Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment (PDQ®)–Health Professional Version - National Cancer Institute 1/11

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

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

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ON THIS PAGE

• General Information About Childhood Acute Myeloid Leukemia (AML)
• Classification of Pediatric Myeloid Malignancies
• Histochemical, Immunophenotypic, and Molecular Evaluation for Childhood AML
• Treatment Option Overview for Childhood AML
• Treatment of Childhood AML
• Acute Promyelocytic Leukemia (APL)
• Transient Abnormal Myelopoiesis (TAM) or Children With Down Syndrome and AML
• Myelodysplastic Syndromes (MDS)
• Therapy-Related AML/Myelodysplastic Syndromes
• Juvenile Myelomonocytic Leukemia (JMML)
• Chronic Myelogenous Leukemia (CML)
• Special Considerations for the Treatment of Children With Cancer
• Survivorship and Adverse Late Sequelae
• Changes to This Summary (08/20/2019)
• About This PDQ Summary

General Information About Childhood Acute Myeloid Leukemia (AML)

In This Section

• Characteristics of Myeloid Leukemias and Other Myeloid Malignancies in Children
• Conditions Associated With Myeloid Malignancies

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

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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 January 31, 2019.
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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]
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