Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies

Summary Type: Treatment
Summary Audience: Health professionals
Summary Language: English
Summary Description: Expert-reviewed information summary about the treatment of childhood acute myeloid leukemia, myelodysplastic syndromes, and other myeloproliferative disorders.

Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies

General Information

This cancer treatment information summary provides an overview of the prognosis, diagnosis, classification, and treatment of childhood acute myeloid (myelogenous) leukemia (AML) and other childhood myeloid malignancies.

The National Cancer Institute provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public. These summaries are updated regularly according to the latest published research findings by an Editorial Board of pediatric oncology specialists.

Cancer in children and adolescents is rare. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others in order to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ Supportive Care summaries for specific information about supportive care for children and adolescents with cancer.)

Guidelines for pediatric cancer centers and their role in the treatment of children with cancer have been outlined by the American Academy of Pediatrics.1 At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site. The designations in PDQ that treatments are “standard” or “under clinical evaluation” are not to be used as a basis for reimbursement determinations.

In recent decades, dramatic improvements in survival have been achieved for children and adolescents with cancer. Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Myeloid leukemias in children

The myeloid leukemias in childhood represent a spectrum of hematopoietic malignancies. Over 90% of myeloid leukemias are acute and the remainder include chronic and/or subacute myeloproliferative disorders such as chronic myelogenous leukemia (CML) and juvenile myelomonocytic leukemia (JMML). Myelodysplastic syndromes (MDS) are rare in children.

AML is defined as a clonal disorder caused by malignant transformation of a bone marrow-derived, self-renewing stem cell or progenitor, which demonstrates a decreased rate of self-destruction and also aberrant differentiation. These events lead to increased accumulation in the bone marrow and other organs by these malignant myeloid cells. To be called acute, the bone marrow usually must include greater than 20% leukemic blasts, with some exceptions as noted in subsequent sections.

CML represents the most common of the chronic myeloproliferative disorders in childhood but still only comprises about 5% of childhood myeloid leukemia. Although CML has been diagnosed in very young children, most patients are 6 years or older. CML is a clonal panmyelopathy that involves all hematopoietic cell lineages. While the white blood cell count can be extremely elevated, the bone marrow does not show increased numbers of leukemic blasts during the chronic phase of this disease. CML is nearly always characterized by the presence of the Philadelphia chromosome, a translocation between chromosomes 9 and 22, i.e., t(9;22). Other chronic myeloproliferative syndromes such as polycythemia vera and essential thrombocytosis are extremely rare in children.

JMML is caused by malignant transformation of a primitive hematopoietic stem cell or progenitor and represents the most common myeloproliferative syndrome observed in young children. JMML is characterized clinically by occurring primarily in children aged 2 years or younger who commonly present with hepatosplenomegaly, lymphadenopathy, fever, and skin rash along with an elevated white blood cell count and increased circulating monocytes. In addition, patients often have an elevated hemoglobin F, hypersensitivity of the leukemic cells to granulocyte colony-stimulating factor, and monosomy 7.

The transient myeloproliferative disorder (TMD) (also termed transient leukemia) observed in infants with Down syndrome represents a clonal expansion of myeloblasts that can be difficult to distinguish from AML. Most importantly, TMD spontaneously regresses in most cases within the first 3 months of life. TMD blasts are most commonly megakaryoblastic and have distinctive mutations involving the GATA1 gene.2,3 TMD may occur in phenotypically normal infants with genetic mosaicism in the bone marrow for trisomy 21. While TMD is generally not characterized by cytogenetic abnormalities other than trisomy 21, the presence of additional cytogenetic findings may connote an increased risk for developing subsequent AML.4 Approximately 20% of infants with Down syndrome and TMD eventually develop AML, with most cases diagnosed within the first 3 years of life.3,4 Early death from TMD-related complications occurs in 10% to 20% of affected children.4,5 Infants with progressive organomegaly, visceral effusions, and laboratory evidence of progressive liver dysfunction are at a particularly high risk for early mortality.4,

The myelodysplastic syndromes in children represent a heterogeneous group of disorders characterized by ineffective hematopoiesis, impaired maturation of myeloid progenitors, cytopenias, and dysplastic morphologic changes. Although the majority of patients have normocellular or hypercellular bone marrows without increased numbers of leukemic blasts, some patients may present with a very hypocellular bone marrow, making the distinction between severe aplastic anemia difficult.

