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

General Information About Childhood Myeloid Malignancies

Go to Patient Version

Approximately 20% of childhood leukemias are of myeloid origin and represent a spectrum of hematopoietic malignancies.[1] Most myeloid leukemias in children are acute; the remainder include chronic and/or subacute myeloproliferative disorders, such as chronic myeloid leukemia and juvenile myelomonocytic leukemia. Myelodysplastic neoplasms (MDS) occur much less frequently in children than in adults and almost invariably represent clonal, preleukemic conditions that often 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 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 of these malignant cells in the bone marrow and other organs. To be called acute, the bone marrow usually must have greater than 20% immature leukemic blasts, with some exceptions. For more information, see the sections on Treatment Option Overview for Childhood AML and Treatment of Childhood AML.
  • Myeloid leukemias of Down syndrome.
    • Transient abnormal myelopoiesis (TAM). TAM is also called transient myeloproliferative disorder or transient leukemia. The TAM observed in infants with Down syndrome represents a clonal expansion of myeloblasts with GATA1 variants in the setting of a coexisting trisomy 21 that can be difficult to distinguish from AML. Most importantly, TAM spontaneously regresses within the first 3 months of life in most cases. TAM occurs in 4% to 10% of infants with Down syndrome.[2-4]
    • Myeloid leukemia of Down syndrome (MLDS). MLDS is defined by the presence of myeloblasts with GATA1 variants in the setting of a coexisting trisomy 21 occurring in children older than 3 months. It is distinct from myeloid leukemias in children without trisomy 21 and GATA1 variants. Treatment with chemotherapy results in overall excellent survival. Less-intense therapeutic regimens are used and can reduce morbidity in these children with Down syndrome who experience greater toxicity than children without Down syndrome. However, children with Down syndrome who are older than 4 years most often have AML similar to children without Down syndrome (i.e., without the GATA1 variant). These patients require the more intensive chemotherapeutic regimens used in children without Down syndrome.

    For more information about TAM and MLDS, see Childhood Myeloid Proliferations Associated With Down Syndrome Treatment.

  • Myelodysplastic neoplasms (MDS). MDS in children, identified when the marrow blast proportion is less than 20%, represents a heterogeneous group of disorders characterized by ineffective hematopoiesis, impaired maturation of myeloid progenitors with dysplastic morphological features, and cytopenias. Although the underlying cause of MDS in children is unclear, there is often an association with marrow failure syndromes or germline conditions that predispose to myeloid malignancy/dysfunction. Most patients with MDS may have hypercellular bone marrows without increased numbers of leukemic blasts. However, some patients may present with hypocellular bone marrow, making the distinction between severe aplastic anemia and MDS difficult.[5,6]

    The presence of a karyotype abnormality in a hypocellular marrow is consistent with MDS, and transformation to AML should be expected. Patients with MDS are typically referred for stem cell transplant before transformation to AML.

    If a patient with MDS has a common defining genetic variant that is seen in AML, the clinician should be aware that, despite the relatively low proportion of blasts, the child should be treated similarly to those with blast proportions of 20% or more.

    In children with Down syndrome younger than 4 years, the finding of MDS likely represents an early presentation of typical AML, and patients should be treated with regimens used for AML in Down syndrome.

    For more information, see Childhood Myelodysplastic Neoplasms Treatment.

  • Juvenile myelomonocytic leukemia (JMML). JMML represents the most common myeloproliferative neoplasm 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.[7] In addition, patients often have elevated hemoglobin F, hypersensitivity of the leukemic cells to granulocyte-macrophage colony-stimulating factor (GM-CSF), monosomy 7, and leukemia cell variants in a gene involved in RAS pathway signaling (e.g., NF1, KRAS, NRAS, PTPN11, or CBL).[7-9]

    For more information, see Juvenile Myelomonocytic Leukemia Treatment.

  • Chronic myeloid 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 leukemias.[1] Although CML has been reported in very young children, most patients are aged 6 years and older.

    CML is a clonal panmyelopathy that involves all hematopoietic cell lineages. While the WBC count can be extremely elevated, the bone marrow does not show increased numbers of leukemic blasts during the chronic phase of this disease. CML is caused by the presence of the Philadelphia chromosome, a translocation between chromosomes 9 and 22 (i.e., t(9;22)) resulting in fusion of the BCR and ABL1 genes.

    For more information, see Childhood Chronic Myeloid Leukemia Treatment.

    Other chronic myeloproliferative neoplasms, such as polycythemia vera, primary myelofibrosis, and essential thrombocytosis, are extremely rare in children.

  • Acute promyelocytic leukemia (APL). APL is a distinct subtype of AML and occurs in about 7% of children with AML.[1,10] Several factors that make APL unique include the following:
    • Clinical presentation of universal coagulopathy (disseminated intravascular coagulation) and unique morphological characteristics (French-American-British [FAB] M3 or its variants).
    • Unique molecular etiology as a result of the involvement of the RARA oncogene.
    • Unique sensitivity to the differentiating agent tretinoin and to the proapoptotic agent arsenic trioxide.[11]

    For more information, see Childhood Acute Promyelocytic Leukemia Treatment.

References
  1. Smith MA, Ries LA, Gurney JG, et al.: Leukemia. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649, pp 17-34. Also available online. Last accessed August 11, 2022.
  2. Roberts I, Alford K, Hall G, et al.: GATA1-mutant clones are frequent and often unsuspected in babies with Down syndrome: identification of a population at risk of leukemia. Blood 122 (24): 3908-17, 2013. [PUBMED Abstract]
  3. Zipursky A: Transient leukaemia--a benign form of leukaemia in newborn infants with trisomy 21. Br J Haematol 120 (6): 930-8, 2003. [PUBMED Abstract]
  4. Gamis AS, Smith FO: Transient myeloproliferative disorder in children with Down syndrome: clarity to this enigmatic disorder. Br J Haematol 159 (3): 277-87, 2012. [PUBMED Abstract]
  5. Hasle H, Niemeyer CM: Advances in the prognostication and management of advanced MDS in children. Br J Haematol 154 (2): 185-95, 2011. [PUBMED Abstract]
  6. Schwartz JR, Ma J, Lamprecht T, et al.: The genomic landscape of pediatric myelodysplastic syndromes. Nat Commun 8 (1): 1557, 2017. [PUBMED Abstract]
  7. Niemeyer CM, Arico M, Basso G, et al.: Chronic myelomonocytic leukemia in childhood: a retrospective analysis of 110 cases. European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS) Blood 89 (10): 3534-43, 1997. [PUBMED Abstract]
  8. Loh ML: Recent advances in the pathogenesis and treatment of juvenile myelomonocytic leukaemia. Br J Haematol 152 (6): 677-87, 2011. [PUBMED Abstract]
  9. Stieglitz E, Taylor-Weiner AN, Chang TY, et al.: The genomic landscape of juvenile myelomonocytic leukemia. Nat Genet 47 (11): 1326-33, 2015. [PUBMED Abstract]
  10. von Neuhoff C, Reinhardt D, Sander A, et al.: Prognostic impact of specific chromosomal aberrations in a large group of pediatric patients with acute myeloid leukemia treated uniformly according to trial AML-BFM 98. J Clin Oncol 28 (16): 2682-9, 2010. [PUBMED Abstract]
  11. Melnick A, Licht JD: Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 93 (10): 3167-215, 1999. [PUBMED Abstract]

Inherited and Acquired Conditions Associated With AML and Other Myeloid Malignancies

Risk Factors for Acute Myeloid Leukemia (AML) and Other Myeloid Malignancies

Genetic abnormalities (cancer predisposition syndromes) are associated with the development of AML and other myeloid malignancies. These inherited/familial syndromes are recognized as a unique category in the 5th edition of the World Health Organization (WHO) Classification of Hematolymphoid Tumors. There are also several acquired conditions that increase the risk of developing AML and other myeloid malignancies (categorized below). These inherited and acquired conditions can induce leukemogenesis through mechanisms that include chromosomal imbalances or instabilities, defects in DNA repair, altered cytokine receptor or signal transduction pathway activation, and altered protein synthesis.[1-3]

