National Cancer Institute

Expert-reviewed information summary about the treatment of childhood acute myeloid leukemia, myelodysplastic syndromes, and other myeloproliferative disorders.

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood acute myeloid leukemia and other myeloid malignancies. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Childhood AML Treatment

Childhood Acute Myeloid Leukemia Treatment

General Information About Childhood Acute Myeloid Leukemia (AML)

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:

  • 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.

    TAM blasts most commonly have megakaryoblastic differentiation characteristics and distinctive mutations involving the gene. 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.

    Early death from TAM-related complications occurs in 10% to 20% of affected infants. 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. (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.

    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. 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., , , , or ). (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. 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 and 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. 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.

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.

  • 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.
    • germline syndrome (particularly in JMML).
    • Li-Fraumeni syndrome ( mutations).
  • Severe aplastic anemia.
  • Paroxysmal nocturnal hemoglobinuria.
  • Amegakaryocytic thrombocytopenia.
  • Acquired monosomy 7.
  • Familial platelet disorder with a propensity to develop AML (associated with germline mutations).
  • Familial MDS and AML syndromes with germline mutations.
  • Familial MDS and AML syndromes with germline mutations.
  • Telomere biology disorders resulting from a mutation in or (i.e., occult dyskeratosis congenita).

Nonsyndromic genetic susceptibility to AML is also being studied. For example, homozygosity for a specific polymorphism has been associated with an increased risk of infant AML.

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. 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. 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 () translocations, which collectively constituted nearly half of the cases of childhood AML, were classified as . 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.

In 2008, the WHO expanded the number of cytogenetic abnormalities linked to AML classification and, for the first time, included specific gene mutations ( and ) 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

  • AML with recurrent genetic abnormalities:
    • AML with t(8;21)(q22;q22), -.
    • AML with inv(16)(p13.1;q22) or t(16;16)(p13.1;q22), .
    • APL with .
    • AML with t(9;11)(p21.3;q23.3), -.
    • AML with t(6;9)(p23;q34.1), .
    • AML with inv(3)(q21.3;q26.2) or t(3;3)(q21.3;q26.2), .
    • AML (megakaryoblastic) with t(1;22)(p13.3;q13.3), .
    • AML with (provisional entity).
    • AML with mutated .
    • AML with biallelic mutations of .
    • AML with mutated (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. 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 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, although the optimal treatment for patients remains unclear.

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. Traditionally, MDS classification systems have been divided into several distinct categories based on the presence of the following:

  • 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. 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. For patients with MDS and excess blasts (5%–20%), the terminology has changed (refractory anemia with excess blasts [RAEB]-1 and RAEB-2 designations are now MDS with excess blasts [MDS-EB]-1 and MDS-EB-2). No changes were made in the childhood MDS classification, and the category of is retained as a provisional entity. The bone marrow and peripheral blood findings for the myelodysplastic syndromes according to the 2008 WHO classification schema are summarized in Tables 3 and 4.

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.

A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases was published in 2003. A retrospective comparison of the WHO classification to the Category, Cytology, and Cytogenetics system (CCC) and to a Pediatric WHO adaptation for MDS/MPD, has shown that the latter two systems appear to more effectively classify childhood MDS than the more general WHO system. For instance, refractory anemia with ring sideroblasts is rare in children, and refractory anemia and refractory anemia with excess blasts is more common. When such refractory cytopenias with excess blasts (5%–20%) are associated with recurrent cytogenetic abnormalities usually associated with AML, a diagnosis of the latter should be made and treated accordingly.

The WHO classification schema under myelodysplastic/myeloproliferative neoplasms has a subgroup that includes juvenile myelomonocytic leukemia (JMML) (formerly juvenile chronic myeloid leukemia), chronic myelomonocytic leukemia (CMML), and Philadelphia chromosome (Ph)–negative chronic myelogenous leukemia (CML). This group can show mixed myeloproliferative and sometimes myelodysplastic features. JMML shares some characteristics with adult CMML but is a distinct syndrome (refer to Table 8 below). A subgroup of children younger than 4 years at diagnosis with JMML associated with monosomy 7 are considered to have a subtype of JMML characterized by lower WBC count, higher percentage of circulating monocytes, higher mean cell volume for red blood cells, a lower bone marrow myeloid to erythroid ratio, and, often, normal to moderately increased fetal hemoglobin.

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 JMML, only a blast count of less than 5% and a platelet count of more than 100 x 10/L were associated with a better survival in MDS, and a platelet count of more than 40 x 10/L predicted a better outcome in JMML. These results suggest that MDS and JMML in children may be significantly different disorders than adult-type MDS.

MDS in children with monosomy 7 and high-grade MDS behaves more like MDS in adults and are best classified as adult MDS and treated with allogeneic hematopoietic stem cell transplantation. The risk group or grade of MDS is defined according to International Prognostic Scoring System guidelines.

Diagnostic and Molecular Evaluation

Histochemical evaluation

The treatment for children with AML differs significantly from that for ALL. As a consequence, it is critical 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, periodic acid-Schiff, Sudan Black B, and esterase. In most cases, the staining pattern with these histochemical stains will distinguish AML from AMML and ALL (refer to Table 5). Histochemical stains have been mostly replaced by flow cytometric immunophenotyping.

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 acute leukemias of ambiguous lineage. The expression of various cluster determinant (CD) proteins 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 AML cases, 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 AML cases. The aberrant expression of lymphoid-associated antigens by AML cells is relatively common but generally has no prognostic significance.

Immunophenotyping can also be helpful in distinguishing the following 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 AML cells but rarely expressed on APL cells. In addition, APL is characterized by bright CD33 expression and by CD117 (c-Kit) expression in most cases, heterogeneous expression of CD13 with CD34, CD11a, and CD18 often negative or low. The APL microgranular variant M3v more commonly expresses CD34 along with CD2.
  • 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).

Less than 5% of cases of acute leukemia in children are of ambiguous lineage, expressing features of both myeloid and lymphoid lineage. These cases are distinct from ALL with myeloid coexpression in that the predominant lineage cannot be determined by immunophenotypic and histochemical studies. The definition of leukemia of ambiguous lineage varies among studies, although most investigators now use criteria established by the European Group for the Immunological Characterization of Leukemias (EGIL) or the more stringent WHO criteria. In the WHO classification, the presence of MPO is required to establish myeloid lineage. This is not the case for the EGIL classification. The 2016 revision to the WHO classification also denotes that in some cases, leukemia with otherwise classic B-cell ALL immunophenotype may also express low-intensity MPO without other myeloid features, and the clinical significance of that finding is unclear such that one should be cautious before designating these cases as MPAL.

Cytogenetic Evaluation and Molecular Abnormalities

Genetic analyses of leukemia (using both conventional cytogenetic methods and molecular methods) are performed on children with acute myeloid leukemia (AML) because both chromosomal and molecular abnormalities are important diagnostic and prognostic markers. 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), t(15;17), inv(16), 11q23 abnormalities, t(1;22)). 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 abnormalities can aid in risk stratification and treatment allocation. For example, mutations of and are associated with favorable outcome while certain mutations of portend a high risk of relapse, and identifying these mutations may allow for targeted therapy.

The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia emphasizes that recurrent chromosomal translocations in pediatric AML may be unique or have a different prevalence than in adult AML. The pediatric AML chromosomal translocations that are found by conventional chromosome analysis and those that are cryptic (identified only with fluorescence hybridization or molecular techniques) occur at higher rates than in adults. These recurrent translocations are summarized in Table 6. Table 6 also shows, in the bottom three rows, additional relatively common recurrent translocations observed in children with AML.

A unifying concept for the role of specific mutations in AML is that mutations that promote proliferation (Type I) and mutations that block normal myeloid development (Type II) are both required for full conversion of hematopoietic stem/precursor cells to malignancy. Support for this conceptual construct comes from the observation that there is generally mutual exclusivity within each type of mutation, such that a single Type I and a single Type II mutation are present within each case. Further support comes from genetically engineered models of AML for which cooperative events rather than single mutations are required for leukemia development. Type I mutations are commonly in genes involved in growth factor signal transduction and include mutations in , , , , and . Type II genomic alterations include the common translocations and mutations associated with favorable prognosis (t(8;21), inv(16), t(16;16), t(15;17), , and ). rearrangements (translocations and partial tandem duplication) are also classified as Type II mutations.

Specific recurring cytogenetic and molecular abnormalities are briefly described below. The abnormalities are listed by those in clinical use that identify patients with favorable or unfavorable prognosis, followed by other abnormalities. The nomenclature of the 2016 revision to the WHO classification of myeloid neoplasms and acute leukemia is incorporated for disease entities where relevant.

Molecular abnormalities associated with a favorable prognosis

Molecular abnormalities associated with a favorable prognosis include the following:

  • Core-binding factor (CBF) AML includes cases with and fusion genes that disrupt the activity of core-binding factor, which contains and . These are specific entities in the 2016 revision to the WHO classification of myeloid neoplasms and acute leukemia.
    • AML with t(8;21)(q22;q22.1); : In leukemias with t(8;21), the () gene on chromosome 21 is fused with the () gene on chromosome 8. The t(8;21) translocation is associated with the FAB M2 subtype and with granulocytic sarcomas. Adults with t(8;21) have a more favorable prognosis than do adults with other types of AML. Children with t(8;21) have a more favorable outcome than do children with AML characterized by normal or complex karyotypes, with 5-year overall survival (OS) of 74% to 90%. The t(8;21) translocation occurs in approximately 12% of children with AML.
    • AML with inv(16)(p13.1;q22) or t(16;16)(p13.1;q22); : In leukemias with inv(16), the gene () at chromosome band 16q22 is fused with the gene at chromosome band 16p13. The inv(16) translocation is associated with the FAB M4Eo subtype. Inv(16) confers a favorable prognosis for both adults and children with AML, with a 5-year OS of about 85%. Inv(16) occurs in 7% to 9% of children with AML. As noted above, cases with and cases with have distinctive secondary mutations; secondary mutations are primarily restricted to genes that activate receptor tyrosine kinase signaling (, , and ).

    Both and subtypes commonly show mutations in genes that activate receptor tyrosine kinase signaling (e.g., , , and ); and are the most commonly mutated genes for both subtypes. mutations may indicate increased risk of treatment failure for patients with core-binding factor AML, although the prognostic significance of mutations may be dependent on the mutant-allele ratio (high ratio unfavorable) and/or the specific type of mutation (exon 17 mutations unfavorable). A study of children with AML observed mutations in 24% of cases (79% being exon 17 mutations) and mutations in 15%, but neither were significantly associated with outcome.

    Although both and fusion genes disrupt the activity of core-binding factor, cases with these genomic alterations have distinctive secondary mutations.

    • cases also have frequent mutations in genes regulating chromatin conformation (e.g., and ) (40% of cases) and genes encoding members of the cohesin complex (20% of cases). Mutations in and and mutations in members of the cohesin complex are rare in leukemias.
    • A study of 204 adults with AML found that mutations (present in 17% of cases) and or mutations (present in 25% of cases) lacked prognostic significance. Similar results, albeit with smaller numbers, were reported for children with AML and and mutations.
  • Acute promyelocytic leukemia (APL) with : APL represents about 7% of children with AML. 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 arsenic trioxide and the differentiating effects of all- retinoic acid. The t(15;17) translocation or other more complex chromosomal rearrangements may lead to the production of a fusion protein involving the retinoid acid receptor alpha and PML. The WHO 2016 revision does not include the t(15;17) cytogenetic designation to stress the significance of the fusion, which may be cryptic or result from complex karyotypic changes.

    Utilization of quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) for PML-RARA transcripts has become standard practice. Quantitative RT-PCR allows identification of the three common transcript variants and is used for monitoring response on treatment and early detection of molecular relapse. Other much less common translocations involving the retinoic acid receptor alpha can also result in APL (e.g., t(11;17)(q23;q21) involving the gene). Identification of cases with the t(11;17)(q23;q21) is important because of their decreased sensitivity to all- retinoic acid.

  • AML with mutated : 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. Immunohistochemical methods can be used to accurately identify patients with mutations by the demonstration of cytoplasmic localization of . Mutations in the NPM1 protein that diminish its nuclear localization are primarily associated with a subset of AML with a normal karyotype, absence of CD34 expression, and an improved prognosis in the absence of –internal tandem duplication () mutations in adults and younger adults.

    Studies of children with AML suggest a lower rate of occurrence of mutations in children compared with adults with normal cytogenetics. mutations occur in approximately 8% of pediatric patients with AML and are uncommon in children younger than 2 years. mutations are associated with a favorable prognosis in patients with AML characterized by a normal karyotype. For the pediatric population, conflicting reports have been published regarding the prognostic significance of an mutation when a - mutation is also present. One study reported that an mutation did not completely abrogate the poor prognosis associated with having a - mutation, but other studies showed no impact of a - mutation on the favorable prognosis associated with an mutation.

  • AML with biallelic mutations of : Mutations in the () gene occur in a subset of children and adults with cytogenetically normal AML. In adults younger than 60 years, approximately 15% of cytogenetically normal AML cases have mutations in . Outcomes for adults with AML with mutations appear to be relatively favorable and similar to that of patients with core-binding factor leukemias. Studies in adults with AML have demonstrated that double-mutant, but not single-mutant, AML is independently associated with a favorable prognosis, leading to the WHO 2016 revision that requires biallelic mutations for the disease definition.

    mutations occur in 5% to 8% of children with AML and have been preferentially found in the cytogenetically normal subtype of AML with FAB M1 or M2; 70% to 80% of pediatric patients have double-mutant alleles, which is predictive of a significantly improved survival, similar to the effect observed in adult studies. Although both double-mutant and single-mutant alleles of were associated with a favorable prognosis in children with AML in one large study, a second study observed inferior outcome for patients with single mutations. However, very low numbers of children with single-allele mutants were included in these two studies (only 13 total patients), which makes a conclusion regarding the prognostic significance of single-allele mutations in children premature. In newly diagnosed patients with double-mutant AML, germline screening should be considered in addition to usual family history queries, because 5% to 10% of these patients are reported to have a germline mutation.

  • Myeloid leukemia associated with Down syndrome ( mutations): mutations are present in most, if not all, Down syndrome children with either transient abnormal myelopoiesis (TAM) or acute megakaryoblastic leukemia (AMKL). mutations were also observed in 9% of non–Down syndrome children and 4% of adults with AMKL (with coexistence of amplification of the Down syndrome Critical Region on chromosome 21 in 9 of 10 cases). is a transcription factor that is required for normal development of erythroid cells, megakaryocytes, eosinophils, and mast cells.

    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.