There are genetic risks associated with the development of AML. There is a high concordance rate of AML in identical twins, which is believed to be in large part a result of shared circulation and the inability of one twin to reject leukemic cells from the other twin.6,7,8 There is an estimated 2-fold to 4-fold risk of fraternal twins both developing leukemia up to about the age of 6 years, after which the risk is not significantly greater than that of the general population.9,10 The development of AML has also been associated with a variety of predisposition syndromes that result from chromosomal imbalances or instabilities, defects in DNA repair, altered cytokine receptor or signal transduction pathway activation, as well as altered protein synthesis. (Refer to the following list of inherited and acquired genetic syndromes associated with myeloid malignancies.)

    Inherited and Acquired Genetic Syndromes Associated with Myeloid Malignancies
  • Inherited syndromes
    • Chromosomal imbalances:
      • Down syndrome
      • Familial monosomy 7 syndrome
    • Chromosomal instability syndromes:
      • Fanconi anemia
      • Dyskeratosis congenita
      • Bloom syndrome
    • Syndromes of growth and cell survival signaling pathway defects:
      • Neurofibromatosis type 1 (particularly JMML development)
      • Noonans syndrome (particularly JMML development)
      • Severe congenital neutropenia (Kostmann syndrome)
      • Diamond-Blackfan anemia
      • Familial platelet disorder with a propensity to develop AML (FPD/AML)
      • Congenital amegakaryocytic thrombocytopenia (CAMT)
  • Acquired syndromes
    • Severe aplastic anemia
    • Paroxysmal nocturnal hemoglobinuria
    • Amegakaryocytic thrombocytopenia (AAMT)
    • Acquired monosomy 7

1 Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997.

2 Hitzler JK, Cheung J, Li Y, et al.: GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome. Blood 101 (11): 4301-4, 2003.

3 Mundschau G, Gurbuxani S, Gamis AS, et al.: Mutagenesis of GATA1 is an initiating event in Down syndrome leukemogenesis. Blood 101 (11): 4298-300, 2003.

4 Massey GV, Zipursky A, Chang MN, et al.: A prospective study of the natural history of transient leukemia (TL) in neonates with Down syndrome (DS): Children's Oncology Group (COG) study POG-9481. Blood 107 (12): 4606-13, 2006.

5 Homans AC, Verissimo AM, Vlacha V: Transient abnormal myelopoiesis of infancy associated with trisomy 21. Am J Pediatr Hematol Oncol 15 (4): 392-9, 1993.

6 Zuelzer WW, Cox DE: Genetic aspects of leukemia. Semin Hematol 6 (3): 228-49, 1969.

7 Miller RW: Persons with exceptionally high risk of leukemia. Cancer Res 27 (12): 2420-3, 1967.

8 Inskip PD, Harvey EB, Boice JD Jr, et al.: Incidence of childhood cancer in twins. Cancer Causes Control 2 (5): 315-24, 1991.

9 Kurita S, Kamei Y, Ota K: Genetic studies on familial leukemia. Cancer 34 (4): 1098-101, 1974.

10 Greaves M: Pre-natal origins of childhood leukemia. Rev Clin Exp Hematol 7 (3): 233-45, 2003.

Classification of Pediatric Myeloid Malignancies

FAB classification for childhood acute myeloid leukemia

The first most comprehensive morphologic-histochemical classification system for acute myeloid leukemia (AML) was developed by the French-American-British (FAB) Cooperative Group.1,2,3,4,5 This classification system categorizes AML into the following major subtypes primarily based on morphology and immunohistochemical detection of lineage markers:

  • M0: acute myeloblastic leukemia without differentiation.6,7 M0 AML, also referred to as minimally differentiated AML, does not express myeloperoxidase (MPO) at the light microscopy level, but may show characteristic granules by electron microscopy. M0 AML can be defined by expression of cluster determinant (CD) markers such as CD13, CD33 and CD117 (c-KIT) in the absence of lymphoid differentiation. To be categorized as M0, the leukemic blasts must not display specific morphologic or histochemical features of either AML or acute lymphoblastic leukemia (ALL).
  • M1: acute myeloblastic leukemia with minimal differentiation but with the expression of MPO that is detected by immunohistochemistry or flow cytometry.
  • M2: acute myeloblastic leukemia with differentiation.
  • M3: acute promyelocytic leukemia (APL) hypergranular type.Identifying this subtype is critical since the risk of fatal hemorrhagic complication prior to or during induction is high and the appropriate therapy is different than for other subtypes of AML. (Refer to the Acute Promyelocytic Leukemia section of this summary for more information on treatment options under clinical evaluation.)
  • M3v: APL, microgranular variant. Cytoplasm of promyelocytes demonstrates a fine granularity, and nuclei are often folded. Same clinical, cytogenetic, and therapeutic implications as FAB M3.
  • M4: acute myelomonocytic leukemia (AMML).
  • M4Eo: AMML with eosinophilia (abnormal eosinophils with dysplastic basophilic granules).
  • M5: acute monocytic leukemia (AMoL).
    • M5a: AMoL without differentiation (monoblastic).
    • M5b: AMoL with differentiation.
  • M6: acute erythroid leukemia (AEL).
  • M7: acute megakaryocytic leukemia (AMKL). Diagnosis of M7 can be difficult without the use of flow cytometry as the blasts can be morphologically confused with lymphoblasts. Characteristically, the blasts display cytoplasmic blebs. Marrow aspiration can be difficult due to myelofibrosis, and marrow biopsy with reticulin stain can be helpful.

Other extremely rare subtypes of AML include acute eosinophilic leukemia and acute basophilic leukemia.

Fifty percent to 60% of children with AML can be classified as having M1, M2, M3, M6, or M7 subtypes; approximately 40% have M4 or M5 subtypes. About 80% of children younger than 2 years with AML have a M4 or M5 subtype. The response to cytotoxic chemotherapy among children with the different subtypes of AML is relatively similar. One exception is FAB subtype M3, for which all-trans retinoic acid plus chemotherapy achieves remission and cure in approximately 70% to 80% of children with AML.

WHO classification system

The World Health Organization (WHO) Classification System incorporates clinical, morphologic (i.e., FAB Classification information), immunophenotypic, cytogenetic, and molecular data.8,9,10,

    WHO classification of acute myeloid leukemias
  1. AML with recurrent genetic abnormalities:
    1. AML with t(8;21)(q22;q22); (AML1 [CBFA]/ETO).
    2. AML with abnormal marrow eosinophils.
      1. inv(16)(p13q22).
      2. t(16;16)(p13;q22) (CBFB/MYH11).
    3. Acute promyelocytic leukemia (AML with t(15;17)(q22;q12) (PML/RARA) and variants (included as M3 in the FAB classification).
    4. AML with 11q23 (MLL) abnormalities.
  2. AML with multilineage dysplasia (de novo or following a myelodysplastic syndrome-most cases of refractory anemia with excess of blasts in transformation fall in the latter category).
  3. AML, therapy-related:
    1. Alkylating agent-related AML.
    2. Topoisomerase II inhibitor-related AML.
  4. Acute leukemia of ambiguous lineage:
    1. Undifferentiated acute leukemia (leukemic blasts show no or minimal signs of morphologic and/or protein expression signs of maturation).
    2. Bilineal acute leukemia (more than one cell lineage that demonstrates leukemic transformation).
    3. Biphenotypic acute leukemia (a single population of leukemic blasts have simultaneous expression of protein expression markers of different hematopoetic cell lineages).
  5. AML not otherwise categorized (including the FAB morphology-based M0 to M2, and M4 to M7 categories):
    1. AML minimally differentiated (FAB M0).
    2. AML without maturation (FAB M1).
    3. AML with maturation (FAB M2).
    4. AML (FAB M4).
    5. Acute monoblastic and monocytic leukemia (FAB M5a and M5b, respectively).
    6. Acute erythroid leukemia (FAB M6).
      1. Erythroleukemia (FAB M6a).
      2. Pure erythroid leukemia (FAB M6b).
    7. Acute megakaryoblastic leukemia (FAB M7).
    8. Acute basophilic leukemia.
    9. Acute panmyelosis with myelofibrosis.
    10. Myeloid (granulocytic) sarcoma.

