martes, 8 de octubre de 2019

Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment (PDQ®)–Health Professional Version - National Cancer Institute 1/8

Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment (PDQ®)–Health Professional Version - National Cancer Institute

National Cancer Institute



Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment (PDQ®)–Health Professional Version

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General Information About Childhood Acute Myeloid Leukemia (AML)

Dramatic improvements in survival have been achieved for children and adolescents with cancer.[1] Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. For acute myeloid leukemia (AML), the 5-year survival rate increased over the same time from less than 20% to 68% for children younger than 15 years and from less than 20% to 57% for adolescents aged 15 to 19 years.[1]

Characteristics of Myeloid Leukemias and Other Myeloid Malignancies in Children

Approximately 20% of childhood leukemias are of myeloid origin and they represent a spectrum of hematopoietic malignancies.[2] The majority of myeloid leukemias are acute, and the remainder include chronic and/or subacute myeloproliferative disorders such as chronic myelogenous leukemia and juvenile myelomonocytic leukemia. Myelodysplastic syndromes occur much less frequently in children than in adults and almost invariably represent clonal, preleukemic conditions that may evolve from congenital marrow failure syndromes such as Fanconi anemia and Shwachman-Diamond syndrome.
The general characteristics of myeloid leukemias and other myeloid malignancies are described below:
  • Acute myeloid leukemia (AML). AML is defined as a clonal disorder caused by malignant transformation of a bone marrow–derived, self-renewing stem cell or progenitors, leading to accumulation of immature, nonfunctional myeloid cells. 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% immature leukemic blasts, with some exceptions as noted in subsequent sections. (Refer to the Treatment Option Overview for Childhood AML and Treatment of Childhood AML sections of this summary for more information.)
  • Transient abnormal myelopoiesis (TAM). TAM is also termed transient myeloproliferative disorder or transient leukemia. The TAM observed in infants with Down syndrome represents a clonal expansion of myeloblasts that can be difficult to distinguish from AML. Most importantly, TAM spontaneously regresses in most cases within the first 3 months of life. TAM occurs in 4% to 10% of infants with Down syndrome.[3-5]
    TAM blasts most commonly have megakaryoblastic differentiation characteristics and distinctive mutations involving the GATA1 gene.[6,7] TAM may occur in phenotypically normal infants with genetic mosaicism in the bone marrow for trisomy 21. While TAM is generally not characterized by cytogenetic abnormalities other than trisomy 21, the presence of additional cytogenetic findings may predict an increased risk of developing subsequent AML.[8] Approximately 20% of infants with TAM of Down syndrome eventually develop AML, with most cases diagnosed within the first 3 years of life.[7,8]
    Early death from TAM-related complications occurs in 10% to 20% of affected infants.[8-10] Infants with progressive organomegaly, visceral effusions, high blast count (>100,000 cells/μL) and laboratory evidence of progressive liver dysfunction are at a particularly high risk of early mortality.[8,10] (Refer to the Children With Down Syndrome and AML or Transient Abnormal Myelopoiesis [TAM] section of this summary for more information.)
  • Myelodysplastic syndrome (MDS). MDS in children represents a heterogeneous group of disorders characterized by ineffective hematopoiesis, impaired maturation of myeloid progenitors with dysplastic morphologic features, and cytopenias. Although the underlying cause of MDS in children is unclear, there is often an association with marrow failure syndromes. Most patients with MDS may have hypercellular bone marrows without increased numbers of leukemic blasts, but some patients may present with a very hypocellular bone marrow, making the distinction between severe aplastic anemia and MDS difficult.[11]
    The presence of a karyotype abnormality in a hypocellular marrow is consistent with MDS and transformation to AML should be expected. Given the high association of MDS evolving into AML, patients with MDS are typically referred for stem cell transplantation before transformation to AML. (Refer to the Myelodysplastic Syndromes [MDS] section of this summary for more information.)
  • Juvenile myelomonocytic leukemia (JMML). JMML represents the most common myeloproliferative syndrome observed in young children. JMML occurs at a median age of 1.8 years.
    JMML characteristically presents with hepatosplenomegaly, lymphadenopathy, fever, and skin rash along with an elevated white blood cell (WBC) count and increased circulating monocytes.[12] In addition, patients often have an elevated hemoglobin F, hypersensitivity of the leukemic cells to granulocyte-macrophage colony-stimulating factor (GM-CSF), monosomy 7, and leukemia cell mutations in a gene involved in RAS pathway signaling (e.g., NF1, KRAS/NRAS, PTPN11, or CBL).[12-14] (Refer to the Juvenile Myelomonocytic Leukemia [JMML] section of this summary for more information.)
  • Chronic myelogenous leukemia (CML). CML is primarily an adult disease but represents the most common of the chronic myeloproliferative disorders in childhood, accounting for approximately 10% of childhood myeloid leukemia.[2] Although CML has been reported in very young children, most patients are aged 6 years and older.
    CML is a clonal panmyelopathy that involves all hematopoietic cell lineages. While the WBC 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 caused by the presence of the Philadelphia chromosome, a translocation between chromosomes 9 and 22 (i.e., t(9;22)) resulting in fusion of the BCR and ABL1 genes. (Refer to the Chronic Myelogenous Leukemia [CML] section of this summary for more information.)
    Other chronic myeloproliferative syndromes, such as polycythemia vera and essential thrombocytosis, are extremely rare in children.