Inherited syndromes

  • Chromosomal imbalances:
    • Down syndrome.
    • Familial monosomy 7.
  • Chromosomal instability syndromes:
    • Fanconi anemia.
    • Dyskeratosis congenita.
    • Bloom syndrome.
  • Syndromes of growth and cell survival signaling pathway defects:
    • Neurofibromatosis type 1 (particularly JMML development).
    • Noonan syndrome (particularly JMML development).
    • Severe congenital neutropenia (Kostmann syndrome, HAX1, C6PC3, CSF3R, VPS45, JAGN1, GFI1, CXCR4, and WAS variants) and cyclic neutropenia (ELANE variants).
    • Shwachman-Diamond syndrome.
    • Diamond-Blackfan anemia.
    • Congenital amegakaryocytic thrombocytopenia (MPL variants).
    • CBL germline syndrome (particularly in JMML).
    • Li-Fraumeni syndrome (TP53 variants).
  • Inherited thrombocytopenia and platelet disorders with germline predisposition to myeloid neoplasia (RUNX1, ANKRD26, and ETV6 variants).
  • GATA2 deficiency (GATA2 variants).

Nonsyndromic genetic susceptibility to AML and other myeloid malignancies is also being studied. For example, homozygosity for a specific IKZF1 polymorphism has been associated with an increased risk of AML.[4-6]

The 5th edition of the WHO classification system has categorized the myeloid neoplasms with germline predisposition as follows:[3]

  • Myeloid neoplasms with germline predisposition without a preexisting platelet disorder or organ dysfunction.[3]
    • Germline CEBPA pathogenic or likely pathogenic variant (CEBPA-associated familial AML).
    • Germline DDX41 pathogenic or likely pathogenic variant.
    • Germline TP53 pathogenic or likely pathogenic variant (Li-Fraumeni syndrome).
  • Myeloid neoplasms with germline predisposition and preexisting platelet disorders.[3]
    • Germline RUNX1 pathogenic or likely pathogenic variant (familial platelet disorder with associated myeloid malignancy, FPD-MM).
    • Germline ANKRD26 pathogenic or likely pathogenic variant (thrombocytopenia 2).
    • Germline ETV6 pathogenic or likely pathogenic variant (thrombocytopenia 5).
  • Myeloid neoplasms with germline predisposition and potential organ dysfunction.[3]
    • Germline GATA2 pathogenic or likely pathogenic variant (GATA2 deficiency).
    • Bone marrow failure syndromes.
      • Severe congenital neutropenia (SCN).
      • Shwachman-Diamond syndrome (SDS).
      • Fanconi anemia (FA).
    • Telomere biology disorders.
    • RASopathies (neurofibromatosis type 1, Noonan syndrome, and Noonan syndrome–like disorders).
    • Down syndrome.
    • Germline SAMD9 pathogenic or likely pathogenic variant (MIRAGE syndrome).
    • Germline SAMD9L pathogenic or likely pathogenic variant (SAMD9L-related ataxia pancytopenia syndrome).
    • Biallelic germline BLM pathogenic or likely pathogenic variant (Bloom syndrome).

There is a high concordance rate of leukemia in identical twins. However, this finding 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.[7-9] 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.[10,11]

References
  1. Puumala SE, Ross JA, Aplenc R, et al.: Epidemiology of childhood acute myeloid leukemia. Pediatr Blood Cancer 60 (5): 728-33, 2013. [PUBMED Abstract]
  2. West AH, Godley LA, Churpek JE: Familial myelodysplastic syndrome/acute leukemia syndromes: a review and utility for translational investigations. Ann N Y Acad Sci 1310: 111-8, 2014. [PUBMED Abstract]
  3. Khoury JD, Solary E, Abla O, et al.: The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia 36 (7): 1703-1719, 2022. [PUBMED Abstract]
  4. Ross JA, Linabery AM, Blommer CN, et al.: Genetic variants modify susceptibility to leukemia in infants: a Children's Oncology Group report. Pediatr Blood Cancer 60 (1): 31-4, 2013. [PUBMED Abstract]
  5. de Rooij JD, Beuling E, van den Heuvel-Eibrink MM, et al.: Recurrent deletions of IKZF1 in pediatric acute myeloid leukemia. Haematologica 100 (9): 1151-9, 2015. [PUBMED Abstract]
  6. Zhang X, Huang A, Liu L, et al.: The clinical impact of IKZF1 mutation in acute myeloid leukemia. Exp Hematol Oncol 12 (1): 33, 2023. [PUBMED Abstract]
  7. Zuelzer WW, Cox DE: Genetic aspects of leukemia. Semin Hematol 6 (3): 228-49, 1969. [PUBMED Abstract]
  8. Miller RW: Persons with exceptionally high risk of leukemia. Cancer Res 27 (12): 2420-3, 1967. [PUBMED Abstract]
  9. Inskip PD, Harvey EB, Boice JD, et al.: Incidence of childhood cancer in twins. Cancer Causes Control 2 (5): 315-24, 1991. [PUBMED Abstract]
  10. Kurita S, Kamei Y, Ota K: Genetic studies on familial leukemia. Cancer 34 (4): 1098-101, 1974. [PUBMED Abstract]
  11. Greaves M: Pre-natal origins of childhood leukemia. Rev Clin Exp Hematol 7 (3): 233-45, 2003. [PUBMED Abstract]

Classification of Pediatric Myeloid Malignancies

Over the past 40 years, myeloid malignancies have been categorized using several classification systems that have built upon ever-improving methods of diagnosis. Initially, the French-American-British (FAB) classification system was created primarily based on morphologically distinct subgroups that were defined histochemically and, eventually, immunologically. The World Health Organization's (WHO) classification system for acute myeloid leukemia (AML) was developed after the FAB system, and it is the primary system used now. The WHO classification was initially and primarily based on cytogenetics and morphology, and it now also uses molecular genetics. It has gone through several iterations, with the latest publication in 2022 (5th edition of the WHO Classification of Hematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms). A third classification system, the International Consensus Classification (ICC) of Myeloid Neoplasms and Acute Leukemias, has been published and is primarily used as a tool for clinical trial development instead of clinical use.

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

The first comprehensive morphological-histochemical classification system for AML was developed by the FAB Cooperative Group.[1-5] This classification system, which has been replaced by the WHO system, categorized AML into major subtypes primarily on the basis of morphology and immunohistochemical detection of lineage markers.

The major subtypes of AML include the following:

  • M0: Acute myeloblastic leukemia without differentiation.[6,7] M0 AML, also referred to as minimally differentiated AML, does not express myeloperoxidase (MPO) at the light microscopy level but may show characteristic granules by electron microscopy. M0 AML can be defined by expression of cluster determinant (CD) markers such as CD13, CD33, and CD117 (c-KIT) in the absence of lymphoid differentiation.
  • M1: Acute myeloblastic leukemia with minimal differentiation but with the expression of MPO that is detected by immunohistochemistry or flow cytometry.
  • M2: Acute myeloblastic leukemia with differentiation.
  • M3: Acute promyelocytic leukemia (APL) hypergranular type. For more information, see Childhood Acute Promyelocytic Leukemia Treatment.
  • 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.

Although the FAB classification was superseded by the WHO classification described below, it remains relevant as the basis of the WHO's subcategory of AML, defined by differentiation. AML, defined by differentiation, is used for patients whose AML does not meet the criteria for classification within all the current and newly discovered cytogenetic-specific, molecular-specific, and myelodysplastic neoplasms (MDS) or treatment-related AML categories.