Histochemical evaluation

The treatment for children with AML differs significantly from that for ALL. As a consequence, it is crucial to distinguish AML from ALL. Special histochemical stains performed on bone marrow specimens of children with acute leukemia can be helpful to confirm their diagnosis. The stains most commonly used include myeloperoxidase, PAS, Sudan Black B, and esterase. In most cases the staining pattern with these histochemical stains will distinguish AML from AMML and ALL (see below). This approach is being replaced by immunophenotyping using flow cytometry.

Table 1. Histochemical Staining Patterns

M0AML, APL (M1-M3) AMML (M4)AMoL (M5)AEL (M6)AMKL (M7)ALL(a) These reactions are inhibited by fluoride.Myeloperoxidase-++----Nonspecific esterases Chloracetate -++±---Alpha-naphthol acetate--+ (a)+ (a)-± (a)-Sudan Black B-++----PAS --±±+-+

Immunophenotypic evaluation

The use of monoclonal antibodies to determine cell-surface antigens of AML cells is helpful to reinforce the histologic diagnosis. Various lineage-specific monoclonal antibodies that detect antigens on AML cells should be used at the time of initial diagnostic workup, along with a battery of lineage-specific T-lymphocyte and B-lymphocyte markers to help distinguish AML from ALL and bilineal (as defined above) or biphenotypic leukemias. The expression of various proteins, termed cluster designations (CD), that are relatively lineage-specific for AML include CD33, CD13, CD14, CDw41 (or platelet antiglycoprotein IIb/IIIa), CD15, CD11B, CD36, and antiglycophorin A. Lineage-associated B-lymphocytic antigens CD10, CD19, CD20, CD22, and CD24 may be present in 10% to 20% of AMLs, but monoclonal surface immunoglobulin and cytoplasmic immunoglobulin heavy chains are usually absent; similarly, CD2, CD3, CD5, and CD7 lineage-associated T-lymphocytic antigens are present in 20% to 40% of AMLs.11,12,13 The aberrant expression of lymphoid-associated antigens by AML cells is relatively common but generally has no prognostic significance.11,12,

Immunophenotyping can also be helpful in distinguishing some FAB subtypes of AML. Testing for the presence of HLA-DR can be helpful in identifying APL. Overall, HLA-DR is expressed on 75% to 80% of AMLs but rarely expressed on APL. In addition, APL cases with PML/RARA were noted to express CD34/CD15 and demonstrate a heterogenous pattern of CD13 expression.14 Testing for the presence of glycoprotein Ib, glycoprotein IIb/IIIa, or Factor VIII antigen expression is helpful in making the diagnosis of M7 (megakaryocytic leukemia). Glycophorin expression is helpful in making the diagnosis of M6 (erythroid leukemia).15,

Cytogenetic evaluation and molecular abnormalities

Chromosomal analyses of the leukemia should be performed on children with AML because they are important diagnostic and prognostic markers.16,17,18 Clonal chromosomal abnormalities have been identified in the blasts of about 75% of children with AML and are useful in defining subtypes with particular characteristics (e.g., t(8;21) with M2, t(15;17) with M3, inv(16) with M4 Eo, 11q23 abnormalities with M4 and M5, t(1;22) with M7). Leukemias with the chromosomal abnormalities t(8;21) and inv(16) are called core-binding factor leukemias; core-binding factor (a transcription factor involved in hematopoietic stem cell differentiation) is disrupted by each of these abnormalities.

Molecular probes and newer cytogenetic techniques (e.g., fluorescence in situ hybridization [FISH]) can detect cryptic abnormalities that were not evident by standard cytogenetic banding studies.19 This is clinically important when optimal therapy differs, as in APL. Use of these techniques can identify cases of APL when the diagnosis is suspected but the t(15;17) is not identified by routine cytogenetic evaluation. The presence of the Philadelphia chromosome in children with AML most likely represents chronic myelogenous leukemia (CML) that has transformed to AML rather than de novo AML.