Conditions Associated With Myeloid Malignancies

Genetic abnormalities (cancer predisposition syndromes) are associated with the development of AML. There is a high concordance rate of AML in identical twins; however, this is not believed to be related to genetic risk, but rather to shared circulation and the inability of one twin to reject leukemic cells from the other twin during fetal development.[15-17] There is an estimated twofold to fourfold increased risk of developing leukemia for the fraternal twin of a pediatric leukemia patient up to about age 6 years, after which the risk is not significantly greater than that of the general population.[18,19]
The development of AML has also been associated with a variety of inherited, acquired, and familial syndromes that result from chromosomal imbalances or instabilities, defects in DNA repair, altered cytokine receptor or signal transduction pathway activation, and altered protein synthesis.[20,21]
Inherited syndromes
  • Chromosomal imbalances:
    • Down syndrome.
    • Familial monosomy 7.
  • Chromosomal instability syndromes:
    • Fanconi anemia.
    • Dyskeratosis congenita.
    • Bloom syndrome.
  • Syndromes of growth and cell survival signaling pathway defects:
    • Neurofibromatosis type 1 (particularly JMML development).
    • Noonan syndrome (particularly JMML development).
    • Severe congenital neutropenia (Kostmann syndrome).
    • Shwachman-Diamond syndrome.
    • Diamond-Blackfan anemia.
    • Congenital amegakaryocytic thrombocytopenia.
    • CBL germline syndrome (particularly in JMML).
    • Li-Fraumeni syndrome (TP53 mutations).
Acquired syndromes
  • Severe aplastic anemia.
  • Paroxysmal nocturnal hemoglobinuria.
  • Amegakaryocytic thrombocytopenia.
  • Acquired monosomy 7.
Familial MDS and AML syndromes
  • Familial platelet disorder with a propensity to develop AML (associated with germline RUNX1 mutations).
  • Familial MDS and AML syndromes with germline GATA2 mutations.
  • Familial MDS and AML syndromes with germline CEBPA mutations.[22]
  • Telomere biology disorders resulting from a mutation in TERC or TERT (i.e., occult dyskeratosis congenita).
Nonsyndromic genetic susceptibility to AML is also being studied. For example, homozygosity for a specific IKZF1 polymorphism has been associated with an increased risk of infant AML.[23]
References
  1. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PUBMED Abstract]
  2. Smith MA, Ries LA, Gurney JG, et al.: Leukemia. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649, pp 17-34. Also available online. Last accessed October 04, 2019.
  3. Roberts I, Alford K, Hall G, et al.: GATA1-mutant clones are frequent and often unsuspected in babies with Down syndrome: identification of a population at risk of leukemia. Blood 122 (24): 3908-17, 2013. [PUBMED Abstract]