Molecular abnormalities associated with an unfavorable prognosis

Molecular abnormalities associated with an unfavorable prognosis include the following:

  • Chromosomes 5 and 7: Chromosomal abnormalities associated with poor prognosis in adults with AML include those involving chromosome 5 (monosomy 5 and del(5q)) and chromosome 7 (monosomy 7). These cytogenetic subgroups represent approximately 2% and 4% of pediatric AML cases, respectively, and are also associated with poor prognosis in children.

    In the past, patients with del(7q) were also considered to be at high risk of treatment failure, and data from adults with AML support a poor prognosis for both del(7q) and monosomy 7. However, outcome for children with del(7q), but not monosomy 7, appears comparable to that of other children with AML. The presence of del(7q) does not abrogate the prognostic significance of favorable cytogenetic characteristics (e.g., inv(16) and t(8;21)).

    Chromosome 5 and 7 abnormalities appear to lack prognostic significance in AML patients with Down syndrome who are aged 4 years and younger.

  • AML with inv(3)(q21.3;q26.2) or t(3;3)(q21.3;q26.2); , : at chromosome 3q26 codes for two proteins, EVI1 and MDS1-EVI1, both of which are transcription regulators. The inv(3) and t(3;3) abnormalities lead to overexpression of EVI1 and to reduced expression of GATA2. These abnormalities are associated with poor prognosis in adults with AML, but are very uncommon in children (<1% of pediatric AML cases).

    Abnormalities involving can be detected in some AML cases with other 3q abnormalities and are also associated with poor prognosis.

  • mutations: Presence of a - mutation appears to be associated with poor prognosis in adults with AML, particularly when both alleles are mutated or there is a high ratio of the mutant allele to the normal allele. - mutations also convey a poor prognosis in children with AML. The frequency of - mutations in children is lower than that observed in adults, especially for children younger than 10 years, for whom 5% to 10% of cases have the mutation (compared with approximately 30% in adults). The prevalence of - is increased in certain genomic subtypes of pediatric AML, including those with the fusion gene, of which 80% to 90% have -. Approximately 15% of patients with - have -, and patients with both - and - have a poorer prognosis than do patients who have - without -.

    For APL, - and point mutations occur in 30% to 40% of children and adults. Presence of the - mutation is strongly associated with the microgranular variant (M3v) of APL and with hyperleukocytosis. It remains unclear whether mutations are associated with poorer prognosis in patients with APL who are treated with modern therapy that includes all- retinoic acid and arsenic trioxide.

    Activating point mutations of have also been identified in both adults and children with AML, although the clinical significance of these mutations is not clearly defined.

Other molecular abnormalities observed in pediatric AML

Other molecular abnormalities observed in pediatric AML include the following:

  • () gene rearrangements: gene rearrangement occurs in approximately 20% of children with AML. These cases, including most AMLs secondary to epipodophyllotoxin, are generally associated with monocytic differentiation (FAB M4 and M5). rearrangements are also reported in approximately 10% of FAB M7 (AMKL) patients (see below).

    The most common translocation, representing approximately 50% of -rearranged cases in the pediatric AML population, is t(9;11)(p22;q23), in which the gene is fused with gene. The WHO 2016 revision defined as a distinctive disease entity. However, more than 50 different fusion partners have been identified for the gene in patients with AML.

    The median age for 11q23/-rearranged cases in children is approximately 2 years, and most translocation subgroups have a median age at presentation of younger than 5 years. However, significantly older median ages are seen at presentation of pediatric cases with t(6;11)(q27;q23) (12 years) and t(11;17)(q23;q21) (9 years).

    Outcome for patients with de novo AML and gene rearrangement is generally reported as being similar to that for other patients with AML. However, as the gene can participate in translocations with many different fusion partners, the specific fusion partner appears to influence prognosis, as demonstrated by a large international retrospective study evaluating outcome for 756 children with 11q23- or -rearranged AML. For example, cases with t(1;11)(q21;q23), representing 3% of all 11q23/-rearranged AML, showed a highly favorable outcome, with a 5-year event-free survival (EFS) of 92%.

    While reports from single clinical trial groups have variably described more favorable prognosis for patients with AML who have t(9;11)(p21.3;q23.3)/, the international retrospective study did not confirm the favorable prognosis for this subgroup. An international collaboration evaluating pediatric AMKL patients observed that the presence of t(9;11), which was seen in approximately 5% of AMKL cases, was associated with an inferior outcome compared with other AMKL cases.

    -rearranged AML subgroups that appear to be associated with poor outcome include the following:

    • Cases with the t(10;11) translocation are a group at high risk of relapse in bone marrow and the CNS. Some cases with the t(10;11) translocation have fusion of the gene with the - at 10p12, while others have fusion of with at 10p11.2. An international retrospective study found that these cases, which present at a median age of approximately 1 year, have a 5-year EFS of 20% to 30%.
    • Patients with t(6;11)(q27;q23) have a poor outcome, with a 5-year EFS of 11%.
    • Patients with t(4;11)(q21;q23) also have a poor outcome, with a 5-year EFS of 29%.
    • A follow-up study by the international collaborative group demonstrated that additional cytogenetic abnormalities further influenced outcome of children with translocations, with complex karyotypes and trisomy 19 predicting poor outcome and trisomy 8 predicting a more favorable outcome.
  • AML with t(6;9)(p23;q34.1); : t(6;9) leads to the formation of a leukemia-associated fusion protein DEK-NUP214. This subgroup of AML has been associated with a poor prognosis in adults with AML, and occurs infrequently in children (less than 1% of AML cases). The median age of children with AML is 10 to 11 years, and approximately 40% of pediatric patients have -.

    t(6;9) AML appears to be associated with a high risk of treatment failure in children, particularly for those not proceeding to allogeneic stem cell transplantation.

  • Molecular subgroups of non–Down syndrome acute megakaryoblastic leukemia (AMKL): AMKL accounts for approximately 10% of pediatric AML and includes substantial heterogeneity at the molecular level. Molecular subtypes of AMKL are listed below.
    • : is a fusion resulting from a cryptic chromosome 16 inversion (inv(16)(p13.3q24.3)). It occurs almost exclusively in non–Down syndrome AMKL, representing 16% to 27% of pediatric AMKL and presenting with a median age of 1 year. It appears to be associated with unfavorable outcome, with EFS at 2 years less than 20% in two reports that included 28 patients.
    • -rearranged: Cases with translocations represent 10% to 17% of pediatric AMKL, with () being the most common fusion partner. -rearranged cases appear to be associated with inferior outcome among children with AMKL, with OS rates at 4 to 5 years of approximately 30%. An international collaboration evaluating pediatric AMKL observed that the presence of t(9;11)/, which was seen in approximately 5% of AMKL cases (n = 21), was associated with an inferior outcome (5-year OS, approximately 20%) compared with other AMKL cases and other -rearrangements (n = 17), each with a 5-year OS of 50% to 55%. Inferior outcome was not observed for patients (n = 17) with other -rearrangements.
    • : is observed in approximately 10% of pediatric AMKL cases and is observed at much lower rates in non-AMKL cases. cases showed a trend towards inferior prognosis, although the small number of cases studied limits confidence in this assessment.
    • : The t(1;22)(p13;q13) translocation that produces is uncommon (<1% of pediatric AML) and is restricted to acute megakaryocytic leukemia (AMKL). Studies have found that t(1;22)(p13;q13) is observed in 10% to 18% of children with AMKL who have evaluable cytogenetics or molecular genetics. Most AMKL cases with t(1;22) occur in infants, with the median age at presentation (4–7 months) being younger than that for other children with AMKL. Cases with detectable fusion transcripts in the absence of t(1;22) have also been reported because these young patients usually have hypoplastic bone marrow.

      An international collaborative retrospective study of 51 t(1;22) cases reported that patients with this abnormality had a 5-year EFS of 54.5% and an OS of 58.2%, similar to the rates for other children with AMKL. In another international retrospective analysis of 153 cases with non–Down syndrome AMKL who had samples available for molecular analysis, the 4-year EFS for patients with t(1;22) was 59% and OS was 70%, significantly better than AMKL patients with other specific genetic abnormalities (, , rearrangements, monosomy 7).

    • HOX-rearranged: Cases with a gene fusion involving a HOX cluster gene represented 15% of pediatric AMKL in one report. This report observed that these patients appear to have a relatively favorable prognosis, although the small number of cases studied limits confidence in this assessment.
    • mutated: -truncating mutations in non–Down syndrome AMKL arise in young children (median age, 1–2 years) and are associated with amplification of the Down syndrome critical region on chromosome 21. These patients represented approximately 10% of non–Down syndrome AMKL and appeared to have a favorable outcome if there were no prognostically unfavorable fusion genes also present, although the number of patients studied was small (n = 8).
  • t(8;16) (): The t(8;16) translocation fuses the gene on chromosome 8p11 to on chromosome 16p13. t(8;16) AML rarely occurs in children. In an international Berlin-Frankfurt-Münster (BFM) AML study of 62 children, presence of this translocation was associated with younger age at diagnosis (median, 1.2 years), FAB M4/M5 phenotype, erythrophagocytosis, leukemia cutis, and disseminated intravascular coagulation. Outcome for children with t(8;16) AML appears similar to other types of AML.

    A substantial proportion of infants diagnosed with t(8;16) AML in the first month of life show spontaneous remission, although AML recurrence may occur months to years later. These observations suggest that a policy could be considered in cases of t(8;16) AML diagnosed in the neonatal period if close long-term monitoring can be ensured.

  • t(7;12)(q36;p13): The t(7;12)(q36;p13) translocation involves on chromosome 12p13 and variable breakpoints on chromosome 7q36 in the region of (). The translocation may be cryptic by conventional karyotyping and in some cases may be confirmed only by FISH. This alteration occurs virtually exclusively in children younger than 2 years, is mutually exclusive with the () rearrangement, and is associated with a high risk of treatment failure.
  • gene fusions: has been reported to form leukemogenic gene fusions with more than 20 different partners. In the pediatric AML setting, the two most common fusion genes are and (), with the former observed in one report in approximately 15% of cytogenetically normal pediatric AML and the latter observed in approximately 10% of pediatric AMKL (see above). AML cases with either fusion gene show high expression of and genes, indicative of a stem cell phenotype.

    The fusion gene, which is often cytogenetically cryptic, results from the fusion of (chromosome 11p15) with (chromosome 5q35). This alteration occurs in approximately 4% to 7% of pediatric AML cases. The highest frequency in the pediatric population is in the 5- to 9-year age group (approximately 8%), with lower frequency in younger children (approximately 2% in children younger than 2 years). - cases present with high WBC count (median, 147 × 10/L in one study). Most AML cases do not show cytogenetic aberrations. A high percentage of cases (74% to 90%) have .

    A study that included 12 children with - AML reported that although all patients achieved CR, presence of independently predicted poor prognosis, and children with AML had a high risk of relapse, with a resulting 4-year EFS of approximately 10%. In another study that included children (n = 38) and adults (n = 7) with - AML, presence of both - and - independently predicted poor prognosis; patients with both lesions had a low CR rate (approximately 30%) and a low 3-year EFS rate (approximately 15%).

  • mutations: Although mutations in have been identified in 20% to 25% of patients with AML, the prognostic significance of these mutations has not been clearly shown. Mutations in are observed more commonly than mutations in in pediatric AML cases. mutations occur with similar frequency for all Type II alteration subtypes, with the exception of APL, for which mutations are seldom observed.
  • mutations: Mutations in occur in approximately 5% of AML, but in 10% to 40% of AML with core-binding factor abnormalities.

    The presence of activating mutations in adults with this AML subtype appears to be associated with a poorer prognosis compared with core-binding factor AML without mutations. The prognostic significance of mutations occurring in pediatric core-binding factor AML remains unclear, although the largest pediatric study reported to date observed no prognostic significance for mutations.

  • mutations: WT1, a zinc-finger protein regulating gene transcription, is mutated in approximately 10% of cytogenetically normal cases of AML in adults. The mutation has been shown in some, but not all studies to be an independent predictor of worse disease-free survival, EFS, and OS of adults.

    In children with AML, mutations are observed in approximately 10% of cases. Cases with mutations are enriched among children with normal cytogenetics and -, but are less common among children younger than 3 years. AML cases with are enriched for both - and mutations. In univariate analyses, mutations are predictive of poorer outcome in pediatric patients, but the independent prognostic significance of mutation status is unclear because of its strong association with - and its association with . The largest study of mutations in children with AML observed that children with mutations in the absence of - had outcomes similar to that of children without mutations, while children with both mutation and - had survival rates less than 20%.

  • mutations: Mutations of the () gene have been identified in approximately 20% of adult AML patients and are uncommon in patients with favorable cytogenetics but occur in one-third of adult patients with intermediate-risk cytogenetics. Mutations in this gene are independently associated with poor outcome. mutations are virtually absent in children.
  • and mutations: Mutations in and , which code for isocitrate dehydrogenase, occur in approximately 20% of adults with AML, and they are enriched in patients with mutations. The specific mutations that occur in and create a novel enzymatic activity that promotes conversion of alpha-ketoglutarate to 2-hydroxyglutarate. This novel activity appears to induce a DNA hypermethylation phenotype similar to that observed in AML cases with loss of function mutations in .

    Mutations in and are rare in pediatric AML, occurring in 0% to 4% of cases. There is no indication of a negative prognostic effect for and mutations in children with AML.

  • mutations: is the gene encoding the granulocyte colony-stimulating factor (G-CSF) receptor, and activating mutations in are observed in 2% to 3% of pediatric AML cases. These mutations lead to enhanced signaling through the G-CSF receptor, and they are primarily observed in AML with either mutations or with core-binding factor abnormalities ( and ). The clinical characteristics of and prognosis for patients with mutations do not seem to be significantly different from those of patients without mutations.

    Activating mutations in are also observed in patients with severe congenital neutropenia. These mutations are not the cause of severe congenital neutropenia, but rather arise as somatic mutations and can represent an early step in the pathway to AML. In one study of patients with severe congenital neutropenia, 34% of patients who had not developed a myeloid malignancy had mutations detectable in peripheral blood neutrophils and mononuclear cells, while 78% of patients who had developed a myeloid malignancy showed mutations. A study of 31 patients with severe congenital neutropenia who developed AML or MDS observed mutations in approximately 80%, and also observed a high frequency of mutations (approximately 60%), suggesting cooperation between and mutations for leukemia development within the context of severe congenital neutropenia.

Treatment Option Overview for Childhood AML

Leukemia is considered to be disseminated in the hematopoietic system at diagnosis, even in children with acute myeloid leukemia (AML) who present with isolated chloromas (also called granulocytic or myeloid sarcomas). If these children do not receive systemic chemotherapy, they invariably develop AML in months or years. AML may invade nonhematopoietic (extramedullary) tissue such as meninges, brain parenchyma, testes or ovaries, or skin (leukemia cutis). Extramedullary leukemia is more common in infants than in older children with AML.