    Specific recurring cytogenetic and molecular abnormalities include:
  • AML with t(8;21): In leukemias with t(8;21), the AML1 (RUNX1, CBFA2) gene on chromosome 21 is fused with the ETO gene on chromosome 8. The t(8;21) translocation is associated with the FAB M2 subtype and with granulocytic sarcomas.20,21 Adults with t(8;21) have a more favorable prognosis than adults with other types of AML.16,22 Most reports of recent studies describe a more favorable outcome for children with t(8;21) AML than the average outcome for all children with AML.16,23,24,25
  • AML with inv(16): In leukemias with inv(16), the CBFß gene at chromosome band 16q22 is fused with the MYH11 gene at chromosome band 16p13. The inv(16) translocation is associated with the FAB M4Eo subtype.26 Inv(16) confers a favorable prognosis for both adults and children with AML.16,23,24,25,
  • AML with t(15;17): AML with t(15;17) is invariably associated with APL, a distinct subtype of AML that is treated differently than other types of AML because of its marked sensitivity to the differentiating effects of all-trans retinoic acid. The t(15;17) translocation leads to the production of a fusion protein involving the retinoid acid receptor alpha and PML.27 Other much less common translocations involving the retinoic acid receptor alpha can also result in APL (e.g., t(11;17) involving the PLZF gene).28 Identification of cases with the t(11;17) is important because of their decreased sensitivity to all-trans retinoic acid.27,28,
  • AML with MLL gene rearrangements: Translocations of chromosomal band 11q23 involving the MLL gene, including most AML secondary to epipodophyllotoxin,29 are associated with monocytic differentiation (FAB M4 and M5) and generally have an unfavorable prognosis.30,31 One exception to the poor prognostic significance of translocations at chromosome band 11q23 may be for children with t(9;11) in which the MLL gene is fused with the AF9 gene. In some reports, outcome has been relatively favorable for children whose leukemia cells have t(9;11),25,31,32 though favorable outcome has not been observed in other series.24

    The t(10;11) translocation has been reported to define a group at particularly high risk of relapse in bone marrow and the central nervous system (CNS).33 Some cases with the t(10;11) translocation have fusion of the MLL gene with the AF10 (MLLT10) gene on chromosome 10, with most of these cases having the FAB M5 subtype.34 AML with t(10;11) may also have fusion of the CALM gene on chromosome 11 with the AF10 gene.35 Based on the limited number of cases reported, prognosis appears poor for cases with t(10;11) regardless of the type of gene fusion present.36,