World Health Organization (WHO) Classification System for Childhood AML

In 2001, the WHO proposed a new classification system that incorporated diagnostic cytogenetic information and that more reliably correlated with outcome. In this classification, patients with t(8;21), inv(16), t(15;17), or KMT2A (MLL) translocations, which collectively made up nearly half of childhood AML cases, were classified as AML with recurrent cytogenetic abnormalities. This classification system also decreased the required bone marrow percentage of leukemic blasts for the diagnosis of AML from 30% to 20%. An additional clarification was made so that patients with recurrent cytogenetic abnormalities did not need to meet the minimum blast requirement to be considered an AML patient.[8-10]

In 2008, the WHO expanded the number of cytogenetic abnormalities linked to AML classification and, for the first time, included specific gene variants (CEBPA and NPM) in its classification system.[11]

In 2016, and again in 2022, the WHO classification underwent revisions to incorporate the expanding knowledge of leukemia biomarkers, which are important to the diagnosis, prognosis, and treatment of leukemia.[12,13] With emerging technologies aimed at genetic, epigenetic, proteomic, and immunophenotypic classification, AML classification will continue to evolve and provide informative prognostic and biological guidelines to clinicians and researchers.

2022 WHO classification of hematolymphoid tumors (5th edition)

  • AML with defining genetic abnormalities:
    • Acute promyelocytic leukemia with PML::RARA fusion.
    • Acute myeloid leukemia with RUNX1::RUNX1T1 fusion.
    • Acute myeloid leukemia with CBFB::MYH11 fusion.
    • Acute myeloid leukemia with DEK::NUP214 fusion.
    • Acute myeloid leukemia with RBM15::MRTFA fusion.
    • Acute myeloid leukemia with BCR::ABL1 fusion.
    • Acute myeloid leukemia with KMT2A rearrangement.
    • Acute myeloid leukemia with MECOM rearrangement.
    • Acute myeloid leukemia with NUP98 rearrangement.
    • Acute myeloid leukemia with NPM1 variant.
    • Acute myeloid leukemia with CEBPA variant.
    • Acute myeloid leukemia, myelodysplasia-related.
    • Acute myeloid leukemia with other defined genetic alterations.
  • AML, defined by differentiation:
    • Acute myeloid leukemia with minimal differentiation.
    • Acute myeloid leukemia without maturation.
    • Acute myeloid leukemia with maturation.
    • Acute basophilic leukemia.
    • Acute myelomonocytic leukemia.
    • Acute monoblastic/monocytic leukemia.
    • Pure erythroid leukemia.
    • Acute megakaryoblastic leukemia.

The inaugural WHO Classification of Pediatric Tumors was also published in 2022. It focuses on a multilayered approach to AML classification, encompassing multiple clinico-pathological parameters and seeking a genetic basis for disease classification wherever possible.[13,14] The recurrent translocations and other genomic alterations that are used to define specific pediatric AML entities in the pediatric WHO classification are listed in Table 1.

Table 1. Pediatric Acute Myeloid Leukemia (AML) With Recurrent Gene Alterations Included in the WHO Classification of Pediatric Tumorsa
Diagnostic CategoryApproximate Prevalence in Pediatric AML
aAdapted from Pfister et al.[14]
bCryptic chromosomal translocation.
AML with t(8;21)(q22;q22); RUNX1::RUNX1T113%–14%
AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB::MYH114%–9%
APL with t(15;17)(q24.1;q21.2); PML::RARA6%–11%
AML with KMT2A-rearrangement 25%
AML with t(6;9)(p23;q34.1); DEK::NUP2141.7%
AML with inv(3)(q21q26)/t(3;3)(q21;q26); GATA2, RPN1::MECOM<1%
AML with ETV6 fusion 0.8%
AML with t(8;16)(p11.2;p13.3); KAT6A::CREBBP 0.5%
AML with t(1;22)(p13.3;q13.1); RBM15::MRTFA (MKL1)0.8%
AML with CBFA2T3::GLIS2 (inv(16)(p13q24))b3%
AML with NUP98 fusionb10%
AML with t(16;21)(p11;q22); FUS::ERG 0.3%–0.5%
AML with NPM1 variants8%
AML with variants in the bZIP domain of CEBPA5%
Histochemical evaluation

It is critical to distinguish AML from acute lymphoblastic leukemia (ALL) because the treatment for children with AML differs significantly from that for 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 and variably positive in AML include myeloperoxidase, nonspecific esterases, and Sudan Black B, whereas periodic acid-Schiff is usually positive in ALL, M6 AML (AEL), and, occasionally, M4 and M5 FAB subtypes. In most cases, the pattern with these histochemical stains will distinguish AML from ALL. However, histochemical stains have been mostly replaced by flow cytometric immunophenotyping for diagnostic purposes.

Immunophenotypic evaluation

The use of monoclonal antibodies via flow cytometry to determine cell-surface antigens of AML cells is now the primary tool used to diagnose AML. 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 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, lineage-associated T-lymphocytic antigens CD2, CD3, CD5, and CD7 are present in 20% to 40% of AML cases.[15-17] The aberrant expression of lymphoid-associated antigens by AML cells is relatively common but generally has no prognostic significance.[15,16]

Immunophenotyping can also be helpful in distinguishing the following FAB classification subtypes of AML:

  • APL: Testing for the presence of HLA-antigen D related (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.[18,19] 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 is often negative or low.[18,19] The APL microgranular variant M3v more commonly expresses CD34 along with CD2.[18,20]
  • M7: Testing for the presence of glycoprotein Ib, glycoprotein IIb/IIIa, or Factor VIII antigen expression is helpful in diagnosing M7 (megakaryocytic leukemia).
  • M6: Glycophorin expression is helpful in diagnosing M6 (erythroid leukemia).

2022 WHO classification of acute leukemias of mixed or ambiguous lineage (5th edition)

Less than 5% of cases of acute leukemia in children are of ambiguous lineage, expressing features of both myeloid and lymphoid lineage.[21-23] 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.[13,24-26] In the WHO classification, the presence of MPO is required to establish myeloid lineage. This is not the case for the EGIL classification. The 5th edition of 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. The clinical significance of that finding is unclear, suggesting that caution should be used in designating these cases as mixed-phenotype acute leukemia (MPAL).[13]

For the group of acute leukemias that have characteristics of both AML and ALL, the acute leukemias of ambiguous lineage, the WHO classification system is summarized in Table 2.[27] The criteria for lineage assignment for a diagnosis of MPAL are provided in Table 3. Note that similar disease categories and diagnostic criteria are included in the International Consensus Classification of Leukemias of Ambiguous Origin.[28]

Leukemias of mixed phenotype may be seen in various presentations, including the following:

  1. Bilineal leukemias in which there are two distinct populations of cells, usually one lymphoid and one myeloid.
  2. Biphenotypic leukemias in which individual blast cells display features of both lymphoid and myeloid lineage.

Biphenotypic cases represent the majority of mixed-phenotype leukemias.[21] Some studies suggest that patients with biphenotypic leukemia may fare better with a lymphoid, as opposed to a myeloid, treatment regimen.[22,23,29,30]; [31][Level of evidence C1]

A large retrospective study from the international Berlin-Frankfurt-Münster (BFM) group demonstrated that initial therapy with an ALL-type regimen was associated with a superior outcome compared with AML-type or combined ALL/AML regimens, particularly in cases with CD19 positivity or other lymphoid antigen expression. In this study, hematopoietic stem cell transplant (HSCT) in first CR was not beneficial, with the possible exception of cases with morphological evidence of persistent marrow disease (≥5% blasts) after the first month of treatment.[30]