Childhood AML is diagnosed when bone marrow has 20% or greater blasts. The blasts have the morphologic and histochemical characteristics of one of the French-American-British (FAB) subtypes of AML. It can also be diagnosed by biopsy of a chloroma. For treatment purposes, patients with clonal cytogenetic abnormalities typically associated with AML, such as t(8;21)(), inv(16)(), t(9;11)() or t(15;17)() and who have less than 20% bone marrow blasts, are considered to have AML rather than a myelodysplastic syndrome.

Complete remission (CR) has traditionally been defined in the United States using morphologic criteria such as the following:

  • Peripheral blood counts (white blood cell [WBC] count, differential [absolute neutrophil count >1,000/μL], and platelet count >100,000/μL) rising toward normal.
  • Mildly hypocellular to normal cellular marrow with fewer than 5% blasts.
  • No clinical signs or symptoms of the disease, including in the central nervous system (CNS) or at other extramedullary sites.

Alternative definitions of remission using morphology are used in AML because of the prolonged myelosuppression caused by intensive chemotherapy and include CR with incomplete platelet recovery and CR with incomplete marrow recovery (typically absolute neutrophil count). Whereas the use of incomplete platelet recovery provides a clinically meaningful response, the traditional CR definition remains the gold standard because patients in CR were found to be more likely to survive longer than those in incomplete platelet recovery.

Achieving a hypoplastic bone marrow (using morphology) is usually the first step in obtaining remission in AML with the exception of the M3 subtype (acute promyelocytic leukemia [APL]); a hypoplastic marrow phase is often not necessary before the achievement of remission in APL. Additionally, early recovery marrows in any of the subtypes of AML may be difficult to distinguish from persistent leukemia, although the application of flow cytometric immunophenotyping and cytogenetic/molecular testing have made this less problematic. Correlation with blood cell counts and clinical status is imperative in passing final judgment on the results of early bone marrow findings in AML. If the findings are in doubt, the bone marrow aspirate should be repeated in 1 to 2 weeks.

In addition to morphology, more precise methodology (e.g., multiparameter flow cytometry or quantitative reverse transcriptase–polymerase chain reaction [RT-PCR]) is used to assess response and has been shown to be of greater prognostic significance than morphology. (Refer to the Prognostic Factors in Childhood AML section of this summary for more information about these methodologies.)

Treatment Approach

The mainstay of the therapeutic approach is systemically administered combination chemotherapy. Approaches involving risk-group stratification and biologically targeted therapies are being tested to improve antileukemic treatment while sparing normal tissue. Optimal treatment of AML requires control of bone marrow and systemic disease. Treatment of the CNS, usually with intrathecal medication, is a component of most pediatric AML protocols but has not yet been shown to contribute directly to an improvement in survival. CNS irradiation is not necessary in patients, either as prophylaxis or for those presenting with cerebrospinal fluid leukemia that clears with intrathecal and systemic chemotherapy.

Treatment is ordinarily divided into the following two phases:

  • Induction (to induce remission).
  • Postremission consolidation/intensification (to reduce the risk of relapse).

Postremission therapy may consist of varying numbers of courses of intensive chemotherapy and/or allogeneic hematopoietic stem cell transplantation (HSCT). For example, ongoing trials of the Children’s Oncology Group (COG) and the United Kingdom Medical Research Council (MRC) use similar chemotherapy regimens consisting of two courses of induction chemotherapy followed by two to three additional courses of intensification chemotherapy.

Maintenance therapy is not part of most pediatric AML protocols because two randomized clinical trials failed to show a benefit for maintenance therapy when given after modern intensive chemotherapy. The exception to this generalization is made for APL, because maintenance therapy was shown to improve event-free survival (EFS) and overall survival (OS) when all- retinoic acid (ATRA) was combined with chemotherapy. Some studies of adult APL patients, including studies incorporating arsenic trioxide treatment, have shown no benefit to maintenance.

Attention to both acute and long-term complications is critical in children with AML. Modern AML treatment approaches are usually associated with severe, protracted myelosuppression with related complications. Children with AML should receive care under the direction of pediatric oncologists in cancer centers or hospitals with appropriate supportive care facilities (e.g., specialized blood products; pediatric intensive care; provision of emotional and developmental support). With improved supportive care, toxic death constitutes a smaller proportion of initial therapy failures than in the past. The most recent COG trials reported an 11% to 13% incidence of remission failure because of resistant disease and only 2% to 3% resulted from toxic death during the two induction courses.

Children treated for AML are living longer and require close monitoring for cancer therapy side effects that may persist or develop months or years after treatment. The high cumulative doses of anthracyclines require long-term monitoring of cardiac function. The use of some modalities have declined, including total-body irradiation with HSCT because of its increased risk of growth failure, gonadal and thyroid dysfunction, cataract formation, and second malignancies. (Refer to the Survivorship and Adverse Late Sequelae section of this summary or to the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)

Prognostic Factors in Childhood AML

Prognostic factors in childhood AML can be categorized as follows:

  • Host risk factors.
  • Leukemia risk factors.
  • Therapeutic response risk factors.

Host risk factors

  • Age: Several reports published since 2000 have identified older age as an adverse prognostic factor. The age effect is not large with regard to overall survival, but there is consistency in the observation that any adverse outcomes seen in adolescents compared with younger children are primarily caused by increases in toxic mortality.

    While outcome for infants with ALL remains inferior to that of older children, outcome for infants with AML is similar to that of older children when they are treated with standard AML regimens. Infants have been reported to have a 5-year survival of 60% to 70%, although with increased treatment-associated toxicity, particularly during induction.

  • Race/Ethnicity: In both the Children's Cancer Group (CCG) CCG-2891 and COG-2961 (NCT00002798) studies, Caucasian children had higher OS rates than African American and Hispanic children. A trend for lower survival rates for African American children compared with Caucasian children was also observed in children treated on St. Jude Children’s Research Hospital AML clinical trials.
  • Down syndrome: For children with Down syndrome who develop AML, survival is generally favorable. The prognosis is particularly good (event-free survival exceeding 80%) for children younger than 4 years at diagnosis, the age group that accounts for the vast majority of Down syndrome patients with AML.
  • Body mass index: In the COG-2961 (NCT00002798) study, obesity (body mass index more than 95th percentile for age) was predictive of inferior survival. Inferior survival was attributable to early treatment-related mortality that was primarily caused by infectious complications. Obesity has been associated with inferior survival in children with AML, primarily caused by a higher rate of fatal infections during the early phases of treatment.

Leukemia risk factors

  • White blood cell (WBC) count: WBC count at diagnosis has been consistently noted to be inversely related to survival. Patients with high presenting leukocyte counts have a higher risk of developing pulmonary and CNS complications and have a higher risk of induction death.

    In APL, WBC at initial diagnosis alone is used to distinguish standard-risk and high-risk APL. A WBC count of 10,000 cells/μL or more denotes high risk, and these patients have an increased risk of both early death and relapse.

  • FAB subtype: Associations between FAB subtype and prognosis have been more variable.
    • M3 subtype. The M3 (APL) subtype has a favorable outcome in studies using ATRA in combination with chemotherapy and arsenic trioxide consolidation.
    • M7 subtype. Some studies have indicated a relatively poor outcome for M7 (megakaryocytic leukemia) in patients without Down syndrome, although reports suggest an intermediate prognosis for this group of patients when contemporary treatment approaches are used.

      In a retrospective study of non–Down syndrome M7 patients with samples available for molecular analysis, the presence of specific genetic abnormalities ( [cryptic inv(16)(p13q24)], [], t(11;12)(p15;p13), [] rearrangements, monosomy 7) was associated with a significantly worse outcome than for other M7 patients. By contrast, the 10% of non–Down syndrome AMKL patients with mutations appeared to have a favorable outcome if there were no prognostically unfavorable fusion genes also present, as did patients with -rearrangement.

    • M0 subtype. The M0, or minimally differentiated subtype, has been associated with a poor outcome.
  • CNS disease: CNS involvement at diagnosis is categorized on the basis of the presence or absence of blasts in cerebrospinal fluid (CSF), as follows:
    • CSF negative for blasts on cytospin, regardless of CSF WBC count.
    • CSF with fewer than five WBC/μL and cytospin positive for blasts.
    • CSF with five or more WBC/μL and cytospin positive for blasts in an atraumatic (<100 RBC/μL) or a traumatic tap in which the WBC/RBC ratio in the CSF is more than or equal to twice the ratio in the peripheral blood. CNS3 disease also includes patients with clinical signs of CNS leukemia (e.g., cranial nerve palsy, brain/eye involvement, or radiographic evidence of an intracranial, intradural chloroma).

      CNS2 disease has been observed in approximately 13% to 16% of children with AML and CNS3 disease in 11% to 17% of children with AML. Studies have variably shown that patients with CNS2/CNS3 were younger, more often had hyperleukocytosis, and had higher incidences of t(9;11), t(8;21), or inv(16).

      While CNS involvement (CNS2 or CNS3) at diagnosis has not been shown to be correlated with OS in most studies, a COG analysis of children with AML enrolled from 2003 to 2010 on two consecutive and identical backbone trials found that CNS involvement, especially CNS3 status, was associated with inferior outcomes, including complete remission rate, EFS, disease-free survival, and an increased risk of relapse involving the CNS. Another trial showed it to be associated with an increased risk of isolated CNS relapse. Finally, the COG study did not find an adverse impact of traumatic lumbar punctures at diagnosis upon eventual outcome.

  • Cytogenetic and molecular characteristics: Cytogenetic and molecular characteristics are also associated with prognosis. (Refer to the Cytogenetic evaluation and molecular abnormalities subsection in the Classification of Pediatric Myeloid Malignancies section of this summary for detailed information.) Cytogenetic and molecular characteristics that are currently used in the COG clinical trials for treatment assignment include the following:
    • : inv(16)/t(16;16) and t(8;21), t(15;17), biallelic mutations, and mutations.
    • : monosomy 7, monosomy 5/del(5q), 3q abnormalities, and - with high-allelic ratio.

Therapeutic response risk factors

  • Response to therapy/minimal residual disease (MRD): Early response to therapy, generally measured after the first course of induction therapy, is predictive of outcome and can be assessed by standard morphologic examination of bone marrow, cytogenetic analysis, fluorescence hybridization, or more sophisticated techniques to identify MRD (e.g., multiparameter flow cytometry, quantitative RT-PCR). Multiple groups have shown that the level of MRD after one course of induction therapy is an independent predictor of prognosis.

    Molecular approaches to assessing MRD in AML (e.g., using quantitative RT-PCR) have been challenging to apply because of the genomic heterogeneity of pediatric AML and the instability of some genomic alterations. Quantitative RT-PCR detection of () fusion transcripts can effectively predict higher risk of relapse for patients in clinical remission. Other molecular alterations such as mutations and fusion transcripts have also been successfully employed as leukemia-specific molecular markers in MRD assays, and for these alterations, the level of MRD has shown prognostic significance. The presence of - has been shown to be discordant between diagnosis and relapse, although when its presence persists (usually associated with a high-allelic ratio at diagnosis), it can be useful in detecting residual leukemia.

    For APL, MRD detection at the end of induction therapy lacks prognostic significance, likely related to the delayed clearance of differentiating leukemic cells destined to eventually die. However, the kinetics of molecular remission after completion of induction therapy is prognostic, with the persistence of minimal disease after three courses of therapy portending increased risk of relapse.

    Flow cytometric methods have been used for MRD detection and can detect leukemic blasts based on the expression of aberrant surface antigens that differ from the pattern observed in normal progenitors. A CCG study of 252 pediatric patients with AML in morphologic remission demonstrated that MRD as assessed by flow cytometry was the strongest prognostic factor predicting outcome in a multivariate analysis. Other reports have confirmed both the utility of flow cytometric methods for MRD detection in the pediatric AML setting and the prognostic significance of MRD at various time points after treatment initiation.

Risk Classification Systems

Risk classification for treatment assignment has been used by several cooperative groups performing clinical trials in children with AML. In the COG, stratifying therapeutic choices on the basis of risk factors is a relatively recent approach for the non-APL, non–Down syndrome patient. Classification is most directly derived from the observations of the MRC AML 10 trial for EFS and OS and further applied based on the ability of the pediatric patient to undergo reinduction and obtain a second complete remission and their subsequent OS after first relapse.

The following COG trials have used a risk classification system to stratify treatment choices:

The high-risk group of patients are guided to transplantation in first remission with the most appropriate available donor. Patients in the low-risk group are instructed to pursue transplantation if they relapse. Validation of this approach awaits analysis.

Risk factors used for stratification vary by pediatric and adult cooperative clinical trial groups and the prognostic impact of a given risk factor may vary in their significance depending on the backbone of therapy used. Other pediatric cooperative groups use some or all of these same factors, generally choosing risk factors that have been reproducible across numerous trials and sometimes including additional risk factors previously used in their risk group stratification approach.

Treatment of Childhood AML

The general principles of therapy for children and adolescents with acute myeloid leukemia (AML) are discussed below, followed by a more specific discussion of the treatment of children with Down syndrome and acute promyelocytic leukemia (APL).

Overall survival (OS) rates have improved over the past three decades for children with AML, with 5-year survival rates now in the 55% to 65% range. Overall remission-induction rates are approximately 85% to 90%, and event-free survival (EFS) rates from the time of diagnosis are in the 45% to 55% range. There is, however, a wide range in outcome for different biological subtypes of AML (refer to the Cytogenetic Evaluation and Molecular Abnormalities and Risk classification systems under clinical evaluation sections of this summary for more information); after taking specific biological factors of their leukemia into account, the predicted outcome for any individual patient may be much better or much worse than the overall outcome for the general population of children with AML.

Induction Therapy

Contemporary pediatric AML protocols result in 85% to 90% complete remission (CR) rates. Approximately 2% to 3% of patients die during the induction phase, most often caused by treatment-related complications. To achieve a CR, inducing profound bone marrow aplasia (with the exception of the M3 APL subtype) is usually necessary with currently used combination-chemotherapy regimens. Because induction chemotherapy produces severe myelosuppression, morbidity and mortality from infection or hemorrhage during the induction period may be significant.

Treatment options for children with AML during the induction phase may include the following:


The two most effective and essential drugs used to induce remission in children with AML are cytarabine and an anthracycline. Commonly used pediatric induction therapy regimens use cytarabine and an anthracycline in combination with other agents such as etoposide and/or thioguanine.

Evidence (induction chemotherapy regimen):

The anthracycline that has been most used in induction regimens for children with AML is daunorubicin, although idarubicin and the anthracenedione mitoxantrone have also been used. Randomized trials have attempted to determine whether any other anthracycline or anthracenedione is superior to daunorubicin as a component of induction therapy for children with AML. In the absence of convincing data that another anthracycline or mitoxantrone produces superior outcome over daunorubicin when given at an equitoxic dose, daunorubicin remains the anthracycline most commonly used during induction therapy for children with AML in the United States.