  • Other unfavorable chromosomal abnormalities: Chromosomal abnormalities associated with poor prognosis in adults with AML include those involving chromosome 7 (monosomy 7 and del(7q)), chromosome 5 (monosomy 5 and del(5q)) and the long arm of chromosome 3 (inv(3)(q21q26) or t(3;3)(q21q26)).16,22 These cytogenetic subgroups are also associated with poor prognosis in children with AML, though abnormalities of the long arm of chromosome 3q and 5q are extremely rare in children with AML.22,37,38,
  • AML with t(1;22): The t(1;22)(p13;q13) translocation is restricted to acute megakaryoblastic leukemia (AMKL) and occurs in as many as one third of AMKL cases in children.39,40,41 Most AMKL cases with t(1;22) occur in infants, and the translocation is uncommon in children with Down syndrome who develop AMKL.39,41 In leukemias with t(1;22), the OTT (RBM15) gene on chromosome 1 is fused to the MAL (MLK1) gene on chromosome 22.42,43 Cases with detectable OTT/MAL fusion transcripts in the absence of t(1;22) have been reported, as well.41 In the small number of children reported, the presence of the t(1;22) appears to be associated with poor prognosis, though long-term survivors have been noted following intensive therapy.41,44,
  • AML with FLT3 mutations: Presence of a FLT3 internal-tandem duplication (ITD) mutation appears to be associated with poor prognosis in adults with AML,45 particularly when both alleles are mutated or there is a high ratio of the mutant allele to the normal allele.46,47 FLT3-ITD mutations also occur in pediatric AML cases,48,49,50,51 and as with adults, FLT3-ITD mutations appear to be associated with poor prognosis in children with AML.48,49,50,51 The frequency of FLT3-ITD mutations in children appears to be lower than that observed for adults, especially for children younger than 10 years, for whom 5% to 10% of cases have the mutation (compared with approximately 30% for adults).50,51 Activating point mutations of FLT3 have also been identified in both adults and children with AML,46,50,52 though the clinical significance of these mutations is not clearly defined. Gene expression profiling of pediatric AML has shown that within FLT3-mutant cases, relative expression of the genes RUNX3 and ATRX can define high, intermediate, and low risk prognostic groups.53 FLT3-ITD and point mutations occur in 30% to 40% of children and adults with APL.49,54,55,56 Presence of the FLT3-ITD mutation is strongly associated with the microgranular variant (M3v) of APL and with hyperleukocytosis.49,56 It remains unclear whether FLT3 mutations are associated with poorer prognosis in patients with APL who are treated with modern therapy that includes all-trans retinoic acid.54,55
  • ras and tyrosine kinase receptor mutations: Although mutations in ras have been identified in approximately 25% of patients with AML, the prognostic significance has not been clearly shown.57,58 Mutations in c-KIT occur in less than 5% of AML, but in up to 10% to 40% of AML with core-binding factor abnormalities.50,59,60 The presence of the activating c-KIT mutations in this subgroup of AML appears to be associated with a poor prognosis.60,61 When patients with ras, c-KIT or FLT3-ITD mutations are considered as a single group, they have a significantly worse outcome than patients without these mutations and may benefit, at least in terms of disease-free survival, from allogeneic hematopoietic stem cell transplantation.50,62,
  • GATA1 mutations: GATA1 mutations are present in most, if not all, Down syndrome children with either transient myeloproliferative disease (TMD) or AMKL.63,64,65,66 GATA1 mutations are not observed in non–Down syndrome children with AMKL or in Down syndrome children with other types of leukemia.65,66 GATA1 is a transcription factor that is required for normal development of erythroid cells, megakaryocytes, eosinophils, and mast cells.67 GATA1 mutations confer increased sensitivity to cytarabine by down-regulating cytidine deaminase expression, possibly providing an explanation for the superior outcome of children with Down syndrome and M7 AML when treated with cytarabine-containing regimens.68
  • Nucleophosmin (NPM1) mutations: NPM1 is a protein that has been linked to ribosomal protein assembly and transport as well as being a molecular chaperone involved in preventing protein aggregation in the nucleolus. NPM1 has also been identified as a partner in several chromosomal translocations in leukemia and lymphoma. Mutations in the NPM1 protein that diminish its nuclear localization have been shown to be primarily associated with a subset of AML with a normal karyotype and an improved prognosis in the absence of FLT3-ITD mutations in adults and younger adults.69,70,71,72 Preliminary studies of children with AML suggest a similar rate of occurrence of this mutation in patients with normal cytogenetics and who lack a known genetic marker.73,

Classification of myelodysplastic syndromes in children

The FAB classification of myelodysplastic syndromes (MDS) is not completely applicable to children.74,75 In adults, MDS is divided into several distinct categories based on the presence of myelodysplasia, types of cytopenia, specific chromosomal abnormalities, and the percentage of myeloblasts.75,76,77,78

A modified classification schema for MDS and myeloproliferative disorders has been developed by the WHO. The primary WHO classification changes include:

  • Cases with 20% to 29% blasts should be called AML, thus eliminating refractory anemia with excess blasts in transformation (RAEB-T).
  • RAEB is now divided into RAEB-1 (5%-9% bone marrow [BM] blasts) and RAEB-2 (10%-19% BM blasts).
  • Multilineage dysplasia will be highlighted under refractory anemia with ringed sideroblasts (RARS) or refractory anemia (RA).
  • Juvenile myelomonocytic leukemia (JMML) and proliferative chronic myelomonocytic leukemia (CMML) will be under MDS/MPD (myeloproliferative disorder).
  • MDS unclassified will include severe myelofibrosis.
  • MDS associated with isolated del(5q) will be a separate category.
  • Monocytosis (under 13,000 monocytes) will be listed under the other subtypes rather than a separate category.