  4. Zipursky A: Transient leukaemia--a benign form of leukaemia in newborn infants with trisomy 21. Br J Haematol 120 (6): 930-8, 2003. [PUBMED Abstract]
  5. Gamis AS, Smith FO: Transient myeloproliferative disorder in children with Down syndrome: clarity to this enigmatic disorder. Br J Haematol 159 (3): 277-87, 2012. [PUBMED Abstract]
  6. 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. [PUBMED Abstract]
  7. 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. [PUBMED Abstract]
  8. 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. [PUBMED Abstract]
  9. 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. [PUBMED Abstract]
  10. Gamis AS, Alonzo TA, Gerbing RB, et al.: Natural history of transient myeloproliferative disorder clinically diagnosed in Down syndrome neonates: a report from the Children's Oncology Group Study A2971. Blood 118 (26): 6752-9; quiz 6996, 2011. [PUBMED Abstract]
  11. Hasle H, Niemeyer CM: Advances in the prognostication and management of advanced MDS in children. Br J Haematol 154 (2): 185-95, 2011. [PUBMED Abstract]
  12. Niemeyer CM, Arico M, Basso G, et al.: Chronic myelomonocytic leukemia in childhood: a retrospective analysis of 110 cases. European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS) Blood 89 (10): 3534-43, 1997. [PUBMED Abstract]
  13. Loh ML: Recent advances in the pathogenesis and treatment of juvenile myelomonocytic leukaemia. Br J Haematol 152 (6): 677-87, 2011. [PUBMED Abstract]
  14. Stieglitz E, Taylor-Weiner AN, Chang TY, et al.: The genomic landscape of juvenile myelomonocytic leukemia. Nat Genet 47 (11): 1326-33, 2015. [PUBMED Abstract]
  15. Zuelzer WW, Cox DE: Genetic aspects of leukemia. Semin Hematol 6 (3): 228-49, 1969. [PUBMED Abstract]
  16. Miller RW: Persons with exceptionally high risk of leukemia. Cancer Res 27 (12): 2420-3, 1967. [PUBMED Abstract]
  17. Inskip PD, Harvey EB, Boice JD, et al.: Incidence of childhood cancer in twins. Cancer Causes Control 2 (5): 315-24, 1991. [PUBMED Abstract]
  18. Kurita S, Kamei Y, Ota K: Genetic studies on familial leukemia. Cancer 34 (4): 1098-101, 1974. [PUBMED Abstract]
  19. Greaves M: Pre-natal origins of childhood leukemia. Rev Clin Exp Hematol 7 (3): 233-45, 2003. [PUBMED Abstract]
  20. Puumala SE, Ross JA, Aplenc R, et al.: Epidemiology of childhood acute myeloid leukemia. Pediatr Blood Cancer 60 (5): 728-33, 2013. [PUBMED Abstract]
  21. West AH, Godley LA, Churpek JE: Familial myelodysplastic syndrome/acute leukemia syndromes: a review and utility for translational investigations. Ann N Y Acad Sci 1310: 111-8, 2014. [PUBMED Abstract]
  22. Tawana K, Wang J, Renneville A, et al.: Disease evolution and outcomes in familial AML with germline CEBPA mutations. Blood 126 (10): 1214-23, 2015. [PUBMED Abstract]
  23. Ross JA, Linabery AM, Blommer CN, et al.: Genetic variants modify susceptibility to leukemia in infants: a Children's Oncology Group report. Pediatr Blood Cancer 60 (1): 31-4, 2013. [PUBMED Abstract]