Evidence (anthracycline):

The intensity of induction therapy influences the overall outcome of therapy. The CCG-2891 study demonstrated that intensively timed induction therapy (4-day treatment courses separated by only 6 days) produced better EFS than standard-timing induction therapy (4-day treatment courses separated by 2 weeks or longer). The MRC has intensified induction therapy by prolonging the duration of cytarabine treatment to 10 days.

In adults, another method of intensifying induction therapy is to use high-dose cytarabine. While studies in nonelderly adults suggest an advantage for intensifying induction therapy with high-dose cytarabine (2–3 g/m/dose) compared with standard-dose cytarabine, a benefit for the use of high-dose cytarabine compared with standard-dose cytarabine in children was not observed using a cytarabine dose of 1 g/m given twice daily for 7 days with daunorubicin and thioguanine. A second pediatric study also failed to detect a benefit for high-dose cytarabine over standard-dose cytarabine when used during induction therapy.

Gemtuzumab ozogamicin

Because further intensification of induction regimens has increased toxicity with little improvement in EFS or OS, alternative approaches, such as the use of gemtuzumab ozogamicin, have been examined.

Evidence (gemtuzumab ozogamicin):

Supportive care

In children with AML receiving modern intensive therapy, the estimated incidence of severe bacterial infections is 50% to 60%, and the estimated incidence of invasive fungal infections is 7.0% to 12.5%. Several approaches have been examined in terms of reducing the morbidity and mortality from infection in children with AML.

Hematopoietic growth factors

Hematopoietic growth factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor (G-CSF) during AML induction therapy have been evaluated in multiple placebo-controlled studies in adults with AML in attempts to reduce the toxicity associated with prolonged myelosuppression. These studies have generally shown a reduction in the duration of neutropenia of several days with the use of either G-CSF or GM-CSF but have not shown significant effects on treatment-related mortality or OS. (Refer to the Treatment Option Overview for AML section in the PDQ summary on Adult Acute Myeloid Leukemia Treatment for more information.)

Routine prophylactic use of hematopoietic growth factors is not recommended for children with AML.

Evidence (hematopoietic growth factors):

Antimicrobial prophylaxis

The use of antibacterial prophylaxis in children undergoing treatment for AML has been supported by several studies. While studies suggest a benefit to the use of antibiotic prophylaxis, prospective randomized trials are needed in this pediatric group of patients.

Evidence (antimicrobial prophylaxis):

Antifungal prophylaxis

The role of antifungal prophylaxis has not been studied in children with AML using randomized, prospective studies.

Evidence (antifungal prophylaxis):


Hospitalization until adequate granulocyte (absolute neutrophil or phagocyte count) recovery has been used to reduce treatment-related mortality. The COG-2961 (NCT00002798) trial was the first to note a significant reduction in treatment-related mortality (19% before mandatory hospitalization was instituted in the trial along with other supportive care changes vs. 12% afterward); OS was also improved in this trial ( <.001). Another analysis of the impact of hospitalization using a survey of institutional routine practice found that those who mandated hospitalization had nonsignificant reduction in patients' treatment-related mortality (adjusted hazard ratio [HR], 0.60 [0.26–1.36, = .22]) compared with institutions who had no set policy. Although there was no significant benefit seen in this study, the authors noted the limitations, including its methodology (survey), an inability to validate cases, and limited power to detect differences in treatment-related mortality. To avoid prolonged hospitalizations until count recovery, some institutions have used outpatient IV antibiotic prophylaxis effectively.

Induction failure (refractory AML)

Induction failure (the morphologic presence of 5% or greater marrow blasts at the end of all induction courses) is seen in 10% to 15% of children with AML. Subsequent outcomes for patients with induction failure are similar to those for patients with AML who relapse early (<12 months after remission).

Granulocytic sarcoma/chloroma

Granulocytic sarcoma (chloroma) describes extramedullary collections of leukemia cells. These collections can occur, albeit rarely, as the sole evidence of leukemia. In a review of three AML studies conducted by the former Children's Cancer Group, fewer than 1% of patients had isolated granulocytic sarcoma, and 11% had granulocytic sarcoma along with marrow disease at the time of diagnosis. This incidence was also seen in the NOPHO-AML 2004 (NCT00476541) trial.

Importantly, the patient who presents with an isolated tumor, without evidence of marrow involvement, must be treated as if there is systemic disease. Patients with isolated granulocytic sarcoma have a good prognosis if treated with current AML therapy.

In a study of 1,459 children with newly diagnosed AML, patients with orbital granulocytic sarcoma and central nervous system (CNS) granulocytic sarcoma had better survival than did patients with marrow disease and granulocytic sarcoma at other sites and AML patients without any extramedullary disease. Most patients with orbital granulocytic sarcoma have a t(8;21) abnormality, which has been associated with a favorable prognosis. The use of radiation therapy does not improve survival in patients with granulocytic sarcoma who have a complete response to chemotherapy, but may be necessary if the site(s) of granulocytic sarcoma do not show complete response to chemotherapy or for disease that recurs locally.

Central Nervous System (CNS) Prophylaxis for AML

CNS involvement by AML and its impact on prognosis has been discussed above in the Prognostic Factors in Childhood AML section of this summary. Therapy with either radiation or intrathecal chemotherapy has been used to treat CNS leukemia present at diagnosis and to prevent later development of CNS leukemia. The use of radiation has essentially been abandoned as a means of prophylaxis because of the lack of documented benefit and long-term sequelae. The COG has used single-agent cytarabine for both CNS prophylaxis and therapy. Other groups have attempted to prevent CNS relapse by using additional intrathecal agents.

Evidence (CNS prophylaxis):

Postremission Therapy for AML

A major challenge in the treatment of children with AML is to prolong the duration of the initial remission with additional chemotherapy or hematopoietic stem cell transplantation (HSCT).

Treatment options for children with AML in postremission may include the following:


Postremission chemotherapy includes some of the drugs used in induction while also introducing non–cross-resistant drugs and, commonly, high-dose cytarabine. Studies in adults with AML have demonstrated that consolidation with a high-dose cytarabine regimen improves outcome compared with consolidation with a standard-dose cytarabine regimen, particularly in patients with inv(16) and t(8;21) AML subtypes. (Refer to the Adult AML in Remission section in the PDQ summary on Adult Acute Myeloid Leukemia Treatment for more information.) Randomized studies evaluating the contribution of high-dose cytarabine to postremission therapy have not been conducted in children, but studies employing historical controls suggest that consolidation with a high-dose cytarabine regimen improves outcome compared with less intensive consolidation therapies.

The optimal number of postremission courses of therapy remains unclear, but appears to require at least three courses of intensive therapy inclusive of the induction course.

Evidence (number of postremission courses of chemotherapy):


The use of HSCT in first remission has been under evaluation since the late 1970s, and evidence-based appraisals concerning indications for autologous and allogeneic HSCT have been published. Prospective trials of transplantation in children with AML suggest that overall, 60% to 70% of children with HLA-matched donors available who undergo allogeneic HSCT during their first remission experience long-term remissions, with the caveat that outcome after allogeneic HSCT is dependent on risk-classification status.

In prospective trials of allogeneic HSCT compared with chemotherapy and/or autologous HSCT, a superior DFS has been observed for patients who were assigned to allogeneic transplantation based on availability of a family 6/6 or 5/6 HLA-matched donor in adults and children. However, the superiority of allogeneic HSCT over chemotherapy has not always been observed. Several large cooperative group clinical trials for children with AML have found no benefit for autologous HSCT over intensive chemotherapy.

Current application of allogeneic HSCT involves incorporation of risk classification to determine whether transplantation should be pursued in first remission. Because of the improved outcome in patients with favorable prognostic features ( cytogenetic or molecular mutations) receiving contemporary chemotherapy regimens and the lack of demonstrable superiority for HSCT in this patient population, this group of patients typically receives matched-family donor (MFD) HSCT only after first relapse and the achievement of a second CR.

There is conflicting evidence regarding the role of allogeneic HSCT in first remission for patients with characteristics (neither low-risk or high-risk cytogenetics or molecular mutations):

Evidence (allogeneic HSCT in first remission for patients with intermediate-risk AML):

Given the improved outcome for patients with intermediate-risk AML in recent clinical trials and the burden of acute and chronic toxicities associated with allogeneic transplantation, many childhood AML treatment groups (including the COG) employ chemotherapy for intermediate-risk patients in first remission and reserve allogeneic HSCT for use after potential relapse.

There are conflicting data regarding the role of allogeneic HSCT in first remission for patients with disease, complicated by the differing definitions of high risk used by different study groups.

Evidence (allogeneic HSCT in first remission for patients with high-risk AML):

Many, but not all, pediatric clinical trial groups prescribe allogeneic HSCT for high-risk patients in first remission. For example, the COG frontline AML clinical trial () prescribes allogeneic HSCT in first remission only for patients with predicted high risk of treatment failure based on unfavorable cytogenetic and molecular characteristics and elevated end-of-induction MRD levels. On the other hand, the AML-BFM trials restrict allogeneic HSCT to patients in second CR and to refractory AML. This was based on results from their AML-BFM 98 study, which found no improvement in DFS or OS for high-risk patients receiving allogeneic HSCT in first CR, as well as the successful treatment using HSCT for a substantial proportion of patients who achieved a second CR. Additionally, late sequelae (e.g., cardiomyopathy, skeletal anomalies, and liver dysfunction or cirrhosis) were increased for children undergoing allogeneic HSCT in first remission on the AML-BFM 98 study.

Because definitions of high-, intermediate-, and low-risk AML are evolving because of the ongoing association of molecular characteristics of the tumor with outcome (e.g., internal tandem duplications, mutations, and mutations) and response to therapy (e.g., MRD assessments postinduction therapy), further analysis of subpopulations of patients treated with allogeneic HSCT will be an ongoing need in current and future clinical trials.

If transplant is chosen in first CR, the optimal preparative regimen and source of donor cells has not been determined, although alternative donor sources, including haploidentical donors, are being studied. There are no data that suggest total-body irradiation (TBI) is superior to busulfan-based myeloablative regimens.

Evidence (myeloablative regimen):

Other than the APL subtype, there are no data that demonstrate that maintenance therapy given after intensive postremission therapy significantly prolongs remission duration. Maintenance chemotherapy failed to show benefit in two randomized studies that used modern intensive consolidation therapy, and maintenance therapy with interleukin-2 also proved ineffective.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Recurrent or Refractory Childhood AML and Other Myeloid Malignancies

The diagnosis of recurrent or relapsed AML according to COG criteria is essentially the same as the criteria for making the diagnosis of AML. Usually this is defined as patients having more than 5% bone marrow blasts who were in previous remission after therapy for a diagnosis of AML according to World Health Organization (WHO) classification criteria.

Despite second remission induction in over one-half of children with AML treated with drugs similar to drugs used in initial induction therapy, the prognosis for a child with recurrent or progressive AML is generally poor.

Recurrent childhood AML

Approximately 50% to 60% of relapses occur within the first year after diagnosis, with most relapses occurring by 4 years from diagnosis. The vast majority of relapses occur in the bone marrow, and CNS relapse is very uncommon.

Prognosis and prognostic factors

Factors affecting the ability to attain a second remission include the following:

  • Length of first remission. Length of first remission is an important factor affecting the ability to attain a second remission; children with a first remission of less than 1 year have substantially lower rates of second remission (50%–60%) than children whose first remission is greater than 1 year (70%–90%). Survival for children with shorter first remissions is also substantially lower (approximately 10%) than that for children with first remissions exceeding 1 year (approximately 40%). The Therapeutic Advances in Childhood Leukemia and Lymphoma Consortium also identified duration of previous remission as a powerful prognostic factor, with 5-year OS rates of 54% ± 10% for patients with greater than 12 months first remission duration and 19% ± 6% for patients with shorter periods of first remission. In this same analysis, outcomes, primarily in early relapsing patients, declined with each attempt to reinduce remission (56% ± 5%, 25% ± 8%, and 17% ± 7% for each consecutive attempt).
  • Molecular alterations. In addition, specific molecular alterations at the time of relapse have been reported to impact subsequent survival. For instance, the presence of either or mutations at first relapse were associated, as independent risk factors, with worse OS in patients achieving a second remission.

Additional prognostic factors were identified in the following studies:

  • In a report of 379 children with AML who relapsed after initial treatment on the German BFM group protocols, a second complete remission rate was 63% and OS was 23%.[] The most significant prognostic factors associated with a favorable outcome after relapse included achieving second complete remission, a relapse greater than 12 months from initial diagnosis, no allogeneic bone marrow transplant in first remission, and favorable cytogenetics (t(8;21), t(15;17), and inv(16)).
  • The international Relapsed AML 2001/01 (NCT00186966) trial also found that early response to salvage therapy was highly prognostic.[]
  • A retrospective study of 71 patients with relapsed AML from Japan reported a 5-year OS rate of 37%. Patients who had an early relapse had a 27% second remission rate compared with 88% for patients who had a late relapse. The 5-year OS rate was higher in patients who underwent HSCT after achieving a second complete remission (66%) than in patients not in remission (17%).
  • Patients who relapsed on two consecutive Nordic Society of Pediatric Hematology and Oncology (NOPHO) AML trials between 1993 to 2012 were analyzed for survival (208 patients relapsed of 543 children initially treated). Second remissions were achieved in 146 children (70%) with a variety of reinduction regimens. Five-year OS was 39%. Favorable prognostic factors included late relapse (≥1 year from diagnosis), no HSCT in first remission, and a core-binding factor AML subtype. For the 128 children who underwent HSCT, the 5-year OS was 61%, as opposed to a 5-year OS of 21% for those who did not include HSCT in their therapy.

Treatment of recurrent AML

Treatment options for children with recurrent AML may include the following:

Regimens that have been successfully used to induce remission in children with recurrent AML have commonly included high-dose cytarabine given in combination with the following agents:

  • Mitoxantrone.
  • Fludarabine and idarubicin.
  • L-asparaginase.
  • Etoposide.
  • Liposomal daunorubicin. A study by the international BFM group compared fludarabine, cytarabine, and G-CSF (FLAG) with FLAG plus liposomal daunorubicin. Four-year OS was 38%, with no difference in survival for the total group; however, the addition of liposomal daunorubicin increased the likelihood of obtaining a remission and led to significant improvement in OS in patients with core-binding factor mutations (82%, FLAG plus liposomal daunorubicin vs. 58%, FLAG; = .04).[]

Regimens built upon clofarabine have also been used;[] as have regimens of 2-chloroadenosine. The COG AAML0523 (NCT00372619) trial evaluated the combination of clofarabine plus high-dose cytarabine in patients with relapsed AML; the response rate was 48% and the OS rate, with 21 of 23 responders undergoing HSCT, was 46%. MRD before HSCT was a strong predictor of survival.[]

The standard-dose cytarabine regimens used in the United Kingdom MRC AML10 study for newly diagnosed children with AML (cytarabine and daunorubicin plus either etoposide or thioguanine) have, when used in the setting of relapse, produced remission rates similar to those achieved with high-dose cytarabine regimens. In a COG phase II study, the addition of bortezomib to idarubicin plus low-dose cytarabine resulted in an overall CR rate of 57%, and the addition of bortezomib to etoposide and high-dose cytarabine resulted in an overall CR rate of 48%.

