Myeloid leukemias in children
Current Clinical Trials

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 ¹ 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 ² 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 ³. 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 ⁴ for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

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.[6-8] 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)
    • Noonan 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

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with childhood acute myeloid leukemia/other myeloid malignancies ⁵. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ⁶.

References

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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
6. Zuelzer WW, Cox DE: Genetic aspects of leukemia. Semin Hematol 6 (3): 228-49, 1969.  [PUBMED Abstract]
   
   
7. Miller RW: Persons with exceptionally high risk of leukemia. Cancer Res 27 (12): 2420-3, 1967.  [PUBMED Abstract]
   
   
8. Inskip PD, Harvey EB, Boice JD Jr, et al.: Incidence of childhood cancer in twins. Cancer Causes Control 2 (5): 315-24, 1991.  [PUBMED Abstract]
   
   
9. Kurita S, Kamei Y, Ota K: Genetic studies on familial leukemia. Cancer 34 (4): 1098-101, 1974.  [PUBMED Abstract]
   
   
10. Greaves M: Pre-natal origins of childhood leukemia. Rev Clin Exp Hematol 7 (3): 233-45, 2003.  [PUBMED Abstract]