Table 2. Acute Leukemias of Ambiguous Lineage According to the 5th Edition (2022) of the World Health Organization Classification of Hematolymphoid Tumorsa
aCredit: Khoury, J.D., Solary, E., Abla, O. et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia 36, 1703–1719 (2022). https://doi.org/10.1038/s41375-022-01613-1.[13] This is an open access article distributed under the terms of the Creative Commons CC BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Acute leukemia of ambiguous lineage with defining genetic abnormalities
Mixed-phenotype acute leukemia with BCR::ABL1 fusion
Mixed-phenotype acute leukemia with KMT2A rearrangement
Acute leukemia of ambiguous lineage with other defined genetic alterations:   
  Mixed-phenotype acute leukemia with ZNF384 rearrangement
 Acute leukemia of ambiguous lineage with BCL11B rearrangement
Acute leukemia of ambiguous lineage, immunophenotypically defined
Mixed-phenotype acute leukemia, B/myeloid
Mixed-phenotype acute leukemia, T/myeloid
 Mixed-phenotype acute leukemia, rare types
Acute leukemia of ambiguous lineage, not otherwise specified
Acute undifferentiated leukemia
Table 3. Lineage Assignment Criteria for Mixed-Phenotype Acute Leukemia According to the 5th Edition (2022) of the World Health Organization Classification of Hematolymphoid Tumorsa
LineageCriterion
aCredit: Khoury, J.D., Solary, E., Abla, O. et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia 36, 1703–1719 (2022). https://doi.org/10.1038/s41375-022-01613-1.[13] This is an open access article distributed under the terms of the Creative Commons CC BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
bCD19 intensity in part exceeds 50% of normal B cell progenitor by flow cytometry.
cCD19 intensity does not exceed 50% of normal B cell progenitor by flow cytometry.
dProvided T lineage not under consideration, otherwise cannot use CD79a.
eUsing anti-CD3 epsilon chain antibody.
B lineage 
CD19 strongb, OR1 or more also strongly expressed: CD10, CD22, or CD79ad
CD19 weakc2 or more also strongly expressed: CD10, CD22, or CD79ad
T lineage 
CD3 (cytoplasmic or surface)eIntensity in part exceeds 50% of mature T-cells level by flow cytometry or immunocytochemistry positive with non-zeta chain reagent
Myeloid lineage 
Myeloperoxidase, OR Intensity in part exceeds 50% of mature neutrophil level
Monocytic differentiation 2 or more expressed: Nonspecific esterase, CD11c, CD14, CD64, or lysozyme

International Consensus Classification (ICC) of Myeloid Neoplasms and Acute Leukemias

The ICC of Myeloid Neoplasms and Acute Leukemias was published in 2022 to further incorporate new discoveries in the biology of myeloid malignancies. The ICC seeks to integrate morphological, clinical, and genomic data into a new classification system.[32] The ICC has not replaced the WHO classification, but it is increasingly being used in the development of international clinical trials.

Genomics of AML

Cytogenetic/molecular features of AML

Genetic analysis of leukemia blast cells (using both conventional cytogenetic methods and molecular methods) is performed on children with AML because both chromosomal and molecular abnormalities are important diagnostic and prognostic markers.[33-37] Clonal chromosomal abnormalities are identified in the blasts of about 75% of children with AML and are useful in defining subtypes with both prognostic and therapeutic significance. Detection of molecular abnormalities can also aid in risk stratification and treatment allocation. For example, variants of NPM and CEBPA are associated with favorable outcomes, while certain variants of FLT3 portend a high risk of relapse. Identifying the latter variants may allow for targeted therapy.[38-41]

Comprehensive molecular profiling of pediatric and adult AML has shown that AML is a disease demonstrating both commonalities and differences across the age spectrum.[42,43]

  • Pediatric AML, in contrast to AML in adults, is typically a disease of recurring chromosomal alterations. For a list of common gene fusions and other recurring genomic alterations, see Table 4.[37,42] Within the pediatric age range, certain gene fusions occur primarily in children younger than 5 years (e.g., NUP98, KMT2A, and CBFA2T3::GLIS2 gene fusions), while others occur primarily in children aged 5 years and older (e.g., RUNX1::RUNX1T1, CBFB::MYH11, and PML::RARA gene fusions).
  • In general, pediatric patients with AML have low rates of variants. Most cases show less than one somatic change in protein-coding regions per megabase.[43] This variant rate is somewhat lower than that observed in adult AML and is much lower than the variant rate for cancers that respond to checkpoint inhibitors (e.g., melanoma).[43]
  • The pattern of gene variants differs between pediatric and adult AML cases. For example, IDH1, IDH2, TP53, RUNX1, and DNMT3A variants are more common in adult AML than in pediatric AML, while NRAS and WT1 variants are significantly more common in pediatric AML.[42-44]
  • The genomic landscape of pediatric AML cases can change from diagnosis to relapse, with variants detectable at diagnosis dropping out at relapse and, conversely, with new variants appearing at relapse. In a study of 20 cases for which sequencing data were available at diagnosis and relapse, a key finding was that the variant allele frequency at diagnosis strongly correlated with persistence of variants at relapse.[45] Approximately 90% of the diagnostic variants with variant allele frequency greater than 0.4 persisted to relapse, compared with only 28% with variant allele frequency less than 0.2 (P < .001). This observation is consistent with previous results showing that presence of a variant in the FLT3 gene resulting from internal tandem duplications (ITD) predicted for poor prognosis only when there was a high FLT3 ITD allelic ratio.

The 5th edition (2022) of the World Health Organization (WHO) Classification of Hematolymphoid Tumors, as well as the Inaugural WHO Classification of Pediatric Tumors, emphasize a multilayered approach to AML classification. These classifications consider multiple clinico-pathological parameters and seek a genetic basis for disease classification wherever possible.[13,14] These karyotypic abnormalities and other genomic alterations are used to define specific pediatric AML entities and are outlined in Table 4.[13,14]

In addition to the cytogenetic/molecular abnormalities that aid AML diagnosis, as defined by the WHO, there are additional entities that, while not disease-defining, have prognostic significance in pediatric AML. All prognostic abnormalities, both those defined by the WHO and these additional abnormalities, have been clustered according to favorable or unfavorable prognosis, as defined by contemporary Children's Oncology Group (COG) clinical trials. These entities are summarized below. After these entities are described, information about additional cytogenetic/molecular and phenotypic features associated with pediatric AML will be described. However, these additional features may not, at present, be used to aid in risk stratification and treatment.

While the t(15;17) fusion that results in the PML::RARA gene product is defined as a pediatric AML risk-defining lesion, given its association with acute promyelocytic leukemia, it is discussed in Childhood Acute Promyelocytic Leukemia.

Table 4. Pediatric Acute Myeloid Leukemia (AML) With Recurrent Gene Alterations Included in the WHO Classification of Pediatric Tumorsa
Diagnostic CategoryApproximate Prevalence in Pediatric AML
aAdapted from Pfister et al.[14]
bCryptic chromosomal translocation.
AML with t(8;21)(q22;q22); RUNX1::RUNX1T113%–14%
AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB::MYH114%–9%
APL with t(15;17)(q24.1;q21.2); PML::RARA6%–11%
AML with KMT2A rearrangement 25%
AML with t(6;9)(p23;q34.1); DEK::NUP2141.7%
AML with inv(3)(q21q26)/t(3;3)(q21;q26); GATA2, RPN1::MECOM<1%
AML with ETV6 fusion 0.8%
AML with t(8;16)(p11.2;p13.3); KAT6A::CREBBP 0.5%
AML with t(1;22)(p13.3;q13.1); RBM15::MRTFA (MKL1)0.8%
AML with CBFA2T3::GLIS2 (inv(16)(p13q24))b3%
AML with NUP98 fusionb10%
AML with t(16;21)(p11;q22); FUS::ERG 0.3%–0.5%
AML with NPM1 variant8%
AML with variants in the bZIP domain of CEBPA5%

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 5th edition of the WHO classification is incorporated for disease entities where relevant.