The selection of additional treatment after the achievement of a second complete remission depends on previous treatment and individual considerations. Consolidation chemotherapy followed by HSCT is conventionally recommended, although there are no controlled prospective data regarding the contribution of additional courses of therapy once a second complete remission is obtained.

Evidence (HSCT after second complete remission):

There is evidence that long-term survival can be achieved in a portion of pediatric patients who undergo a second transplant subsequent to relapse after a first myeloablative transplant. Survival was associated with late relapse (>6 months from first transplant), achievement of complete response before the second procedure, and use of a TBI-based regimen (after receiving a non-TBI regimen for the first procedure). A large prospective cohort study that included children and adults with myeloid diseases showed comparable or superior outcome with busulfan-based regimens compared with TBI.

CNS relapse

Isolated CNS relapse occurs in 3% to 6% of pediatric AML patients. Factors associated with an increased risk of isolated CNS relapse include the following:

  • Age younger than 2 years at initial diagnosis.
  • M5 leukemia.
  • 11q23 abnormalities.
  • CNS2 or CNS3 involvement at initial diagnosis.

The risk of CNS relapse increases with increasing CNS leukemic involvement at initial AML diagnosis (CNS1: 0.6%, CNS2: 2.6%, CNS3: 5.8% incidence of isolated CNS relapse, < .001; multivariate HR for CNS3: 7.82, = .0003). The outcome of isolated CNS relapse when treated as a systemic relapse is similar to that of bone marrow relapse. In one study, the 8-year OS for a cohort of children with an isolated CNS relapse was 26% ± 16%. CNS relapse may also occur in the setting of bone marrow relapse and its likelihood increases with CNS involvement at diagnosis (CNS1: 2.7%, CNS2: 8.5%, CNS3: 9.2% incidence of concurrent CNS relapse, < .001).

Refractory childhood AML (induction failure)

Treatment options for children with refractory AML may include the following:

Like patients with relapsed AML, induction failure patients are typically directed towards HSCT once they attain a remission, because studies suggest a better EFS than in patients treated with chemotherapy only (31.2% vs. 5%, < .0001). Attainment of morphologic CR for these patients is a significant prognostic factor for DFS after HSCT (46% vs. 0%; = .02), with failure primarily resulting from relapse (relapse risk, 53.9% vs. 88.9%; = .02).

Evidence (treatment of refractory childhood AML with gemtuzumab ozogamicin):

Treatment options under clinical evaluation

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the website.

The following are examples of national and/or institutional clinical trials that are currently being conducted:

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Acute Promyelocytic Leukemia (APL)

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) because of several factors, including the following:

  • Clinical presentation of universal coagulopathy (disseminated intravascular coagulation) and unique morphologic characteristics (French-American-British [FAB] M3 or its variants).
  • Unique molecular etiology as a result of the involvement of the oncogene.
  • Unique sensitivity to the differentiating agent all- retinoic acid (ATRA) and to the proapoptotic agent arsenic trioxide.

These unique features of APL mandate a high index of suspicion at diagnosis so as to initiate proper supportive care measures to avoid coagulopathic complications during the first days of therapy. It is also critical to institute a different induction regimen of therapy to minimize the risk of coagulopathic complications and to provide a much improved long-term relapse-free survival and overall survival (OS) than with past approaches to APL and compared with outcomes for patients with the other forms of AML.

Molecular Abnormality

The characteristic chromosomal abnormality associated with APL is t(15;17). This translocation involves a breakpoint that includes the retinoic acid receptor and leads to production of the promyelocytic leukemia (PML)–retinoic acid receptor alpha (RARA) fusion protein.

Patients with a suspected diagnosis of APL can have their diagnosis confirmed by detection of the PML-RARA fusion (e.g., through fluorescence hybridization [FISH], reverse transcriptase–polymerase chain reaction [RT-PCR], or conventional cytogenetics). An immunofluorescence method using an anti-PML monoclonal antibody can rapidly establish the presence of the PML-RARA fusion protein based on the characteristic distribution pattern of PML that occurs in the presence of the fusion protein.

Clinical Presentation

Clinically, APL is characterized by severe coagulopathy that is often present at the time of diagnosis. This is typically manifested with thrombocytopenia, prolonged prothrombin time, partial thromboplastin time, elevated d-dimers, and hypofibrinogenemia. Mortality during induction (particularly with cytotoxic agents used alone) caused by bleeding complications is more common in this subtype than in other FAB or World Health Organization (WHO) classifications. A multicooperative group analysis of children with APL reported that early induction coagulopathic deaths occurred in 25 of 683 children (3.7%); 23 deaths resulted from hemorrhage (19 CNS, 4 pulmonary), and 2 resulted from CNS thrombosis. A lumbar puncture at diagnosis should not be performed until evidence of coagulopathy has resolved.

ATRA therapy is initiated as soon as APL is suspected on the basis of morphological and clinical presentation, because ATRA has been shown to ameliorate bleeding risk for patients with APL. A retrospective analysis identified an increase in early death resulting from hemorrhage in patients with APL in whom ATRA introduction was delayed. Additionally, initiation of supportive measures such as replacement transfusions directed at correction of the coagulopathy is critical during these initial days of diagnosis and therapy. Patients at greatest risk of coagulopathic complications are those presenting with high white blood cell (WBC) counts, high body mass index, hypofibrinogenemia, molecular variants of APL, and the presence of mutations.

APL in children is generally similar to APL in adults, although children have a higher incidence of hyperleukocytosis (defined as WBC count higher than 10 × 10/L) and a higher incidence of the microgranular morphologic subtype. As in adults, children with WBC counts less than 10 × 10/L at diagnosis have significantly better outcomes than do patients with higher WBC counts.

Risk Classification for Treatment Stratification

The prognostic significance of WBC count is used to define high-risk and low-risk patient populations and to assign postinduction treatment, with high-risk patients most commonly defined by WBC count of 10 × 10/L or greater. mutations (either internal tandem duplications or kinase domain mutations) are observed in 40% to 50% of APL cases, with the presence of mutations correlating with higher WBC counts and the microgranular variant (M3v) subtype. The mutation has been associated with an increased risk of induction death and, in some reports, an increased risk of treatment failure.

In the COG AAML0631 (NCT00866918) trial, which included treatment with chemotherapy, ATRA, and arsenic trioxide, risk classification was primarily associated with early death risk (standard risk, 0 of 66 patients vs. high risk, 4 of 35 patients). Relapse risk after remission induction was 4% overall, with one relapse in a standard-risk child and two relapses in high-risk children. High-risk patients on this trial had earlier initiation of idarubicin, with first dose on day 1 rather than day 3 to reduce leukemic burden more rapidly, and one additional consolidation chemotherapy (high-dose cytarabine and idarubicin) and ATRA cycle.

The Central Nervous System (CNS) and APL

CNS involvement at the time of diagnosis is not ascertained in most patients with APL because of the presence of disseminated intravascular coagulation. The COG AAML0631 (NCT00866918) trial identified 28 patients out of 101 enrolled children who had CSF exams at diagnosis, and in 7 of these children, blasts were identified in atraumatic taps. None of the patients experienced a CNS relapse with intrathecal treatment during induction and prophylactic doses during therapy.

Overall, CNS relapse is uncommon for patients with APL, particularly for those with WBC counts of less than 10 × 10/L. In two clinical trials enrolling over 1,400 adults with APL in which CNS prophylaxis was not administered, the cumulative incidence of CNS relapse was less than 1% for patients with WBC counts of less than 10 × 10/L, while it was approximately 5% for those with WBC counts of 10 × 10/L or greater. In addition to high WBC counts at diagnosis, CNS hemorrhage during induction is also a risk factor for CNS relapse. A review of published cases of pediatric APL also observed low rates of CNS relapse. Because of the low incidence of CNS relapse among children with APL presenting with WBC counts of less than 10 × 10/L, CNS surveillance and prophylactic CNS therapy may not be needed for this group of patients, although there is no consensus on this topic.

Treatment of APL

Modern treatment programs for APL are based on the sensitivity of leukemia cells from APL patients to the differentiation-inducing and apoptotic effects of ATRA and arsenic trioxide. APL therapy first diverged from the therapy of other non-APL subtypes of AML with the addition of ATRA to chemotherapy.

Treatment options for children with APL may include the following:

The standard approach to treating children with APL builds upon adult clinical trial results; the approach begins with induction therapy using ATRA given in combination with an anthracycline administered with or without cytarabine. The dramatic efficacy of ATRA against APL results from the ability of pharmacologic doses of ATRA to overcome the repression of signaling caused by the PML-RARA fusion protein at physiologic ATRA concentrations. Restoration of signaling leads to differentiation of APL cells and then to postmaturation apoptosis. Most patients with APL achieve a complete remission (CR) when treated with ATRA, although single-agent ATRA is generally not curative.

A series of randomized clinical trials defined the benefit of combining ATRA with chemotherapy during induction therapy and the utility of using ATRA as maintenance therapy. One regimen uses ATRA in conjunction with standard-dose cytarabine and daunorubicin, while another uses idarubicin and ATRA without cytarabine for remission induction. Almost all children with APL treated with one of these approaches achieves CR in the absence of coagulopathy-related mortality.

Assessment of response to induction therapy in the first month of treatment using morphologic and molecular criteria may provide misleading results because delayed persistence of differentiating leukemia cells can occur in patients who will ultimately achieve CR. Alterations in planned treatment based on these early observations are not appropriate because resistance of APL to ATRA plus anthracycline-containing regimens is extremely rare.

Consolidation therapy has typically included ATRA given with an anthracycline with or without cytarabine. The role of cytarabine in consolidation therapy regimens is controversial. While a randomized study addressing the contribution of cytarabine to a daunorubicin-plus-ATRA regimen in adults with low-risk APL showed a benefit for the addition of cytarabine, regimens using a high-dose anthracycline appear to produce as good as or better results in low-risk patients. For high-risk patients (WBC ≥10 × 10/L), a historical comparison of the Programa para el Tratamiento de Hemopatías Malignas (PETHEMA) LPA 2005 (NCT00408278) trial with the preceding LPA 99 (NCT00465933) trial suggested that the addition of cytarabine to anthracycline-ATRA combinations can lower the relapse rate. The results of the AIDA 2000 (NCT00180128) trial confirmed that the cumulative incidence of relapse for adult patients with high-risk disease can be reduced to approximately 10% with consolidation regimens that contain ATRA, anthracyclines, and cytarabine. Studies using arsenic trioxide–based consolidation have demonstrated excellent survival without cytarabine consolidation.

Maintenance therapy includes ATRA plus mercaptopurine and methotrexate; this combination has shown conflicting benefit, with some randomized trials in adults with APL showing an advantage over ATRA alone and other studies showing no benefit. However, the utility of maintenance therapy in APL may be dependent on multiple factors (e.g., risk group, the anthracycline used during induction, the use of arsenic trioxide, and the intensity of induction and consolidation therapy).

At this time, maintenance therapy remains standard for children with APL. Because of the favorable outcomes observed with chemotherapy plus ATRA and arsenic trioxide (event-free survival [EFS] rates of 70%–90%), hematopoietic stem cell transplantation is not recommended in first CR.

Arsenic trioxide is the most active agent in the treatment of APL, and while initially used in relapsed APL, it has been incorporated into the treatment of newly diagnosed patients. Data supporting the use of arsenic trioxide initially came from trials that included adult patients only, but more recently, its efficacy has been seen on trials that included both pediatric and adult patients and pediatric patients alone.

Evidence (arsenic trioxide therapy):

Numerous trials showed that for children with APL, survival rates exceeding 80% are now achievable using treatment programs that prescribe the rapid initiation of ATRA with appropriate supportive care measures; a rate exceeding 90% was demonstrated in a single trial that added arsenic trioxide to the treatment regimen. For patients in CR for more than 5 years, relapse is extremely rare.[]

Treatment options under clinical evaluation

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

Complications unique to APL therapy

In addition to the previously mentioned universal presence of coagulopathy in patients newly diagnosed with APL, several other unique complications occur in patients with APL for which the clinician should be aware. These include two ATRA-related conditions, pseudotumor cerebri and differentiation syndrome (also called retinoic acid syndrome), and an arsenic trioxide–related complication, QT interval prolongation.

  • Pseudotumor cerebri. Pseudotumor cerebri is typically manifested by headache, papilledema, sixth nerve palsy, visual field cuts, and normal intracranial imaging in the face of an elevated opening lumbar puncture pressure (not often obtained in APL patients). Pseudotumor cerebri is known to be associated with the use of ATRA, presumably by the same mechanism of vitamin A toxicity that leads to increased production of cerebrospinal fluid.

    The incidence of pseudotumor cerebri has been reported to be as low as 1.7% with very strict definitions of the complication and as high as 6% to 16% in three pediatric trials. Pseudotumor cerebri is thought to be more prevalent in children receiving ATRA, leading to lower dosing in contemporary pediatric APL clinical trials. Pseudotumor cerebri most typically occurs during induction at a median of 15 days (range, 1–35 days) after starting ATRA, but is known to occur in other phases of therapy as well. Pseudotumor cerebri incidence and severity may be exacerbated with the concurrent use of azoles via inhibition of cytochrome P450 metabolism of ATRA.

    When a diagnosis of pseudotumor cerebri is suspected, ATRA is held until symptoms abate and then is slowly escalated to full dose as tolerated.

  • Differentiation syndrome. Differentiation syndrome (also known as retinoic acid syndrome or ATRA syndrome) is a life-threatening syndrome thought to be an inflammatory response–mediated syndrome manifested by weight gain, fever, edema, pulmonary infiltrates, pleuro-pericardial effusions, hypotension, and, in the most severe cases, acute renal failure. In the contemporary COG AAML0631 (NCT00866918) study, it was present in 20% of patients during induction and was more prevalent in high-risk children (31%) than in low-risk children (13%), a risk factor also seen in adults with APL. There is a bimodal peak with this syndrome seen in the first and third weeks of induction therapy.

