

• Chronic myelomonocytic leukemia (CMML) (secondary only)

• BCR/ABL negative chronic myeloid leukemia (Ph- CML) II. Down syndrome (DS) disease

• Transient abnormal myelopoiesis (TAM)

• Myeloid leukemia of DS

III. Myelodysplastic syndrome (MDS)

• Refractory cytopenia (RC) (peripheral blood blasts less than 2% and bone marrow blasts less than 5%)

• Refractory anemia with excess blasts (RAEB) (peripheral blood blasts 2-19% and bone marrow blasts 5-19%)

• RAEB in transformation (RAEB-T) (peripheral blood or bone marrow blasts 20-29%)

Abbreviation: RAEB, refractory anemia with excess blasts.

From Hasle H, et al. A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases. Leukemia 2003;17:277-82, with permission.

Constitutional abnormalities are present in 30% of children with MDS. The most common is Down syndrome.

Table 13-14 lists constitutional abnormalities associated with juvenile myelomono-cytic leukemia (JMML) and MDS in children. Familial MDS is observed in 10% of children with MDS, associated with 7- or 7q-chromosome abnormalities.

Therapy-related MDS:

Alkylating agent-induced MDS is characterized by deletions or the loss of a whole chromosome. Latency period: 3-5 years. Epipodophyllotoxin-induced MDS is characterized by translocations involving chromosome band 11q23. Latency period: 1-3 years. Incidence of therapy-related MDS; represents 5% of all childhood MDS and occurs in 13% of children treated for malignancies.

Table 13-14. Constitutional Abnormalities Associated with JMML and MDS in Children

A. Associated with JMML Constitutional conditions

Neurofibromatosis type 1 (NF-1) Noonan syndrome Trisomy 8 mosaicism

B. Associated with MDS Constitutional conditions

Congenital bone marrow failure Fanconi anemia Kostmann syndrome Shwachman-Diamond syndrome Diamond-Blackfan syndrome Trisomy 8 mosaicism

Familial MDS (at least one first-degree relative with MDS/AML) Acquired conditions Prior chemotherapy/radiation Aplastic anemia

From Hasle H, et al. A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases. Leukemia 2003;17:277-82, with permission.

Children with therapy-induced MDS or therapy-induced AML (t-MDS/t-AML) compared to children with de novo AML or MDS, have the following characteristics:

1. Older at presentation, have lower white blood cell (WBC) counts, and are less likely to have hepatomegaly or splenomegaly or hepatosplenomegaly

2. More likely to have trisomy 8 and less likely to have classic AML translocations

3. Less likely to attain remission after induction therapy (50% versus 72%) and less likely to have a longer overall survival (26% versus 47%) and event-free survival (21% vs 39%).

However, their disease-free survival after attaining remission is similar to that of children with de novo AML or MDS (45% versus 53%).

Pathophysiology

MDS is a clonal disease arising either in a pluripotent or multipotent hematopoietic stem cell. It is a heterogeneous disease with different pathophysiologic mechanisms playing roles in its initiation and progression. It has been postulated that initially apoptosis dominates the process and with time, as more genetic abnormalities accumulate in the MDS cells, arrest of maturation and proliferation occurs, resulting in transformation to AML. There is not much information regarding the pathophysio-logic mechanisms of MDS in childhood.

Clinical Features

Clinical features are related to cytopenias (e.g., pallor, bruises, petechiae, infections). Usually, there is no lymphadenopathy or hepatosplenomegaly. Children with refractory anemia may not present with low hemoglobin levels, but they have macrocyto-sis and elevated fetal hemoglobin levels. The presence of hepatosplenomegaly and a WBC greater than 20,000/mm3 is strongly suggestive of AML.

Cytogenetics

Monosomy 7 is the most common cytogenetic abnormality in childhood MDS. Trisomy 8 and 21 are the second most common abnormalities. Monosomy 7 has no prognostic significance in childhood MDS.

If AML-specific chromosomal abnormalities are present, then these patients are considered to have AML and are treated for AML.

Differential Diagnosis

1. Clinical course and the response to therapy for M6 (erythroleukemia), M7 (acute megakaryoblastic leukemia), and AML with monosomy 7 are more similar to MDS than the other types of AML. For this reason, it is important for these conditions to be diagnosed accurately. AML with monosomy 7 has a poor prognosis, whereas it is not an unfavorable prognostic factor in MDS.

2. In a borderline case with 30% blasts, bone marrow examination should be performed after 2 weeks and 400 cells should be counted. If greater than 30% blasts are present in the second bone marrow sample, then a diagnosis of AML is made.

3. It is difficult to distinguish hypoplastic MDS (refractory anemia [RA]) from aplastic anemia in the absence of laboratory abnormalities. The majority of children, who develop MDS following a diagnosis of aplastic anemia, present with MDS within the first 3 years from the diagnosis of aplastic anemia. Patients with mild to moderate aplastic anemia may be more likely to develop a clonal disease than a patient with severe aplastic anemia. Repeated evaluation for both conditions including bone marrow examinations may become necessary to reach a diagnosis.

4. In a case of RA with ringed sideroblasts (RARS) a search for mitochondrial disease is warranted because this subtype of MDS is rare in children.

Prognosis

The International Prognostic Scoring System (IPSS) for MDS is given in Table 13-15 but its applicability to MDS in children remains to be determined. The FPC (hemoglobin F, platelet counts, cytogenetics)-based scoring system for prognostic classification of childhood MDS is listed in Table 13-16.

Table 13-17 shows the IPSS for childhood MDS and JMML. Also, in an analysis reported by the European Working Group on MDS in childhood, preliminary data on childhood MDS revealed poor prognosis in patients with two to three lineage cytopenia and a blast count greater than 5% in bone marrow (see Table 13-17).

Table 13-15. International Prognostic Scoring System for MDS: Survival and AML Evolution

Prognostic variable

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