Table 2. WHO Classification of Myelodysplastic Syndromes

RA RARSRCMDRCMD-RSRAEB-1 RAEB-2MDS-U5qRA= refractory anemia (includes only erythroid dysplasia).RARS= refractory anemia with ringed sideroblasts (includes only erythroid dysplasia).RCMD= refractory cytopenia with multilineage dysplasia. RCMD-RS= refractory cytopenia with multilineage dysplasia and ringed sideroblasts. RAEB-1= refractory anemia with excess blasts-1: 5% to 9% marrow blasts. RAEB-2= refractory anemia with excess blasts-2: 10% to 19% marrow blasts. MDS-U= myelodysplastic syndrome-unclassified.5q= myelodysplastic syndrome associated with isolated del(5q). (Adapted from Brunning, et al. 2001.) 79,Anemia++± ± ± ± ±+Granulocytopenia ± ± + + + Thrombocytopenia ± ± + + + Marrow dysplasiaerythroid + + ± ±myeloid ≥10% in 2 or more myeloid cell lines ≥10% in 2 or more myeloid cell lines ± ± + in 1 myeloid cell line megakaryocytic ± ±±Auer’s rods None None None ± None None Ringed sideroblasts<15% ≥15% <15% ≥15% Peripheral blasts Rare or none None Rare or none Rare or none<5% 5-19% Rare or none <5% Bone marrow blasts<5%<5% <5% <5% 5-9% 10-19% <5% <5% Peripheral monocytosis (>1 x 109/L) No No No No

RARS is rare in children. RA and RAEB are more common. The WHO classification schema has a new subgroup that includes JMML (formerly Juvenile Chronic Myeloid Leukemia), CMML, and Philadelphia (Ph) chromosome–negative CML. This group can show mixed myeloproliferative and sometimes myelodysplastic features. JMML shares some characteristics with adult CMML 80,81,82 but is a distinct syndrome (see below). A subgroup of children younger than 4 years at diagnosis with myelodysplasia have monosomy 7. For this subset of children, their disease is best classified as a subtype of JMML. The International Prognostic Scoring System (IPSS) is used to determine the risk of progression to AML and the outcome in adult patients with MDS. When this system was applied to children with MDS or JMML, only a blast count of less than 5% and a platelet count of more than 100 x 109/L were associated with a better survival in MDS, and a platelet count of more than 40 x 109/L predicted a better outcome in JMML.83 These results suggest that MDS and JMML in children may be significantly different disorders than adult-type MDS. Older children with monosomy 7 and high-grade MDS, however, behave more like adults with MDS and are best classified that way and treated with allogeneic hematopoietic stem cell transplantation.84,85 The risk group or grade of MDS is defined according to IPSS guidelines.86 A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases was published in 2003; however, the usefulness of this classification has yet to be evaluated prospectively in clinical practice.10 A retrospective comparison of the WHO classification with the category, cytology, and cytogenetics system and a Pediatric WHO adaptation for MDS/MPD, has shown that the latter 2 systems are better able to effectively classify childhood MDS than the more general WHO system.87 A prospective study should be done to definitively determine the optimal classification scheme for childhood MDS/MPD.10,

Diagnostic classification of juvenile myelomonocytic leukemia

JMML is a rare leukemia that accounts for less than 1% of childhood leukemia cases.80 JMML typically presents in young children (a median age of approximately 1 year) and occurs more commonly in boys (male to female ratio approximately 2.5:1). Common clinical features at diagnosis include hepatosplenomegaly (97%), lymphadenopathy (76%), pallor (64%), fever (54%), and skin rash (36%).88 In children presenting with clinical features suggestive of JMML, a definitive diagnosis requires the following:89,

Table 3. Diagnostic Criteria for JMML

CategoryItemMinimal laboratory criteria (all 3 have to be fulfilled)1. Ph chromosome negative, no BCR/ABL rearrangement2. Peripheral blood monocyte count >1 x 109/L3. Bone marrow blasts <20%Criteria for definite diagnosis (at least 2 must be fulfilled) 1. Hemoglobin F increased for age2. Myeloid precursors on peripheral blood smear3. White blood count >10 x 109/L4. Clonal abnormality (including monosomy 7) 5. Granulocyte-macrophage colony-stimulating factor (GM-CSF) hypersensitivity of myeloid progenitors in vitro

Distinctive characteristics of JMML cells include in vitro hypersensitivity to GM-CSF and activated ras signaling secondary to mutations in various components of this pathway.90,91,92 While the majority of children with JMML have no detectable cytogenetic abnormalities, a minority show loss of chromosome 7 in bone marrow cells.81,88,93,94,

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