    Because of the increased incidence in high-risk patients, dexamethasone is given with ATRA and/or arsenic therapy to prevent this complication in this subset of patients. Prophylaxis with dexamethasone and hydroxyurea (for cytoreduction) is also administered to standard-risk patients if their WBC count rises to greater than 10,000/uL after the start of ATRA or arsenic. If differentiation syndrome still occurs, the dexamethasone dose may be escalated first, rather than stopping ATRA or arsenic. If this fails to resolve the symptoms or if the symptoms are life-threatening, then ATRA or arsenic should be held and, similar to pseudotumor cerebri, restarted at a lower dose with plans to escalate as tolerated.

  • QT interval prolongation. Arsenic trioxide is associated with QT interval prolongation that can lead to life-threatening arrhythmias (e.g., torsades de pointes). It is essential to monitor electrolytes closely in patients receiving arsenic trioxide and to maintain potassium and magnesium values at midnormal ranges, as well as to be cognizant of other agents known to prolong the QT interval.

Minimal disease monitoring

The induction and consolidation therapies currently employed result in molecular remission, as measured by RT-PCR for PML-RARA, in most APL patients, with 1% or fewer showing molecular evidence of disease at the end of consolidation therapy. While two negative RT-PCR assays after completion of therapy are associated with long-term remission, conversion from negative to positive RT-PCR is highly predictive of subsequent hematologic relapse.

Patients with persistent or relapsing disease on the basis of PML-RARA RT-PCR measurement may benefit from intervention with relapse therapies (refer to the Recurrent Acute Promyelocytic Leukemia (APL) subsection of the Recurrent Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies section of this summary for more information).

Molecular Variants of APL Other Than PML-RARA and Therapeutic Impact

Uncommon molecular variants of APL produce fusion proteins that join distinctive gene partners (e.g., , , , and ) to RARA. Recognition of these rare variants is important because they differ in their sensitivity to ATRA and to arsenic trioxide.

  • PLZF-RARA variant. The PLZF-RARA variant, characterized by t(11;17)(q23;q21), represents about 0.8% of APL, expresses surface CD56, and has very fine granules compared with t(15;17) APL. APL with PLZF-RARA has been associated with a poor prognosis and does not usually respond to ATRA or arsenic trioxide.
  • NPM-RARA or NuMA-RARA variant. The rare APL variants with NPM-RARA (t(5;17)(q35;q21)) or NuMA-RARA (t(11;17)(q13;q21)) translocations may still be responsive to ATRA.

Treatment of Recurrent APL

Historically, 10% to 20% of patients with APL relapse; however, more current studies that incorporated arsenic trioxide therapy showed cumulative incidence of relapse of less than 5%.

In patients initially receiving chemotherapy-based treatments, the duration of first remission is prognostic in APL, with patients who relapse within 12 to 18 months of initial diagnosis having a worse outcome.

An important issue in children who relapse is the previous exposure to anthracyclines, which can range from 400 mg/m to 750 mg/m. Thus, regimens containing anthracyclines are often not optimal for children with APL who suffer relapse.

Treatment options for children with recurrent APL may include the following:

Arsenic trioxide

For children with recurrent APL, the use of arsenic trioxide as a single agent or in regimens including ATRA should be considered, depending on the therapy given during first remission. Arsenic trioxide is an active agent in patients with recurrent APL, with approximately 85% of patients achieving remission after treatment with this agent. Arsenic trioxide is even capable of inducing remissions in patients who relapse after having received arsenic trioxide during initial therapy. APL cells, however, may become resistant to arsenic trioxide through mechanisms including mutation of the PML domain of the fusion oncogene.

For adults with relapsed APL, approximately 85% achieve morphologic remission after treatment with arsenic trioxide. Data are limited on the use of arsenic trioxide in children, although published reports suggest that children with relapsed APL have a response to arsenic trioxide similar to that of adults. Arsenic trioxide is well tolerated in children with relapsed APL. The toxicity profile and response rates in children are similar to that observed in adults.

Because arsenic trioxide causes QT-interval prolongation that can lead to life-threatening arrhythmias, it is essential to monitor electrolytes closely in patients receiving arsenic trioxide and to maintain potassium and magnesium values at midnormal ranges.

Gemtuzumab ozogamicin

The use of gemtuzumab ozogamicin, an anti-CD33/calicheamicin monoclonal antibody, as a single agent resulted in a 91% (9 of 11 patients) molecular remission after two doses and a 100% (13 of 13 patients) molecular remission after three doses, thus demonstrating excellent activity of this agent in relapsed APL.


Retrospective pediatric studies have reported 5-year EFS rates after either autologous or allogeneic transplantation approaches to be similar, at approximately 70%.

Evidence (autologous HSCT):

Such data support the use of autologous transplantation in patients who are MRD-negative in second CR who have poorly matched allogeneic donors.

Because of the rarity of APL in children and the favorable outcome for this disease, clinical trials in relapsed APL to compare treatment approaches are likely not feasible. However, an international expert panel provided recommendations for the treatment of relapsed APL on the basis of the reported pediatric and adult experience.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Children With Down Syndrome and AML or Transient Abnormal Myelopoiesis (TAM)

Myeloid Leukemia Associated With Down Syndrome

Children with Down syndrome have a tenfold to twentyfold increased risk of leukemia compared with children without Down syndrome; however, the ratio of acute lymphoblastic leukemia to acute myeloid leukemia (AML) is typical for childhood acute leukemia. The exception is during the first 3 years of life, when AML, particularly the megakaryoblastic subtype, predominates and exhibits a distinctive biology characterized by mutations and increased sensitivity to cytarabine. Importantly, these risks appear to be similar whether a child has phenotypic characteristics of Down syndrome or whether a child has only genetic bone marrow mosaicism.

TAM Associated With Down Syndrome

In addition to increased risk of AML during the first 3 years of life, about 10% of neonates with Down syndrome develop a TAM (also termed [TMD]). This disorder mimics congenital AML but typically improves spontaneously within the first 3 months of life (median, 49 days), although TAM has been reported to remit as late as 20 months. The late remissions likely reflect a persistent hepatomegaly from TAM-associated hepatic fibrosis rather than active disease.

Although TAM is usually a self-resolving condition, it can be associated with significant morbidity and may be fatal in 10% to 17% of affected infants. Infants with progressive organomegaly, visceral effusions, preterm delivery (less than 37 weeks of gestation), bleeding diatheses, failure of spontaneous remission, laboratory evidence of progressive liver dysfunction (elevated direct bilirubin), renal failure, and very high white blood cell (WBC) count are at particularly high risk of early mortality. Death has been reported to occur in 21% of these patients with high-risk TAM, although only 10% were attributable to TAM and the remaining deaths were caused by coexisting conditions known to be more prominent in neonates with Down syndrome.

The following three risk groups have been identified on the basis of the diagnostic clinical findings of hepatomegaly with or without life-threatening symptoms:

  • Low risk includes those with neither hepatomegaly nor life-threatening symptoms (38% of patients and 92% ± 8% overall survival [OS]).
  • Intermediate risk includes those with hepatomegaly alone (40% of patients and 77% ± 12% OS).
  • High risk includes those with hepatomegaly and life-threatening symptoms (21% of patients and 51% ± 19% OS).

Therapeutic intervention is warranted in patients with apparent severe hydrops or organ failure. Because TAM eventually spontaneously remits, treatment is short in duration and primarily aimed at the reduction of leukemic burden and resolution of immediate symptoms. Several treatment approaches have been used, including the following:

  • Exchange transfusion.
  • Leukapheresis.
  • Low-dose cytarabine. Of these approaches, only cytarabine was found to be consistently beneficial. Dosing has varied between 0.4 to 1.5mg/kg per dose given intravenously or subcutaneously twice a day for 4 to 12 days or 3.3 mg/kg per day given as a continuous infusion for 5 days. While both were equally effective, the higher continuous dose was associated with severe pancytopenia. The use of the lower dose approach reduced early cumulative death from 72% to 24% ( = .001).

The mean time for the development of AML in the 10% to 30% of children who have a spontaneous remission of TAM but then develop AML has been reported to be approximately 16 months, with a range of 1 to 30 months. Thus, most infants with Down syndrome and TAM who later develop AML will do so within the first 3 years of life.

Patients with Down syndrome who develop AML with an antecedent TAM have superior event-free survival (EFS) (91% ± 5%) compared with such children without TAM (70% ± 4%) at 5 years, although this was not observed in other studies. While TAM is generally not characterized by cytogenetic abnormalities other than trisomy 21, the presence of additional cytogenetic findings may connote an increased risk of developing subsequent AML.

Prognosis and Treatment of Children With Down Syndrome and AML

Outcome is generally favorable for children with Down syndrome who develop AML (called myeloid leukemia associated with Down syndrome in the World Health Organization classification).

Prognostic factors for children with Down syndrome and AML include the following:

  • Age. The prognosis is particularly good (EFS exceeding 85%) in children aged 4 years or younger at diagnosis; this age group accounts for the vast majority of Down syndrome patients with AML. Children with Down syndrome who are older than 4 years have a significantly worse prognosis.
  • White blood cell count. A large international Berlin-Frankfurt-Münster (BFM) retrospective study of 451 children with AML and Down syndrome (aged >6 months and <5 years) observed a 7-year EFS of 78% and 7-year OS of 79%. In multivariate analyses, WBC count (≥20 × 10/L) and age (>3 years) were independent predictors of lower EFS. The 7-year EFS for the older population (>3 years) and for the higher WBC-count population still exceeded 60%.
  • AML karyotype. Normal karyotypic AML (other than trisomy 21), which was observed in 29% of patients, independently predicted for inferior OS and EFS (7-year EFS of 65% compared with 82% for patients with aberrant karyotypes). However, this was not seen in a later trial. In this same trial, the presence of trisomy 8 was shown to adversely impact prognosis.
  • Minimal residual disease (MRD). MRD at the end of induction 1 was found to be a strong prognostic factor; this was consistent with the BFM finding that early response correlated with improved OS.

Approximately 29% to 47% of Down syndrome patients present with myelodysplastic syndromes (MDS) (<20% blasts) but their outcomes are similar to those with AML.

Treatment options for newly diagnosed children with Down syndrome and AML include the following:

Appropriate therapy for younger children (aged ≤4 years) with Down syndrome and AML is less intensive than current standard childhood AML therapy. Hematopoietic stem cell transplant is not indicated in first remission.

Evidence (chemotherapy):

Children with mosaicism for trisomy 21 are treated similarly to those children with clinically evident Down syndrome. Although an optimal treatment for these children has not been defined, they are usually treated on AML regimens designed for children without Down syndrome.

Treatment options under clinical evaluation

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

Refractory Disease or Relapse in Children With Down Syndrome

A small number of publications address outcomes in children with Down syndrome who relapse after initial therapy or who have refractory AML. All of these retrospective analyses with varying approaches to therapy found that for these children who relapse or have refractory outcomes, the outlook is poor. Thus, these children are treated similarly to children without Down syndrome, with an intensive reinduction chemotherapy regimen, and if a remission is achieved, therapy is followed by an allogeneic hematopoietic stem cell transplant (HSCT).

Treatment options for children with Down syndrome with refractory or relapsed AML include the following:

Evidence (treatment of children with Down syndrome with refractory or relapsed AML):

Myelodysplastic Syndromes (MDS)

The myelodysplastic syndromes (MDS) and myeloproliferative syndromes (MPS) represent between 5% and 10% of all myeloid malignancies in children. They are a heterogeneous group of disorders, with MDS usually presenting with cytopenias and MPS presenting with increased peripheral white blood cell, red blood cell, or platelet counts. MDS is characterized by ineffective hematopoiesis and increased cell death, while MPS is associated with increased progenitor proliferation and survival. Because they both represent disorders of very primitive, multipotential hematopoietic stem cells, curative therapeutic approaches nearly always require allogeneic hematopoietic stem cell transplantation (HSCT).

Risk Factors

Patients with the following germline mutations or inherited disorders have a significantly increased risk of developing MDS:

  • Fanconi anemia: Caused by germline mutations in DNA repair genes.
  • Dyskeratosis congenita: Resulting from mutations in genes regulating telomere length. Genes mutated in dyskeratosis congenital include , , , , , , , , , , and .
  • Shwachman-Diamond syndrome, Diamond-Blackfan anemia, and other bone marrow failure syndromes: Resulting from mutations in genes encoding ribosome-associated proteins. mutations have been linked to Diamond-Blackfan anemia and MDS predisposition.
  • Severe congenital neutropenia: Caused by mutations in the gene encoding elastase. The 15-year cumulative risk of MDS in patients with severe congenital neutropenia, also known as Kostmann syndrome, has been estimated to be 15%, with an annual risk of MDS/acute myeloid leukemia (AML) of 2% to 3%. It is unclear how mutations affecting this protein and how the chronic exposure of granulocyte colony-stimulating factor (G-CSF) contribute to the development of MDS.
  • Trisomy 21 syndrome: mutations are nearly always present in the transient leukemia associated with Trisomy 21 and MDS in Down syndrome children younger than 3 years.
  • Congenital amegakaryocytic thrombocytopenia (CAMT): Inherited mutations in the or genes are associated with CAMT. Mutations in the gene are the underlying genetic cause of CAMT; there is a less than 10% risk of developing MDS/AML in patients with CAMT.
  • mutations: Germline mutations of have been reported in patients with MDS/AML in conjunction with monocytopenia, B cell and natural killer cell deficiency, pulmonary alveolar proteinosis, and susceptibility to opportunistic infections.
  • or mutations: Inherited mutations in the or genes are associated with familial MDS/AML.

Clinical Presentation

Patients usually present with signs of cytopenias, including pallor, infection, or bruising.

The bone marrow is usually characterized by hypercellularity and dysplastic changes in myeloid precursors. Clonal evolution can eventually lead to the development of AML. The percentage of abnormal blasts is less than 20% and lack common AML recurrent cytogenetic abnormalities (t(8;21), inv(16), t(15;17), or [] translocations).

The less common hypocellular MDS can be distinguished from aplastic anemia in part by its marked dysplasia, clonal nature, and higher percentage of CD34-positive precursors.

Molecular Abnormalities

Although the etiology of MDS has not been elucidated, clues are beginning to emerge. For instance, approximately 20% of malignant myeloid disorders, including MDS in adults, have been shown to have mutations in the gene. Other genes shown to be mutated in MDS include , , , , , (), , , , and . Most of these genes are key elements of epigenetic regulation of the genome and affect DNA methylation and/or histone modification. MDS in both adults and children has been shown to have aberrant DNA methylation patterns, and approximately one-half of cases are characterized by hypermethylation of the promoters for the and genes, both of which play roles in cell cycle regulation.

Mutations in proteins involved in RNA splicing have been described in 45% to 85% of MDS and appear to occur early in the course of the disease. mutation is a common germline defect predisposing to pediatric MDS, with a very high prevalence in adolescents with monosomy 7. mutations do not confer poor prognosis in childhood MDS; however, the high risk of progression to advanced disease must guide decision making towards timely treatment with HSCT.