Abnormalities associated with a favorable prognosis

Cytogenetic/molecular abnormalities associated with a favorable prognosis include the following:

  • Core-binding factor (CBF) AML includes cases with RUNX1::RUNX1T1 and CBFB::MYH11 gene fusions.
    • AML with RUNX1::RUNX1T1 gene fusions (t(8;21)(q22;q22.1)). In leukemias with t(8;21), the RUNX1 gene on chromosome 21 is fused with the RUNX1T1 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.[33] The t(8;21) translocation occurs in approximately 12% of children with AML [34,35,46] and is associated with a more favorable outcome than AML characterized by normal or complex karyotypes.[33,47-49] Overall, the translocation is associated with 5-year overall survival (OS) rates of 74% to 90%.[34,35,46]
    • AML with CBFB::MYH11 gene fusions (inv(16)(p13.1;q22) or t(16;16)(p13.1;q22)). In leukemias with inv(16), the CBFB gene at chromosome band 16q22 is fused with the MYH11 gene at chromosome band 16p13. The inv(16) translocation is associated with the FAB M4Eo subtype and confers a favorable prognosis for both adults and children with AML.[33,47-49] Inv(16) occurs in 7% to 9% of children with AML, for whom the 5-year OS rate is approximately 85%.[34,35]

      Cases with CBFB::MYH11 or RUNX1::RUNX1T1 fusions have distinctive secondary variants, with CBFB::MYH11 secondary variants primarily restricted to genes that activate receptor tyrosine kinase signaling (NRAS, FLT3, and KIT).[50,51] The prognostic significance of activating KIT variants in adults with CBF AML has been studied with conflicting results. A meta-analysis found that KIT variants appear to increase the risk of relapse without an impact on OS for adults with AML and RUNX1::RUNX1T1 fusions.[52] The prognostic significance of KIT variants in pediatric CBF AML remains unclear. Some studies have found no impact of KIT variants on outcomes,[53-55] although, in some instances, the treatment used was heterogenous, potentially confounding the analysis. Other studies have reported a higher risk of treatment failure when KIT variants are present.[56-61] An analysis of a subset of pediatric patients treated with a uniform chemotherapy backbone on the COG AAML0531 study demonstrated that the subset of patients with KIT exon 17 variants had inferior outcomes, compared with patients with CBF AML who did not have the variant. However, treatment with gemtuzumab ozogamicin abrogated this negative prognostic impact.[60] While there was a trend toward inferior outcomes for patients with CBF AML with co-occurring KIT exon 8 abnormalities, this finding was not statistically significant. A second study of 46 patients who were treated uniformly found that KIT exon 17 variants only had prognostic significance in AML with RUNX1::RUNX1T1 fusions but not CBFB::MYH11 fusions.[61]

      While KIT variants are seen in both CBF AML subsets, other secondary variants tend to cluster with one of the two fusions. For example, patients with RUNX1::RUNX1T1 fusions also have frequent variants in genes regulating chromatin conformation (e.g., ASXL1 and ASXL2) (40% of cases) and genes encoding members of the cohesin complex (20% of cases). Variants in ASXL1 and ASXL2 and variants in members of the cohesin complex are rare in cases with leukemia and CBFB::MYH11 fusions.[50,51] Despite this correlation, a study of 204 adults with AML and RUNX1::RUNX1T1 fusions found that ASXL2 variants (present in 17% of cases) and ASXL1 or ASXL2 variants (present in 25% of cases) lacked prognostic significance.[62] Similar results, albeit with smaller numbers, were reported for children with the same abnormalities.[63]

  • AML with NPM1 variant. 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 NPM1 variants by the demonstration of cytoplasmic localization of NPM. Variants 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 FLT3 ITD variants in adults and younger adults.[64-69]

    Studies of children with AML suggest a lower rate of occurrence of NPM1 variants in children compared with adults with normal cytogenetics. NPM1 variants occur in approximately 8% of pediatric patients with AML and are uncommon in children younger than 2 years.[38,39,70,71] NPM1 variants are associated with a favorable prognosis in patients with AML characterized by a normal karyotype.[38,39,71] For the pediatric population, conflicting reports have been published regarding the prognostic significance of an NPM1 variant when a FLT3 ITD variant is also present. One study reported that an NPM1 variant did not completely abrogate the poor prognosis associated with having a FLT3 ITD variant,[38,72] but other studies showed no impact of a FLT3 ITD variant on the favorable prognosis associated with an NPM1 variant.[39,43,71]

  • AML with CEBPA variants. Variants in the CEBPA gene occur in a subset of children and adults with cytogenetically normal AML.[73,74] In adults younger than 60 years, approximately 15% of cytogenetically normal AML cases have variants in CEBPA.[68] Outcomes for adults with AML with CEBPA variants appear to be relatively favorable and similar to that of patients with CBF leukemias.[68,75] Initial studies in adults with AML demonstrated that CEBPA double-variant, but not single-variant, abnormalities were independently associated with a favorable prognosis,[76-81] leading to the WHO 2016 revision that required biallelic variants for the disease definition.[12] However, a study of over 4,700 adults with AML found that patients with single CEBPA variants in the bZIP C-terminal domain have clinical characteristics and favorable outcomes similar to those of patients with double-variant CEBPA AML.[81]

    CEBPA variants occur in approximately 5% of children with AML and have been preferentially found in the cytogenetically normal subtype of AML with FAB M1 or M2.

    • Patients with double CEBPA variants or with single CEBPA bZIP variants have a median age of presentation of 12 to 13 years and have gene expression profiles that are highly related to each other.[74]
    • Approximately 80% of pediatric patients have double-variant alleles (i.e., cases with both a CEBPA TAD domain and a CEBPA bZIP domain variant), which is predictive of significantly improved survival, similar to the effect observed in adult studies.[74,82]
    • In a study of nearly 3,000 children with AML, both patients with CEBPA double variants and those with only a bZIP domain variant were observed to have a favorable prognosis, compared with patients with wild-type CEBPA.[74]

    Given these findings in pediatric AML with CEBPA variants, the presence of a bZIP variant alone confers a favorable prognosis. Importantly, however, there is a small subset of patients with AML and CEBPA variants who have less-favorable outcomes. Specifically, CSF3R variants occur in 10% to 15% of patients with AML and CEBPA variants. CSF3R variants appear to be associated with an increased risk of relapse, but without an impact on OS.[74,83] At present, the occurrence of this secondary variant does not result in stratification to more intensified therapy in pediatric patients with AML.

    While not common, a small percentage of children with AML and CEBPA variants may have an underlying germline variant. In newly diagnosed patients with double-variant CEBPA AML, germline screening should be considered in addition to usual family history queries because 5% to 10% of these patients have a germline CEBPA abnormality that confers an increased malignancy risk.[73,84]

Cytogenetic abnormality associated with a variable prognosis: KMT2A (MLL) gene rearrangements

The 5th edition (2022) of the WHO Classification of Hematolymphoid Tumors includes a diagnostic category of AML with KMT2A rearrangements. Specific translocation partners are not listed because there are more than 80 KMT2A fusion partners.[13]