Classification of Pediatric Myeloid Malignancies

French-American-British (FAB) Classification System for Childhood AML

The first comprehensive morphologic-histochemical classification system for acute myeloid leukemia (AML) was developed by the FAB Cooperative Group.[1-5] This classification system, which has been replaced by the World Health Organization (WHO) system described below, categorized AML into major subtypes primarily on the basis of morphology and immunohistochemical detection of lineage markers.
The major subtypes of AML include the following:
  • 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.
  • 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. (Refer to the Acute Promyelocytic Leukemia section of this summary for more information.)
  • M3v: APL, microgranular variant. Cytoplasm of promyelocytes demonstrates a fine granularity, and nuclei are often folded. M3v has the 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).
    • M6a: Erythroleukemia.
    • M6b: Pure erythroid leukemia (myeloblast component not apparent).
    • M6c: Presence of myeloblasts and proerythroblasts.
  • M7: Acute megakaryocytic leukemia (AMKL).
Other extremely rare subtypes of AML include acute eosinophilic leukemia and acute basophilic leukemia.
The FAB classification was superseded by the WHO classification described below but remains relevant as it forms the basis of the WHO's subcategory of AML, not otherwise specified (AML, NOS).

World Health Organization (WHO) Classification System for Childhood AML

In 2001, the WHO proposed a new classification system that incorporated diagnostic cytogenetic information and that more reliably correlated with outcome. In this classification, patients with t(8;21), inv(16), t(15;17), or KMT2A (MLL) translocations, which collectively constituted nearly half of the cases of childhood AML, were classified as AML with recurrent cytogenetic abnormalities. This classification system also decreased the bone marrow percentage of leukemic blast requirement for the diagnosis of AML from 30% to 20%; an additional clarification was made so that patients with recurrent cytogenetic abnormalities did not need to meet the minimum blast requirement to be considered an AML patient.[8-10]
In 2008, the WHO expanded the number of cytogenetic abnormalities linked to AML classification and, for the first time, included specific gene mutations (CEBPA and NPM) in its classification system.[11] In 2016, the WHO classification underwent revisions to incorporate the expanding knowledge of leukemia biomarkers that are significantly important to the diagnosis, prognosis, and treatment of leukemia.[12] With emerging technologies aimed at genetic, epigenetic, proteomic, and immunophenotypic classification, AML classification will certainly continue to evolve and provide informative prognostic and biologic guidelines to clinicians and researchers.

2016 WHO classification of AML and related neoplasms

  • AML with recurrent genetic abnormalities:
    • AML with t(8;21)(q22;q22), RUNX1-RUNX1T1.
    • AML with inv(16)(p13.1;q22) or t(16;16)(p13.1;q22), CBFB-MYH11.
    • APL with PML-RARA.
    • AML with t(9;11)(p21.3;q23.3), MLLT3-KMT2A.
    • AML with t(6;9)(p23;q34.1), DEK-NUP214.
    • AML with inv(3)(q21.3;q26.2) or t(3;3)(q21.3;q26.2), GATA2, MECOM.
    • AML (megakaryoblastic) with t(1;22)(p13.3;q13.3), RBM15-MKL1.
    • AML with BCR-ABL1 (provisional entity).
    • AML with mutated NPM1.
    • AML with biallelic mutations of CEBPA.
    • AML with mutated RUNX1 (provisional entity).
  • AML with myelodysplasia-related features.
  • Therapy-related myeloid neoplasms.
  • AML, NOS:
    • AML with minimal differentiation.
    • AML without maturation.
    • AML with maturation.
    • Acute myelomonocytic leukemia.
    • Acute monoblastic/monocytic leukemia.
    • Pure erythroid leukemia.
    • Acute megakaryoblastic leukemia.
    • Acute basophilic leukemia.
    • Acute panmyelosis with myelofibrosis.
  • Myeloid sarcoma.
  • Myeloid proliferations related to Down syndrome:
    • Transient abnormal myelopoiesis (TAM).
    • Myeloid leukemia associated with Down syndrome.

