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Dramatic improvements in survival have been achieved for children and adolescents with cancer. 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.
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. 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:
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. 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.[8,9,10] 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.)
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.)
JMML characteristically presents with hepatosplenomegaly, lymphadenopathy, fever, and skin rash along with an elevated white blood cell (WBC) count and increased circulating monocytes. 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).[12,13,14] (Refer to the Juvenile Myelomonocytic Leukemia [JMML] section of this summary for more information.)
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.[15,16,17] 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]
Familial MDS and AML syndromes
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.
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.[1,2,3,4,5] 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:
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.[8,9,10]
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. 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. 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
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.
Leukemias of mixed phenotype may be seen in various presentations, including the following:
Biphenotypic cases represent the majority of mixed phenotype leukemias. 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. Some studies suggest that patients with biphenotypic leukemia may fare better with a lymphoid, as opposed to a myeloid, treatment regimen.[16,17,18,19] 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 possi