Classification of MDS

The French-American-British (FAB) and World Health Organization (WHO) classification systems of MDS and MPS have been difficult to apply to pediatric patients. Alternative classification systems for children have been proposed, but none have been uniformly adopted, with the exception of the modified 2008 WHO classification system. The WHO system has been modified for pediatrics. Refer to Table 3 and Table 4 for the WHO classification schema and diagnostic criteria. The 2016 revision to the WHO MDS classification did not affect classification in children.

The refractory cytopenia subtype represents approximately 50% of all childhood cases of MDS. The presence of an isolated monosomy 7 is the most common cytogenetic abnormality, although it does not appear to portend a poor prognosis compared with its presence in overt AML. However, the presence of monosomy 7 in combination with other cytogenetic abnormalities is associated with a poor prognosis. The relatively common abnormalities of -Y, 20q-, and 5q- in adults with MDS are rare in childhood MDS. The presence of cytogenetic abnormalities that are found in AML defines disease that should be treated as AML and not MDS.

The International Prognostic Scoring System can help to distinguish low-risk from high-risk MDS, although its utility in children with MDS is more limited than in adults because many characteristics differ between children and adults. The median survival for children with high-risk MDS remains substantially better than adults, and the presence of monosomy 7 in children has not had the same adverse prognostic impact as does the presence in adults with MDS.

Treatment of Childhood MDS

Treatment options for children with MDS include the following:


MDS and associated disorders usually involve a primitive hematopoietic stem cell. Thus, allogeneic HSCT is considered to be the optimal approach to treatment for pediatric patients with MDS. Although matched sibling transplantation is preferred, similar survival has been noted with well-matched, unrelated cord blood and haploidentical approaches.

When making treatment decisions, some data should be considered. For example, survival as high as 80% has been reported for patients with early-stage MDS proceeding to transplant within a few months of diagnosis. Additionally, early transplant and not receiving pretransplant chemotherapy have been associated with improved survival in children with MDS.[] Disease-free survival (DFS) has been estimated to be between 50% to 70% for pediatric patients with advanced MDS using myeloablative transplant preparative regimens. While nonmyeloablative preparative transplant regimens are being tested in patients with MDS and AML, such regimens are still investigational for children with these disorders, but may be reasonable in the setting of a clinical trial or when a patient’s organ function is compromised in such a way that they would not tolerate a myeloablative regimen.; []

The question of whether chemotherapy should be used in high-risk MDS has been examined.

Evidence (HSCT):

When analyzing these results, it is important to consider that the subtype refractory anemia with excess blasts in transformation is likely to represent patients with overt AML, while refractory anemia and refractory anemia with excess blasts represents MDS. The WHO classification has now omitted the category of refractory anemia with excess blasts in transformation, concluding that this entity was essentially AML.

Because survival after HSCT is improved in children with early forms of MDS (refractory anemia), transplantation before progression to late MDS or AML should be considered. HSCT should especially be considered when transfusions or other treatment are required, as is usually the case in patients with severe symptomatic cytopenias. The 8-year disease-free survival (DFS) for children with various stages of MDS has been reported to be 65% for those treated with HLA matched donor transplants and 40% for those treated with mismatched unrelated donor transplants.[] A 3-year DFS of 50% was reported with the use of unrelated cord blood donor transplants for children with MDS, when the transplants were done after the year 2001.[]

Because MDS in children is often associated with inherited predisposition syndromes, reports of transplantation in small numbers of patients with these disorders have been documented. For example, in patients with Fanconi anemia and AML or advanced MDS, the 5-year overall survival (OS) has been reported to be 33% to 55%.[] Second transplants have also been used in pediatric patients with MDS/MPD who relapse or suffer graft failure. The 3-year OS was 33% for those retransplanted after relapse and 57% for those transplanted after initial graft failure.[]

For patients with clinically significant cytopenias, supportive care that includes transfusions and prophylactic antibiotics are considered standard of care. The use of hematopoietic growth factors can improve the hematopoietic status, but concerns remain that such treatment could accelerate conversion to AML.

Other therapies

Other supportive therapies that have been studied include the following:

  • Steroid therapy, including glucocorticoids and androgens, have been tried with mixed results.
  • Treatments directed toward scavenging free oxygen radicals with amifostine or the use of differentiation-promoting retinoids, DNA methylation inhibitors (e.g., azacytidine and decitabine), and histone deacetylase inhibitors have all shown some response, but no definitive trials in children with MDS have been reported. Azacytidine has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of MDS in adults on the basis of randomized studies. (Refer to the Disease-Modifying Agents section in the PDQ summary on Myelodysplastic Syndromes Treatment for more information.)
  • Agents such as lenalidomide an analog of thalidomide, have been tested based on findings that demonstrated increased activity in the bone marrow of patients with MDS. Lenalidomide has shown the most efficacy in patients with 5q- syndrome, especially those with thrombocytosis, and is now FDA-approved for use in adults with this finding.
  • Immunosuppression with antithymocyte globulin and/or cyclosporine has also been reported in adults.

Treatment Options Under Clinical Evaluation

The use of a variety of DNA methylation inhibitors and histone deacetylase inhibitors, as well as other therapies designed to induce differentiation, are being studied in both young and older adults with MDS.

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the website.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Therapy-Related AML/Myelodysplastic Syndromes


The development of acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) after treatment with ionizing radiation or chemotherapy, particularly alkylating agents and topoisomerase inhibitors, is termed (t-AML) or (t-MDS). In addition to genotoxic exposures, genetic predisposition susceptibilities (such as polymorphisms in drug detoxification and DNA repair pathway components) may contribute to the occurrence of secondary AML/MDS.

The risk of t-AML/t-MDS is regimen-dependent and often related to the cumulative doses of chemotherapy agents received and the dose and field of radiation administered. Regimens previously used that employed high cumulative doses of either epipodophyllotoxins (e.g., etoposide or teniposide) or alkylating agents (e.g., mechlorethamine, melphalan, busulfan, and cyclophosphamide) induced excessively high rates of t-AML/t-MDS that exceeded 10% in some cases. However, most current chemotherapy regimens that are used to treat childhood cancers have a cumulative incidence of t-AML/t-MDS no greater than 1% to 2%.

t-AML/t-MDS resulting from epipodophyllotoxins and other topoisomerase II inhibitors (e.g., anthracyclines) usually occur within 2 years of exposure and are commonly associated with chromosome 11q23 abnormalities, although other subtypes of AML (e.g., acute promyelocytic leukemia) have been reported. t-AML that occurs after exposure to alkylating agents or ionizing radiation often presents 5 to 7 years later and is commonly associated with monosomies or deletions of chromosomes 5 and 7.

Treatment of Therapy-Related AML/MDS

Treatment options for therapy-related AML/MDS include the following:

The goal of treatment is to achieve an initial complete remission (CR) using AML-directed regimens and then, usually, to proceed directly to hematopoietic stem cell transplantation (HSCT) with the best available donor. However, treatment is challenging because of the following:

Accordingly, CR rates and overall survival (OS) rates are usually lower for patients with t-AML compared with patients with de novo AML. Also, survival for pediatric patients with t-MDS is worse than survival for pediatric patients with MDS not related to previous therapy.

Patients with t-MDS-refractory anemia usually have not needed induction chemotherapy before transplant; the role of induction therapy before transplant is controversial in patients with refractory anemia with excess blasts-1.

Only a few reports describe the outcome of children undergoing HSCT for t-AML.

Evidence (HSCT for t-AML/t-MDS):

Because t-AML is rare in children, it is not known whether the significant decrease in transplant-related mortality after unrelated donor HSCT noted over the past several years will translate to improved survival in this population. Patients should be carefully assessed for pre-HSCT morbidities caused by earlier therapies, and treatment approaches should be adapted to give adequate intensity while minimizing transplant-related mortality.

Juvenile Myelomonocytic Leukemia (JMML)


Juvenile myelomonocytic leukemia (JMML) is a rare leukemia that occurs approximately ten times less frequently than acute myeloid leukemia (AML) in children, with an annual incidence of about 1 to 2 cases per 1 million people. JMML typically presents in young children (median age, approximately 1.8 years) and occurs more commonly in boys (male to female ratio, approximately 2.5:1).

Clinical Presentation and Diagnostic Criteria

Common clinical features at diagnosis include the following:

  • Hepatosplenomegaly (97%).
  • Lymphadenopathy (76%).
  • Pallor (64%).
  • Fever (54%).
  • Skin rash (36%).

In children presenting with clinical features suggestive of JMML, current criteria used for a definitive diagnosis are described in Table 8.

Pathogenesis and Related Syndromes

The pathogenesis of JMML has been closely linked to activation of the oncogene pathway, along with related syndromes (refer to Figure 1). In addition, distinctive RNA expression and DNA methylation patterns have been reported; they are correlated with clinical factors such as age and appear to be associated with prognosis.

Schematic diagram showing ligand-stimulated Ras activation, the Ras-Erk pathway, and gene mutations contributing to the neuro-cardio-facio-cutaneous congenital disorders and JMML.Figure 1. Schematic diagram showing ligand-stimulated Ras activation, the Ras-Erk pathway, and the gene mutations found to date contributing to the neuro-cardio-facio-cutaneous congenital disorders and JMML. NL/MGCL: Noonan-like/multiple giant cell lesion; CFC: cardia-facio-cutaneous; JMML: juvenile myelomonocytic leukemia. Reprinted from Leukemia Research, 33 (3), Rebecca J. Chan, Todd Cooper, Christian P. Kratz, Brian Weiss, Mignon L. Loh, Juvenile myelomonocytic leukemia: A report from the 2nd International JMML Symposium, Pages 355-62, Copyright 2009, with permission from Elsevier.

Children with neurofibromatosis type 1 (NF1) and Noonan syndrome are at increased risk of developing JMML:

  • NF1. Up to 14% of cases of JMML occur in children with NF1.
  • Noonan syndrome. Noonan syndrome is usually inherited as an autosomal dominant condition, but can also arise spontaneously. It is characterized by facial dysmorphism, short stature, webbed neck, neurocognitive abnormalities, and cardiac abnormalities. Germline mutations in are observed in children with Noonan syndrome and in children with JMML.

    Importantly, some children with Noonan syndrome have a hematologic picture indistinguishable from JMML that self-resolves during infancy, similar to what happens in children with Down syndrome and transient myeloproliferative disorder.

    Within a large prospective cohort of 641 patients with Noonan syndrome and a germline mutation, 36 patients (~6%) showed myeloproliferative features, with 20 patients (~3%) meeting the consensus diagnostic criteria for JMML. Of the 20 patients meeting the criteria for JMML, 12 patients had severe neonatal manifestations (e.g., life-threatening complications related to congenital heart defects, pleural effusion, leukemia infiltrates, and/or thrombocytopenia), and 10 of 20 patients died during the first month of life. Among the remaining eight patients, none required intensive therapy at diagnosis or during follow-up. All 16 patients with myeloproliferative features not meeting JMML criteria were alive, with a median follow-up of 3 years, and none of the patients received chemotherapy.

Mutations in the () gene, an E3 ubiquitin-protein ligase that is involved in targeting proteins, particularly tyrosine kinases, for proteasomal degradation occur in 10% to 15% of JMML cases, with many of these cases occurring in children with germline mutations. germline mutations result in an autosomal dominant developmental disorder that is characterized by impaired growth, developmental delay, cryptorchidism, and a predisposition to JMML. Some individuals with germline mutations experience spontaneous regression of their JMML but develop vasculitis later in life. mutations are nearly always mutually exclusive of and mutations.

Genomics of JMML

The genomic landscape of JMML is characterized by mutations in one of five genes of the Ras pathway: , , , , and . In a series of 118 consecutively diagnosed JMML cases with Ras pathway–activating mutations, was the most commonly mutated gene, accounting for 51% of cases (19% germline and 32% somatic) (refer to Figure 2). Patients with mutated accounted for 19% of cases, and patients with mutated accounted for 15% of cases. mutations accounted for 8% of cases and mutations accounted for 11% of cases. Although mutations among these five genes are generally mutually exclusive, 10% to 17% of cases have mutations in two of these Ras pathway genes, a finding that is associated with poorer prognosis.

The mutation rate in JMML leukemia cells is very low, but additional mutations beyond those of the five Ras pathway genes described above are observed. Secondary genomic alterations are observed for genes of the transcriptional repressor complex PRC2 (e.g., was mutated in 7%–8% of cases). Some genes associated with myeloproliferative neoplasms in adults are also mutated at low rates in JMML (e.g., was mutated in 7%–9% of cases). mutations are also observed in a small percentage (4%–12%) of JMML cases. Cases with germline and germline mutations showed low rates of additional mutations (refer to Figure 2).

Chart showing alteration profiles in individual JMML cases.Figure 2. Alteration profiles in individual JMML cases. Germline and somatically acquired alterations with recurring hits in the RAS pathway and PRC2 network are shown for 118 patients with JMML who underwent detailed genetic analysis. Blast excess was defined as a blast count ≥10% but <20% of nucleated cells in the bone marrow at diagnosis. Blast crisis was defined as a blast count ≥20% of nucleated cells in the bone marrow. NS, Noonan syndrome. Reprinted by permission from Macmillan Publishers Ltd: Nature Genetics (Caye A, Strullu M, Guidez F, et al.: Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network. Nat Genet 47 [11]: 1334-40, 2015), copyright (2015).


Several factors affect prognosis in JMML, including the following:

Treatment of JMML

Treatment options for JMML include the following:

  • Hematopoietic stem cell transplant (HSCT).

The role of conventional antileukemia therapy in the treatment of JMML is not defined. The absence of consensus response criteria for JMML complicates determination of the role of specific agents in the treatment of JMML. Some agents that have shown antileukemia activity against JMML include etoposide, cytarabine, thiopurines (thioguanine and mercaptopurine), isotretinoin, and farnesyl inhibitors, but none of these have been shown to improve outcome.; []

HSCT currently offers the best chance of cure for JMML.

Evidence (HSCT):

Disease recurrence is the primary cause of treatment failure for children with JMML after HSCT and occurs in 30% to 40% of cases. While the role of donor lymphocyte infusions is uncertain, reports indicate that approximately 50% of patients with relapsed JMML can be successfully treated with a second HSCT.

Chronic Myelogenous Leukemia (CML)


Chronic myelogenous leukemia (CML) accounts for less than 5% of all childhood leukemia, and in the pediatric age range, occurs most commonly in older adolescents.

Molecular Abnormality

The cytogenetic abnormality most characteristic of CML is the Philadelphia chromosome (Ph), which represents a translocation of chromosomes 9 and 22 (t(9;22)) resulting in a BCR-ABL1 fusion protein.