2016 WHO classification of acute leukemias of ambiguous lineage

For the group of acute leukemias that have characteristics of both AML and acute lymphoblastic leukemia (ALL), the acute leukemias of ambiguous lineage, the WHO classification system is summarized in Table 1.[13,14] The criteria for lineage assignment for a diagnosis of mixed phenotype acute leukemia (MPAL) are provided in Table 2.[12]
Table 1. Acute Leukemias of Ambiguous Lineage According to the World Health Organization Classification of Tumors of Hematopoietic and Lymphoid Tissuesa
ConditionDefinition
NOS = not otherwise specified.
aBéné MC: Biphenotypic, bilineal, ambiguous or mixed lineage: strange leukemias! Haematologica 94 (7): 891-3, 2009.[13] Obtained from Haematologica/the Hematology Journal website http://www.haematologica.orgExit Disclaimer.
Acute undifferentiated leukemiaAcute leukemia that does not express any marker considered specific for either lymphoid or myeloid lineage
Mixed phenotype acute leukemia with t(9;22)(q34;q11.2); BCR-ABL1Acute leukemia meeting the diagnostic criteria for mixed phenotype acute leukemia in which the blasts also have the (9;22) translocation or the BCR-ABL1 rearrangement
Mixed phenotype acute leukemia with t(v;11q23); KMT2A (MLL) rearrangedAcute leukemia meeting the diagnostic criteria for mixed phenotype acute leukemia in which the blasts also have a translocation involving the KMT2A gene
Mixed phenotype acute leukemia, B/myeloid, NOSAcute leukemia meeting the diagnostic criteria for assignment to both B and myeloid lineage, in which the blasts lack genetic abnormalities involving BCR-ABL1 or KMT2A
Mixed phenotype acute leukemia, T/myeloid, NOSAcute leukemia meeting the diagnostic criteria for assignment to both T and myeloid lineage, in which the blasts lack genetic abnormalities involving BCR-ABL1 or KMT2A
Mixed phenotype acute leukemia, B/myeloid, NOS—rare typesAcute leukemia meeting the diagnostic criteria for assignment to both B- and T-lineage
Other ambiguous lineage leukemiasNatural killer–cell lymphoblastic leukemia/lymphoma
Table 2. Lineage Assignment Criteria for Mixed Phenotype Acute Leukemia According to the 2016 Revision to the World Health Organization Classification of Myeloid Neoplasms and Acute Leukemiaa
LineageCriteria
aAdapted from Arber et al.[12]
bStrong defined as equal to or brighter than the normal B or T cells in the sample.
Myeloid LineageMyeloperoxidase (flow cytometry, immunohistochemistry, or cytochemistry); or monocytic differentiation (at least two of the following: nonspecific esterase cytochemistry, CD11c, CD14, CD64, lysozyme)
T LineageStrongb cytoplasmic CD3 (with antibodies to CD3 epsilon chain); or surface CD3
B LineageStrongb CD19 with at least one of the following strongly expressed: CD79a, cytoplasmic CD22, or CD10; or weak CD19 with at least two of the following strongly expressed: CD79a, cytoplasmic CD22, or CD10
Leukemias of mixed phenotype may be seen in various presentations, including the following:
  1. Bilineal leukemias in which there are two distinct populations of cells, usually one lymphoid and one myeloid.
  2. Biphenotypic leukemias in which individual blast cells display features of both lymphoid and myeloid lineage.
Biphenotypic cases represent the majority of mixed phenotype leukemias.[15] B-myeloid biphenotypic leukemias lacking the TEL-AML1 fusion have a lower rate of complete remission (CR) and a significantly worse event-free survival (EFS) compared with patients with precursor B-cell ALL.[15] Some studies suggest that patients with biphenotypic leukemia may fare better with a lymphoid, as opposed to a myeloid, treatment regimen.[16-19] A large retrospective study from the international Berlin-Frankfurt-Münster (BFM) group demonstrated that initial therapy with an ALL-type regimen was associated with a superior outcome compared with AML-type or combined ALL/AML regimens, particularly in cases with CD19 positivity or other lymphoid antigen expression. In this study, hematopoietic stem cell transplantation (HSCT) in first CR was not beneficial, with the possible exception of cases with morphologic evidence of persistent marrow disease (≥5% blasts) after the first month of treatment.[19]

WHO Classification of Bone Marrow and Peripheral Blood Findings for Myelodysplastic Syndromes