  • KMT2A gene rearrangements occur in approximately 20% of children with AML.[34,35] These cases, including most AMLs secondary to epipodophyllotoxin exposure,[85] are generally associated with monocytic differentiation (FAB M4 and M5). KMT2A rearrangements are also reported in approximately 10% of FAB M7 (AMKL) patients.[86,87]
  • The median age for 11q23/KMT2A-rearranged cases in children is approximately 2 years, and most translocation subgroups have a median age at presentation of younger than 5 years.[88] 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).[88]
  • Outcomes for patients with de novo AML and KMT2A gene rearrangements are generally similar to or slightly worse than the outcomes observed in other patients with AML.[33,34,88-90] As the KMT2A gene can participate in translocations with many different fusion partners, the specific fusion partner appears to influence prognosis. This finding was demonstrated by a large international retrospective study that evaluated the outcomes of 756 children with 11q23- or KMT2A-rearranged AML and a second COG analysis that studied KMT2A outcomes within the context of the AAML0531 trial.[88,90]
  • The most common translocation, representing approximately 50% of KMT2A-rearranged cases in the pediatric AML population, is t(9;11)(p22;q23), in which the KMT2A gene is fused with the MLLT3 gene.[88,90] Single clinical trial groups have variably described a more favorable prognosis for these patients. However, neither the international retrospective study nor the COG study confirmed the favorable prognosis for this subgroup.[33,34,88,90] This fusion, which is associated with an intermediate prognosis, is not currently classified as high risk, at least within the COG, unless minimal residual disease (MRD) remains at the end of induction 1.
  • KMT2A-rearranged AML subgroups that are associated with poor outcomes include the following:
    • Cases with the t(10;11) translocation are a group at high risk of relapse in bone marrow and the CNS.[33,35] Some cases with the t(10;11) translocation have fusion of the KMT2A gene with the MLLT10 gene at 10p12, while others have fusion of KMT2A with ABI1 at 10p11.2. An international retrospective study found that these cases, which present at a median age of approximately 1 to 3 years, have a 5-year event-free survival (EFS) rate of 17% to 30%.[88,90]
    • Patients with t(6;11)(q27;q23) (KMT2A::AFDN) have poor outcomes, with 5-year EFS rates of 11% to 15%.[90]
    • Patients with t(4;11)(q21;q23) (KMT2A::AFF1) often present with hyperleukocytosis and also have poor outcomes, with 5-year EFS rates of 0% to 29%.[88,90]
    • Patients with t(11;19)(q23;p13.3) (KMT2A::MLLT1) have poor outcomes, with a 5-year EFS rate of 14%.[90]
    • Based on the data above, the International Berlin-Frankfurt-Münster (iBFM) study group analyzed data regarding outcomes in patients with KMT2A rearrangements enrolled in BFM, COG, and other European cooperative group studies.[91] In keeping with earlier papers,[91] this study classified patients with 6q27 (KMT2A::AFDN, i.e., MLLT4), 4q21 (KMT2A::AFF1, i.e., MLL::MLLT2), 10p12.3 (KMT2A::MLLT10), 10p12.1 (KMT2A::ABI1), and 19p13.3 (KMT2A::MLLT1, i.e., MLL::ENL) as high risk, while all others were considered in the non–high-risk group.[88,90,91] Using this classification, the 5-year EFS rates for patients with non–high-risk, KMT2A-rearranged AML is 54%, compared with 30.3% for patients with high-risk disease.[90] MRD assessment after induction 2 imparts further prognostic significance within the iBFM analysis. However, MRD at the end of induction 1 did not predict for relapse in the context of the COG analysis.[90]
    • With this distinction, non–high-risk KMT2A fusions are, in most cooperative groups, upstaged to high-risk if MRD is noted after induction treatment.[90]
    • When examining outcomes for patients with KMT2A rearrangements, both overall and within the context of high-risk and non–high-risk fusions, treatment with gemtuzumab ozogamicin appeared to abrogate the negative prognostic impact of the variant. Specifically, the EFS rate for patients with KMT2A-rearranged AML was superior with gemtuzumab ozogamicin treatment than without this treatment (48% vs. 29%; P = .003) and comparable with the outcomes observed in patients without KMT2A rearrangements.[90]

Cytogenetic/molecular abnormalities associated with an unfavorable prognosis

Genetic abnormalities associated with an unfavorable prognosis are described below. Some of these are disease-defining alterations that are initiating events and maintained throughout a patient's disease course. Other entities described below are secondary alterations (e.g., FLT3 alterations). Although these secondary alterations do not induce disease on their own, they are able to promote the cell growth and survival of leukemias that are driven by primary genetic alterations.

  • AML with GATA2 or MECOM abnormalities (inv(3)(q21.3;q26.2)/t(3;3)(q21.3;q26.2) or t(3;21)(26.2;q22)). MECOM 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.[92,93] These abnormalities are associated with poor prognosis in adults with AML [33,94,95] but are rare in children (<1% of pediatric AML cases).[34,48,96]

    Abnormalities involving MECOM can also be detected in some AML cases with other 3q abnormalities (e.g., t(3;21)(26.2;q22)). The RUNX1::MECOM fusion is also associated with poor prognosis.[97,98]

  • AML with NPM1::MLF1 (t(3;5)(q25;q34)) gene fusions. This fusion results in a chimeric protein that includes virtually the entire MLF1 gene. This gene does not usually have a function in normal hematopoiesis, but in this context, it is hypothesized to result in ectopic expression of the protein. While incredibly rare in pediatrics (less than 0.5% of cases, most of which occur in adolescence),[99] it is generally associated with poor prognosis.[100]
  • AML with DEK::NUP214 (t(6;9)(p23;q34.1)) gene fusions. t(6;9) leads to the formation of a leukemia-associated fusion protein DEK::NUP214.[101,102] This subgroup of AML has been associated with a poor prognosis in adults with AML,[101,103,104] and occurs infrequently in children (less than 1% of AML cases). The median age of children with AML and DEK::NUP214 fusions is 10 to 11 years, and approximately 40% of pediatric patients have FLT3 ITD.[105,106]

    t(6;9) AML appears to be associated with a high risk of treatment failure in children, particularly for those not proceeding to allogeneic HSCT.[34,102,105,106]

  • AML with KAT6A::CREBBP (t(8;16)(p11.2;p13.3)) gene fusions (if 90 days or older at diagnosis). The t(8;16) translocation fuses the KAT6A gene on chromosome 8p11 to CREBBP on chromosome 16p13. It is associated with poor outcomes in adults, although its prognostic significance in pediatrics is less clear.[43,107] Although this translocation rarely occurs in children, in an iBFM AML study of 62 children, this translocation was associated with younger age at diagnosis (median, 1.2 years), FAB M4/M5 phenotype, erythrophagocytosis, leukemia cutis, and disseminated intravascular coagulation.[108] 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.[108-111] These observations suggest that a watch-and-wait approach could be considered in cases of t(8;16) AML diagnosed in the neonatal period if close long-term monitoring can be ensured.[108] For older children, the prognosis is less favorable, and the typical recommendation is to proceed to HSCT once remission is achieved.
  • AML with FUS::ERG (t(16;21)(p11;q22)) gene fusions. In leukemias with t(16;21)(p11;q22), the FUS gene is joined with the ERG gene, producing a distinctive AML subtype with a gene expression profile that clusters separately from other cytogenetic subgroups.[112] This fusion is rare in pediatrics and represents 0.3% to 0.5% of pediatric AML cases. In a cohort of 31 patients with AML and FUS::ERG fusions, outcomes were poor, with a 4-year EFS rate of 7% and a cumulative incidence of relapse rate of 74%.[112]
  • AML with CBFA2T3::GLIS2 gene fusions. CBFA2T3::GLIS2 is a fusion resulting from a cryptic chromosome 16 inversion (inv(16)(p13.3;q24.3)).[113-117] It occurs commonly in non–Down syndrome AMKL, representing 16% to 27% of pediatric AMKL and presents at a median age of 1 year.[87,115,118-120] Leukemia cells with CBFA2T3::GLIS2 fusions have a distinctive immunophenotype (initially reported as the RAM phenotype),[121,122] with high CD56, dim or negative expression of CD45 and CD38, and a lack of HLA-DR expression. This fusion is a very high-risk lesion associated with poor clinical outcomes.[87,113,117-120]

    In a study of approximately 2,000 children with AML, the CBFA2T3::GLIS2 fusion was identified in 39 cases (1.9%), with a median age at presentation of 1.5 years. All cases observed in children were younger than 3 years.[123] Approximately one-half of cases had M7 megakaryoblastic morphology, and 29% of patients were Black or African American (exceeding the 12.8% frequency in patients lacking the fusion). Children with the fusion were found to be MRD positive after induction 1 in 80% of cases. In an analysis of outcomes from serial COG trials of 37 identified patients, OS at 5 years from study entry was 22.0% for patients with CBFA2T3::GLIS2 fusions versus 63.0% for fusion-negative patients (n = 1,724). Even worse outcomes were demonstrated when the subset of patients with CBFA2T3::GLIS2 AMKL were compared with patients with AMKL without the abnormality. Analysis from the COG AAML0531 and AAML1031 trials revealed OS rates of 43% (± 37%) and 10% (± 19%), respectively, among children with AMKL and this fusion.[120] As CBFA2T3::GLIS2 leukemias express high levels of cell surface FOLR1, a targetable surface antigen by immunotherapeutic approaches, the roles of such agents are planned for study in this high-risk population.[124,125]