Clinical Presentation

CML is characterized by a marked leukocytosis and is often associated with thrombocytosis, sometimes with abnormal platelet function. Bone marrow aspiration or biopsy reveals hypercellularity with relatively normal granulocytic maturation and no significant increase in leukemic blasts. Although reduced leukocyte alkaline phosphatase activity is seen in CML, this is not a specific finding.

CML has the following three clinical phases:

  • Chronic phase. Chronic phase, which lasts for approximately 3 years if untreated, usually presents with symptoms secondary to hyperleukocytosis such as weakness, fever, night sweats, bone pain, respiratory distress, priapism, left upper quadrant pain (splenomegaly), and, rarely, hearing loss and visual disturbances.
  • Accelerated phase. The accelerated phase is characterized by progressive splenomegaly, thrombocytopenia, and increased percentage of peripheral and bone marrow blasts, along with accumulation of karyotypic abnormalities in addition to the Ph chromosome.
  • Blast crisis phase. Blast crisis is notable for the bone marrow, showing greater than 20% blasts or chloromatous lesions and a clinical picture that is indistinguishable from acute leukemia. Approximately two-thirds of blast crisis is myeloid, and the remainder is lymphoid, usually of B lineage. Patients in blast crisis will die within a few months.

Treatment of CML: Historical Perspective

Before the tyrosine kinase inhibitor (TKI) era, allogeneic hematopoietic stem cell transplantation (HSCT) was the primary treatment for children with CML. Published reports from this period described survival rates of 70% to 80% when an HLA–matched-family donor (MFD) was used in the treatment of children in early chronic phase, with lower survival rates when HLA–matched-unrelated donors were used.

Relapse rates were low (less than 20%) when transplant was performed in chronic phase. The primary cause of death was treatment-related mortality, which was increased with HLA–matched-unrelated donors compared with HLA-MFDs in most reports. High-resolution DNA matching for HLA alleles appeared to reduce rates of treatment-related mortality, leading to improved outcome for HSCT using unrelated donors.

Compared with transplantation in chronic phase, transplantation in accelerated phase or blast crisis and in second-chronic phase resulted in significantly reduced survival. The use of T-lymphocyte depletion to avoid graft-versus-host disease resulted in a higher relapse rate and decreased overall survival (OS), supporting the contribution of a graft-versus-leukemia effect to favorable outcome after allogeneic HSCT.

The introduction of the TKI imatinib as a therapeutic drug targeted at inhibiting the BCR-ABL fusion kinase revolutionized the treatment of patients with CML, for both children and adults. As most data on the use of TKIs for CML is from adult clinical trials, the adult experience is initially described, followed by a description of the more limited experience in children.

Treatment of Adult CML With TKIs

Imatinib is a potent inhibitor of the ABL tyrosine kinase, platelet-derived growth factor (PDGF) receptors (alpha and beta), and KIT. Imatinib treatment achieves clinical, cytogenetic, and molecular remissions (as defined by the absence of BCR-ABL fusion transcripts) in a high proportion of CML patients treated in chronic phase.

Evidence (imatinib for adults):

Guidelines for imatinib treatment have been developed for adults with CML on the basis of patient response to treatment, including the timing of achieving complete hematologic response, complete cytogenetic response, and major molecular response (defined as attainment of a 3-log reduction in /control gene ratio).

Poor adherence is a major reason for loss of complete cytogenetic response and imatinib failure for adult CML patients on long-term therapy. The identification of kinase domain mutations at the time of failure or of suboptimal response to imatinib treatment also has clinical implications, because there are alternative BCR-ABL kinase inhibitors (e.g., dasatinib and nilotinib) that maintain their activity against some (but not all) mutations that confer resistance to imatinib.

Two TKIs, dasatinib and nilotinib, have been shown to be effective in patients who have an inadequate response to imatinib, although not in patients with the mutation. Both dasatinib and nilotinib have also received regulatory approval for the treatment of newly diagnosed chronic-phase CML in adults, on the basis of the following studies:

  • Dasatinib. Dasatinib was approved on the basis of a phase III trial that compared dasatinib (100 mg daily) with imatinib (400 mg daily). There was no significant difference in progression-free survival (PFS) or OS. However, after 12 months of treatment, dasatinib was associated with a higher rate of complete cytogenetic response (83% vs. 72%, = .001) and major molecular response (46% vs. 28%, < .0001). Responses were achieved in a shorter time with dasatinib ( < .0001).
  • Nilotinib. Nilotinib (at a dose of either 300 mg or 400 mg twice daily) was compared with imatinib (400 mg daily) in a phase III trial. At 12 months, the rates of complete cytogenetic response were significantly higher for nilotinib (80% for the 300-mg dose and 78% for the 400-mg dose) than were the rates for imatinib (65%) ( < .001 for both comparisons). Also, nilotinib was associated with higher rates of major molecular response (44% for the 300-mg dose and 43% for the 400-mg dose compared with 22% for imatinib, < .001 for both comparisons). The 300-mg twice-daily dose of nilotinib was associated with a more favorable safety profile compared with the 400-mg dose.

Because of the superiority over imatinib in terms of complete cytogenetic response rate and major molecular response rate, both dasatinib and nilotinib are extensively used as firstline therapy in adults with CML. However, despite more rapid responses with dasatinib and nilotinib than with imatinib when used as frontline therapy, PFS and OS appear to be similar for all three agents. Additional follow-up will be required to better define the impact of these agents on long-term PFS and OS.

Bosutinib is another TKI that targets the fusion and has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of all phases of CML in adults who show intolerance to or whose disease shows resistance to previous therapy with another TKI. Bosutinib has not been studied in the pediatric population.

Ponatinib is a inhibitor that is effective against the mutation. Ponatinib induced objective responses in approximately 70% of heavily pretreated adults with chronic-phase CML, with responses observed regardless of the baseline kinase domain mutation. Development of ponatinib has been complicated by the high rate of vascular occlusion observed in patients receiving the agent, with arterial and venous thrombosis and occlusions (including myocardial infarction and stroke) occurring in more than 20% of treated patients. Ponatinib has not been studied in the pediatric population.

For adult CML patients who proceed to allogeneic HSCT, there is no evidence that pretransplant imatinib adversely impacts outcome.

Evidence (imatinib followed by HSCT in adults):

For adult patients treated with a TKI alone (without HSCT), the optimal duration of therapy remains unknown and most patients continue TKI treatment indefinitely.

Evidence (length of imatinib therapy in adults):

Additional research is required before cessation of imatinib or other targeted therapy for selected patients with CML in molecular remission can be recommended as a standard clinical practice.

Treatment of Childhood CML

Treatment options for children with CML may include the following:

Imatinib has shown a high level of activity in children with CML that is comparable with the activity observed in adults.

Evidence (imatinib in children):

As a result of this high level of activity, it is common to initiate imatinib treatment in children with CML rather than proceeding immediately to allogeneic stem cell transplantation. The pharmacokinetics of imatinib in children appears consistent with previous results in adults.

Doses of imatinib used in phase II trials for children with CML have ranged from 260 mg/m to 340 mg/m, which provide comparable drug exposures as the adult flat-doses of 400 mg to 600 mg.

Evidence (imatinib dose in children):

The monitoring guidelines described above for adults with CML are reasonable to use in children.

Imatinib is generally well tolerated in children, with adverse effects generally being mild to moderate and reversible with treatment discontinuation or dose reduction. Growth retardation occurs in most prepubertal children receiving imatinib. Children receiving imatinib and experiencing growth impairment may show some catch-up growth during their pubertal growth spurts, but they are at risk of having lower-than-expected adult height, as most patients do not achieve midparental height.

There are fewer published data regarding the efficacy and toxicities of other TKIs in children with CML. A phase I trial of dasatinib in children showed that drug disposition, tolerability, and efficacy of this agent was similar to that observed in adults. A safe pediatric dose of the other TKIs (nilotinib, bosutinib, ponatinib) has not yet been established.

Treatment of Recurrent or Refractory Childhood CML

Treatment options for children with recurrent or refractory CML may include the following:

In children who develop a hematologic or cytogenetic relapse during treatment with imatinib or who have an inadequate initial response to imatinib, determination of kinase domain mutation status should be considered to help guide subsequent therapy. Depending on the patient’s mutation status, alternative kinase inhibitors such as dasatinib or nilotinib can be considered on the basis of the adult experience with these agents. A pediatric phase I study of dasatinib showed good tolerance for dasatinib in children at doses used to treat adults with CML, and nilotinib is under investigation in children with CML or Ph chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) ().

Dasatinib and nilotinib are active against many mutations that confer resistance to imatinib, although the agents are ineffective in patients with the mutation. In the presence of the mutation, which is resistant to all FDA-approved kinase inhibitors, an allogeneic transplant should be considered.

The question of whether a pediatric patient with CML should receive an allogeneic transplant when multiple TKIs are available remains unanswered; however, reports suggest that PFS does not improve when using HSCT, compared with the sustained use of imatinib. The potential advantages and disadvantages need to be discussed with the patient and family. While HSCT is currently the only known definitive curative therapy for CML, patients discontinuing treatment with TKIs after sustained molecular remissions, who remained in molecular remission, have been reported.

Treatment Options Under Clinical Evaluation

Based on their activity in adults with CML, other TKIs are being studied in children. Dasatinib has undergone phase I testing in children and showed drug disposition, tolerability, and efficacy that was similar to that observed in adults. Nilotinib is under investigation in children with CML or Ph+ ALL in a clinical trial to determine the pharmacokinetics of nilotinib in children ( [CAMN107A2120]). A phase II evaluation of nilotinib in children with CML has been initiated ().

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

  • (A Pharmacokinetic Study of Nilotinib in Pediatric Patients With Ph+ CML or ALL): A clinical trial is assessing the pharmacokinetics of nilotinib in Ph+ CML pediatric patients that are newly diagnosed or resistant or intolerant to imatinib or dasatinib or in refractory or relapsed Ph+ ALL. Efficacy and safety are being evaluated as secondary objectives.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. 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 following pediatric specialists and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life.

  • Primary care physicians.
  • Pediatric surgical subspecialists.
  • Radiation oncologists.
  • Pediatric medical oncologists/hematologists.
  • Rehabilitation specialists.
  • Pediatric nurse specialists.
  • Social workers.

(Refer to the PDQ Supportive and Palliative 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. 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 and their 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 website.

Survivorship and Adverse Late Sequelae

While the issues of long-term complications of cancer and its treatment cross many disease categories, several important issues related to the treatment of myeloid malignancies are worth emphasizing. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)

Selected studies of the late effects of AML therapy in adult survivors who were not treated with hematopoietic stem cell transplant (HSCT) include the following:

Renal, gastrointestinal, and hepatic late adverse effects have been reported to be rare for children undergoing chemotherapy only for treatment of AML.

Selected studies of the late effects of AML therapy in adult survivors who were treated with HSCT include the following:

New therapeutic approaches to reduce long-term adverse sequelae are needed, especially for reducing the late sequelae associated with myeloablative HSCT.

Important resources for details on follow-up and risks for survivors of cancer have been developed, including the COG’s Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers and the National Comprehensive Cancer Network's Guidelines for Acute Myeloid Leukemia. Furthermore, having access to past medical history that can be shared with subsequent medical providers has become increasingly recognized as important for cancer survivors.

Changes to This Summary (11/30/2017)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Classification of Pediatric Myeloid Malignancies

Added text to state that the criteria for lineage assignment for a diagnosis of mixed phenotype acute leukemia (MPAL) are provided in Table 2.

Added Table 2 about the lineage assignment criteria for MPAL according to the 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.

Revised text to state that although both and fusion genes disrupt the activity of core-binding factor, cases with these genomic alterations have distinctive secondary mutations.

Treatment Option Overview for Childhood AML

Added Guest et al. as reference 27.

Added Buldini et al. and Tierens et al. as references 63 and 65, respectively.

Treatment of Childhood AML

Added text to state that in a retrospective analysis of the ALFA-0701 trial of older adults, higher CD33 expression corresponded with greater benefit from treatment with gemtuzumab ozogamicin (cited Olombel et al. as reference 25).

Added text about the reduction in relapse for patients expressing the single nucleotide polymorphism rs12459419 when treated with gemtuzumab ozogamicin (cited Lamba et al. as reference 26).

Added text to state that the evidence for a benefit of gemtuzumab ozogamicin in patients with mutations was mixed; the French ALFA-0701 trial showed a trend towards a benefit, whereas the five-trial meta-analysis study did not find a benefit (cited Castaigne et al. as reference 28). These trials did not examine the outcomes specifically for the combination of gemtuzumab ozogamicin followed by stem cell transplant, as was reported by the Children's Oncology Group (COG).

Added text about nonhigh-risk patients treated without hematopoietic stem cell transplantation who received either four or five cycles of chemotherapy (cited Getz et al. as reference 58).

Added text about the prognostic factors and outcomes of patients treated on two consecutive Nordic Society of Pediatric Hematology and Oncology (NOPHO) AML trials (cited Karlsson et al. as reference 93).

Acute Promyelocytic Leukemia (APL)

Added text to state that a multicooperative group analysis of children with APL reported that early induction coagulopathic deaths occurred in 25 of 683 children (3.7%); 23 deaths resulted from hemorrhage (19 CNS, 4 pulmonary) and 2 resulted from central nervous system thrombosis (cited Abla et al. as reference 11).

Revised text to state that patients at greatest risk of coagulopathic complications are those presenting with high white blood cell counts, high body mass index, hypofibrinogenemia, molecular variants of APL, and the presence of mutations.

Revised text to state that in the COG AAML0631 trial, which included treatment with chemotherapy, all- retinoic acid, and arsenic trioxide, risk classification was primarily associated with early death risk.

Added Complications unique to APL therapy as a new subsection.

Added Minimal disease monitoring as a new subsection.

Children With Down Syndrome and AML or Transient Abnormal Myelopoiesis (TAM)

Added text to state that the presence of trisomy 8 was shown to adversely impact prognosis.

Revised text to state that minimal residual disease at the end of induction 1 was found to be a strong prognostic factor; this was consistent with the Berlin-Frankfurt-Münster finding that early response correlated with improved overall survival.

Myelodysplastic Syndromes (MDS)

Added text to state that genes mutated in dyskeratosis congenital include , , , , , , , , , , and .

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood acute myeloid leukemia and other myeloid malignancies. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment are:

  • Alan Scott Gamis, MD, MPH (Children's Mercy Hospital)
  • Karen J. Marcus, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
  • Michael A. Pulsipher, MD (Children's Hospital Los Angeles)
  • Lewis B. Silverman, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
  • Malcolm A. Smith, MD, PhD (National Cancer Institute)

Any comments or questions about the summary content should be submitted to through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment. Bethesda, MD: National Cancer Institute. Updated . Available at: Accessed . [PMID: 26389454]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.


Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the website can be found on our Contact Us for Help page. Questions can also be submitted to through the website’s Email Us.


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