The FAB classification of myelodysplastic syndromes (MDS) was not completely applicable to children.[20,21] Traditionally, MDS classification systems have been divided into several distinct categories based on the presence of the following:[21-24]
  • Myelodysplasia.
  • Types of cytopenia.
  • Specific chromosomal abnormalities.
  • Percentage of myeloblasts.
A modified classification schema for MDS and myeloproliferative disorders (MPDs) was published by the WHO in 2008 and included subsections that focused on pediatric MDS and MPD.[25] This pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases was initially proposed in 2003.[10] The 2016 revision to the WHO classification has removed focus on the specific lineage (anemia, thrombocytopenia, or neutropenia) and now distinguishes cases with dysplasia in single versus multiple lineages. The category of MDS with excess blasts (MDS-EB) now encompasses the pediatric cases previously classified as refractory anemia with excess blasts (RAEB) or RAEB in transformation (RAEB-T).[26] The category of refractory cytopenia of childhood is retained as a provisional entity. The bone marrow and peripheral blood findings for MDS according to the 2008 WHO classification schema are summarized in Tables 3 and 4.[12,25] When MDS-EB is associated with the recurrent cytogenetic abnormalities that are usually associated with AML, a diagnosis of AML is made and patients are treated accordingly.
Distinguishing MDS from similar-appearing, reactive causes of dysplasia and/or cytopenias is noted to be difficult. In general, the finding of more than 10% dysplasia in a cell lineage is a diagnostic criteria for MDS, however, the WHO 2016 guidelines caution that reactive etiologies, rather than clonal, may have more than 10% dysplasia and should be excluded especially when dysplasia is subtle and/or restricted to a single lineage.[12]
The International Prognostic Scoring System 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 juvenile myelomonocytic leukemia (JMML), only a blast count of less than 5% and a platelet count of more than 100 × 109/L were associated with a better survival in MDS, and a platelet count of more than 40 × 109/L predicted a better outcome in JMML.[27] These results suggest that MDS and JMML in children may be significantly different disorders than adult-type MDS.
Pediatric MDS can be grouped into several general categories, each with distinctive clinical and biological characteristics, as follows:[26]
  • MDS arising from an inherited bone marrow failure syndrome, such as Fanconi anemia, severe congenital neutropenia, and Shwachman-Diamond syndrome.
  • MDS arising from severe aplastic anemia.
  • Secondary MDS arising from cytotoxic insults, such as high-dose alkylating chemotherapy.
  • Primary MDS includes cases of MDS beyond those listed above, acknowledging that some of the cases characterized as primary MDS are also associated with predisposition syndromes.
Genomic characterization of pediatric primary MDS has identified specific subsets defined by alterations in selected genes (refer to the Molecular Abnormalities subsection of this summary for more information about MDS). For example, germline mutations in either GATA2 [28] or SAMD9/SAMD9L [29-31] are especially common in children with deletions of all or part of chromosome 7. Genomic characterization has also shown that primary MDS in children differs from adult MDS at the molecular level.[30,32]
Table 3. World Health Organization (WHO) Classification of Bone Marrow and Peripheral Blood Findings for Myelodysplastic Syndromes (MDS)a
Type of MDSBone MarrowPeripheral Blood
aAdapted from Arber et al.[12]
bNote that cases with pancytopenia would be classified as MDS-U.
cWhen the marrow has <5% myeloblasts, but the peripheral blood has 2%–4% myeloblasts, the diagnosis is MDS-EB-1.
dThe diagnosis of MDS-EB-2 should be made if any one of the following criteria are met: marrow with 10%–19% blasts, peripheral blood with 5%–19% blasts, or presence of Auer rods.
eRecurring chromosomal abnormalities in MDS: Unbalanced: +8, -7 or del(7q), -5 or del(5q), del(20q), -Y, i(17q) or t(17p), -13 or del(13q), del(11q), del(12p) or t(12p), del(9q), idic(X)(q13); Balanced: t(11;16)(q23;p13.3), t(3;21)(q26.2;q22.1), t(1;3)(p36.3;q21.2), t(2;11)(p21;q23), inv(3)(q21q26.2), t(6;9)(p23;q34). The WHO classification notes that the presence of these chromosomal abnormalities in presence of persistent cytopenias of undetermined origin should be considered to support a presumptive diagnosis of MDS when morphological characteristics are not observed.
fThe diagnostic criteria for childhood MDS (refractory cytopenia of childhood [RCC]-provisional entry) include: 1) persistent cytopenia of 1–3 cell lines with <5% bone marrow blasts, <2% peripheral blood blasts, and no ringed sideroblasts and 2) dysplastic changes in 1–3 lineages should be present.
MDS with single lineage dysplasiaUnilineage dysplasia: ≥10% in one myeloid lineage1–2 cytopeniasb
<5% blastsBlasts <1%c
<15% ring sideroblasts 
 