  • AML with NUP98 gene fusions. NUP98 has been reported to form leukemogenic gene fusions with more than 20 different partners. A significant proportion of cases are associated with non–Down syndrome AMKL, although approximately 50% are seen outside of that morphologic subtype.[126,127] The two most common gene fusions in pediatric AML are NUP98::NSD1 and NUP98::KDM5A. In one report, the former fusion was observed in approximately 15% of cytogenetically normal pediatric AML cases, and the latter fusion was observed in approximately 10% of pediatric AMKL cases (see below).[87,115,120,128] AML cases with either NUP98 gene fusion show high expression of HOXA and HOXB genes, indicative of a stem cell phenotype.[102,115] Some of the less common fusions entail HOX genes.[127]

    The NUP98::NSD1 gene fusion, which is often cytogenetically cryptic, results from the fusion of NUP98 (chromosome 11p15) with NSD1 (chromosome 5q35).[102,128-130] This alteration occurs in approximately 4% to 7% of pediatric AML cases.[12,102,128,131,132] It is the most common NUP98 fusion seen. This disease phenotype is characterized by the following:

    • The highest frequency of NUP98::NSD1 fusions in the pediatric population is observed in children aged 5 to 9 years (approximately 8%), with a lower frequency in younger children (approximately 2% in children younger than 2 years).
    • Patients with NUP98::NSD1 fusions present with a high white blood cell (WBC) count (median, 147 × 109/L in one study).[128,129] Most patients with AML and NUP98::NSD1 fusions do not show cytogenetic aberrations.[102,128] There is a slight male predominance for patients with this fusion (64.5% vs. 32.2%).[127]
    • A high percentage of patients with NUP98::NSD1 fusions (74%–90%) have co-occurring FLT3 ITD AML.[128,129,131]
    • In one of a series of COG studies, 108 children with NUP98::NSD1 fusions demonstrated lower rates of complete remission (CR) (38%, P < .001) and higher rates of MRD (73%, P < .001), compared with a cohort of patients without NUP98 fusions. Patients with NUP98::NSD1 fusions also had inferior EFS rates (17% vs. 47%; P < .001) and OS rates (36% vs. 64%; P < .001), compared with the reference cohort.[127] In another study that included children (n = 38) and adults (n = 7) with AML and NUP98::NSD1 fusions, presence of both NUP98::NSD1 fusions and FLT3 ITD independently predicted poor prognosis. Patients with both lesions had a low CR rate (approximately 30%) and a low 3-year EFS rate (approximately 15%).[129]
    • In a study of children with refractory AML, NUP98 was overrepresented compared with a cohort who did achieve remission (21% [6 of 28 patients] vs. <4%).[133]

    A cytogenetically cryptic translocation, t(11;12)(p15;p13), results in the NUP98::KDM5A gene fusion.[134] Approximately 2% of all pediatric AML patients have NUP98::KDM5A fusions, and these cases tend to present at a young age (median age, 3 years).[135] Additional clinical characteristics are as follows:

    • Cases with NUP98::KDM5A fusions tend to be AMKL (34%), followed by FAB M5 (21%), and FAB M6 (17%) histologies.[135] NUP98::KDM5A fusions are observed in approximately 10% of pediatric AMKL cases,[87,118] and patients with this fusion tend to present with lower WBC counts than patients with NUP98::NSD1 fusions.
    • Other genetic aberrations associated with pediatric AML, including FLT3 variants, are uncommon in patients with NUP98::KDM5A fusions.[135]
    • Prognosis for children with NUP98::KDM5A fusions is inferior to that of other children with AML (5-year EFS rate, 29.6% ± 14.6%; OS rate, 34.1% ± 16.1%) in one series.[135] Another study that included 32 patients with NUP98::KDM5A fusions demonstrated similar CR rates to the reference population but inferior OS (30%, P < .001) and EFS rates (25%; P = .01).[127]
  • AML with 12p13.2 rearrangements (ETV6 and any partner gene). The ETS family of genes encode transcription factors responsible for cellular growth and development. The ETV6 gene encodes a transcription factor that serves as a tumor suppressor gene and is the most frequent ETS family rearranged partner in pediatric AML. The cryptic translocation t(7;12)(q36;p13) encodes ETV6::MNX1, the most frequent ETV6-rearranged fusion partner, which occurs in approximately 1% of pediatric AML cases (enriched in infants). It is associated with poor clinical outcomes.[136] It is also strongly associated with trisomy 19.[136] The transcription may be cryptic by conventional karyotyping and, in some cases, may be confirmed only by fluorescence in situ hybridization (FISH).[137,138] This alteration occurs virtually exclusively in children younger than 2 years, with a median age of diagnosis of 6 months.[136] It appears to be associated with a high risk of treatment failure.[34,35,71,137,139,140] A literature review of 17 cases showed a 3-year EFS rate of 24% and OS rate of 42%.[43,136,141]
  • AML with 12p deletion to include 12p13.2 (loss of ETV6). ETV6 deletions are exceedingly rare in pediatric AML. In one pediatric series, 4 of 259 patients (1.5%) had an ETV6 deletion.[141,142] This abnormality is enriched in adult patients with chromosome 7 abnormalities and in patients with TP53 variants.[143] However, in a second pediatric series, there was a reported correlation with CBF AML.[142] According to this latter series, relapse risk rates for patients with and without deletions in ETV6 were 63% and 45%, respectively (P = .3), with corresponding disease-free survival (DFS) rates of 32% and 53%, respectively (P = .2). However, there was a high prevalence of CBF AML in patients with ETV6 deletions. In the context of CBF AML, the deletion was associated with adverse outcomes. Patients with CBF AML, with and without ETV6 deletions, had EFS rates of 0% and 63%, respectively (P = .002). Of the patients with CBF AML who achieved an initial CR, those with an ETV6 deletion had a risk of relapse rate of 88%, compared with 38% for those without the deletion (P = .08). The corresponding DFS rates were 0% for patients with an ETV6 deletion, compared with 61% for those without the deletion (P = .009).[142]
  • Chromosome 5 and 7 abnormalities. Chromosomal abnormalities associated with poor prognosis in adults with AML include those involving chromosome 5 (del(5q)) and chromosome 7 (monosomy 7).[33,94,144] These cytogenetic subgroups represent approximately 2% and 4% of pediatric AML cases, respectively, and are also associated with poor prognosis in children.[34,94,144-147] Chromosome 5 and 7 abnormalities appear to lack prognostic significance in AML patients with Down syndrome who are aged 4 years and younger.[148]

    Increasing data show that the presence of monosomy 7 is associated with a higher risk of a patient having germline GATA2, SAMD9 or SAMD9L pathogenic variants. Cases associated with an underlying RUNX1-altered familial platelet disorder, telomere biology disorder, and germline ERCC6L2 pathogenic variants have also been reported.[149] Germline testing should be considered when monosomy 7 disease is identified.

    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.[36] However, outcome for children with del(7q), but not monosomy 7, appears comparable to that of other children with AML.[35,146] The presence of del(7q) does not abrogate the prognostic significance of favorable cytogenetic characteristics (e.g., inv(16) and t(8;21)).[33,146]

  • AML with 10p12.3 rearrangements (MLLT10::any partner gene). MLLT10 frequently forms fusions with partners other than KMT2A, and these fusions are also associated with a poor prognosis. A retrospective review of 2,226 children enrolled in serial COG trials identified 23 children with non-KMT2A::MLLT10 fusions. Nearly one-half of patients (13 of 23) had MLLT10::PICALM fusions, and the EFS rate of this heterogenous group was 12.7%.[150] Another study focused on the prognostic impact of the MLLT10::PICALM fusion, which results in aberrant hematopoiesis and loss of chromatin-mediated gene regulation. Within this specific subset, the 20 pediatric patients with MLLT10::PICALM fusions had a poor prognosis. The 5-year EFS rate was 22%, and the OS rate was 26%.[151]
  • FLT3 variants. Presence of a FLT3 ITD variant appears to be associated with poor prognosis in adults with AML,[152] particularly when both alleles are altered or there is a high ratio of the variant allele to the normal allele.[153] FLT3 ITD variants also convey a poor prognosis in children with AML.[41,72,154-156] The frequency of FLT3 ITD variants 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 variant (compared with approximately 30% in adults).[155,156]