MDS with ring sideroblasts (MDS-RS)Erythroid dysplasia only
<5% blastsNo blasts
≥15% ring sideroblasts 
 
MDS with multilineage dysplasiaDysplasia in ≥10% of cells in ≥2 myeloid lineages1–3 cytopenias
<5% blastsBlasts (none or <1%)c
±15% ring sideroblasts 
No Auer rodsNo Auer rods
 <1×109 monocytes/L
 
MDS with excess blasts-1 (MDS-EB-1)Single lineage or multilineage dysplasiaCytopenia(s)
5%–9% blastsc<5% blastsc
No Auer rodsNo Auer rods
 <1×109 monocytes/L
 
MDS with excess blasts-2 (MDS-EB-2)Single lineage or multilineage dysplasiaCytopenia(s)
10%–19% blastsd5%–19% blastsd
Auer rods ±dAuer rods ±d
 <1×109 monocytes/L
 
MDS with isolated del(5q)Normal to increased megakaryocytes (hypolobulated nuclei)Anemia
<5% blastsBlasts (none or <1%)
No Auer rodsNormal to increased platelet count
Isolated del(5q) 
 
MDS-unclassifiable (MDS-U)Dysplasia in <10% of cells in ≥1 myeloid cell lineageCytopenias
Cytogenetic abnormality associated with diagnosis of MDSe≤1% blastsc
<5% blasts 
 
Provisional entity: Refractory cytopenia of childhood (RCC)fRefer to Table 4 for more information.
Table 4. Definitions for Minimal Diagnostic Criteria for Childhood Myelodysplastic Syndrome (MDS) (Provisional Entity: Refractory Cytopenia of Childhood [RCC])a
 Erythroid LineageMyeloid LineageMegakaryocyte Lineage
aAdapted from Baumann et al.[33]
bBone marrow trephine/biopsy may be required as bone marrow in childhood RCC is often hypocellular.
cCharacteristics include abnormal nuclear lobulation, multinuclear cells, presence of nuclear bridges.
dPresence of pseudo–Pelger-Huet cells, hypo- or agranular cytoplasm, giant band forms.
eMegakaryocytes have variable size and often round or separated nuclei; the absence of megakaryocytes does not exclude the diagnosis of RCC.
Bone Marrow AspiratebDysplasia and/or megablastoid changes in ≥10% of erythroid precursorscDysplasia in ≥10% of granulocytic precursors and neutrophilsMicromegakaryocytes plus other dysplastic featurese
 <5% blastsd 
 
Bone Marrow BiopsyPresence of erythroid precursorsNo additional criteriaMicromegakaryocytes plus other dysplastic featurese
Increased proerythroblasts Immunohistochemistry positive for CD61 and CD41
Increased number of mitoses  
 
Peripheral Blood Dysplasia in ≥10% of neutrophils 
 <2% blasts 
References
  1. Bennett JM, Catovsky D, Daniel MT, et al.: Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol 33 (4): 451-8, 1976. [PUBMED Abstract]
  2. Bennett JM, Catovsky D, Daniel MT, et al.: Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group. Ann Intern Med 103 (4): 620-5, 1985. [PUBMED Abstract]
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