    The prevalence of FLT3 ITD is increased in certain genomic subtypes of pediatric AML, including cases with the NUP98::NSD1 gene fusion, 80% to 90% of which have a co-occurring FLT3 ITD.[128,129]

    The prognostic significance of FLT3 ITD is modified by the presence of other recurring genomic alterations.[128,129] For patients who have FLT3 ITD, the presence of either WT1 variants or NUP98::NSD1 fusions is associated with poorer outcomes (EFS rates below 25%) than for patients who have FLT3 ITD without these alterations.[43] Conversely, a co-occurring cryptic DEK::NUP214 fusion may be more favorable, particularly with the addition of a FLT3 inhibitor to standard front-line chemotherapy. When FLT3 ITD is accompanied by NPM1 variants, the outcome is relatively favorable and is similar to that of pediatric AML cases without FLT3 ITD.[43] The latter subset is the one scenario in which the presence of the FLT3 ITD variant does not necessarily upstage a patient to high risk, based on the favorable outcomes seen with the co-occurring variants.[43]

    Activating single nucleotide variants of FLT3 have also been identified in both adults and children with AML, although the clinical significance of these variants is not clearly defined. Some of these single nucleotide variants appear to be specific to pediatric patients.[43]

  • RAM phenotype. The RAM phenotype is characterized by high-intensity CD56 expression, dim-to-negative expression of CD45 and CD38, and a lack of HLA-DR expression. These patients tend to be younger, with a median age of 1.6 years in the initially reported series. This phenotype is enriched in patients with non-Down syndrome–related AMKL.[157] Clinically, patients with the RAM phenotype have inferior outcomes. In the initial series, patients in the RAM cohort had a 3-year EFS rate of 16%, compared with 51% for patients in the non-RAM cohort (P < .001). Patients in the RAM cohort also had inferior survival compared with patients with high CD56 expression, who lacked other phenotypic features of the RAM phenotype. OS was also inferior compared with the patients without the RAM phenotype (26% vs. 69%, P = .001). In a subanalysis, the OS of the patients in the RAM cohort was also markedly worse than patients in the CD56-positive (non-RAM) cohort (26% vs. 66%, P < .001) and the CD56-negative cohort (26% vs. 70%, P < .001).[157] Many, but not all, patients with a RAM phenotype have evidence of a CBFA2T3::GLIS2 fusion that, in itself, confers very high-risk disease. In a published series, approximately 60% of patients with the RAM phenotype at diagnosis were subsequently found to have this cryptic fusion that also confers higher-risk disease.[157]

Additional cytogenetic/molecular abnormalities that may have prognostic significance

This section includes cytogenetic/molecular abnormalities that are seen at diagnosis and do not impact disease risk stratification but may have prognostic significance.

  • AML with RUNX1::CBFA2T3 (t(16;21)(q24;q22)) gene fusions. In leukemias with t(16;21)(q24;q22), the RUNX1 gene is fused with the CBFA2T3 gene, and the gene expression profile is closely related to that of AML cases with t(8;21) and RUNX1::RUNX1T1 fusions.[112] Patients present at a median age of 7 years. This cancer is rare, representing approximately 0.1% to 0.3% of pediatric AML cases. Among 23 patients with RUNX1::CBFA2T3 fusions, five presented with secondary AML, including two patients who had a primary diagnosis of Ewing sarcoma. Outcomes were favorable for the cohort of 23 patients, with a 4-year EFS rate of 77% and a cumulative incidence of relapse rate of 0%.[112]
  • RAS variants. Although variants in RAS have been identified in 20% to 25% of patients with AML, the prognostic significance of these variants has not been clearly shown.[71,158] Variants in NRAS are more commonly observed than variants in KRAS in pediatric AML cases.[71,159] RAS variants occur with similar frequency for all Type II alteration subtypes, with the exception of APL, for which RAS variants are seldom observed.[71]
  • AML with RBM15::MRTFA gene fusions. The t(1;22)(p13;q13) translocation that produces RBM15::MRTFA fusions (also known as RBM15::MKL1) is uncommon (<1% of pediatric AML) and is restricted to AMKL.[34,119,160-163] Studies have found that t(1;22)(p13;q13) is observed in 10% to 20% of children with AMKL who have evaluable cytogenetics or molecular genetics.[86,87,118,120] Most AMKL cases with t(1;22) occur in infants, with the median age at presentation (4–7 months) being younger than for other children with AMKL.[86,115,120,164] Cases with detectable RBM15::MKL1 fusion transcripts in the absence of t(1;22) have also been reported because these young patients usually have hypoplastic bone marrow.[161]

    An international collaborative retrospective study of 51 t(1;22) cases reported that patients with this abnormality had a 5-year EFS rate of 54.5% and an OS rate of 58.2%, similar to the rates for other children with AMKL.[86] In another international retrospective analysis of 153 cases with non–Down syndrome AMKL who had samples available for molecular analysis, the 4-year EFS rate for patients with t(1;22) was 59% and the OS rate was 70%, significantly better than for AMKL patients with other specific genetic abnormalities (CBFA2T3::GUS2 fusions, NUP98::KDM5A fusions, KMT2A rearrangements, monosomy 7).[118] Similar outcomes were seen in the COG AAML0531 and AAML1031 phase III trials (5-year OS rates, 86% ± 26% [n = 7] and 54% ± 14% [n = 14] for AAML0531 and AAML1031, respectively).[120]

  • HOX rearrangements. Cases with a gene fusion involving a HOX cluster gene represented 15% of pediatric AMKL in one report.[87] 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.
  • GATA1 variants. GATA1-truncating variants in non–Down syndrome AMKL arise in young children (median age, 1–2 years) and are associated with amplification of the RCAN1 gene on chromosome 21.[87] 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).[87]
  • Hypodiploidy. Hypodiploidy is defined as a modal chromosome number of less than or equal to 45. This occurs rarely in pediatric patients with AML. In a retrospective cohort analysis, the iBFM AML study group aimed to characterize hypodiploidy in pediatric patients with AML. The study excluded several patient groups, including patients with APL, Down syndrome, or loss of chromosome 7.[165] Their observations included the following:
    • Hypodiploidy was observed in 1.3% of children with AML. Approximately 80% of patients had a modal chromosome number of 45, and the remaining 20% of patients had a modal chromosome number of either 43 or 44.
    • Most patients (>80%) with a modal chromosome number of 43 or 44 also met the criteria for complex karyotype. In this study, a complex karyotype was defined as at least three independent chromosomal abnormalities, regardless of whether these were structural abnormalities or defects in chromosome number, and an absence of recurrent aberrations as defined by the WHO.
    • Patients with a modal chromosome number of 43 or 44 had decreased EFS rates and OS rates when compared with patients who had 45 chromosomes (EFS rate, 21% vs. 37%; P = .07; OS rate, 33% vs. 56%; P = .1).
  • UBTF tandem duplication. UBTF is located at chromosome 17q21.31, and it codes for a nucleolar protein that interacts with ribosomal DNA to mediate RNA polymerase 1 ribosomal RNA transcription.[166]
    • UBTF tandem duplication (UBTF-TD) is mutually exclusive with other leukemia driver genomic alterations. Like other leukemogenic drivers, it is maintained at relapse.
    • UBTF genomic alterations involving heterozygous somatic variants resulting in in-frame tandem duplication of UBTF exon 13 are observed in approximately 4% of pediatric AML cases.
    • UBTF-TD AML in the pediatric population primarily occurs during adolescence (median age, 12–14 years). It is also observed in adults younger than 60 years, but it is uncommon among AML in older adult patients.
    • FLT3 ITD is common in cases of AML with UBTF-TD. Approximately two-thirds of cases have FLT3 ITD. In addition, approximately 40% of cases with UBTF-TD AML have WT1 variants.
    • In the AAML1031 clinical trial, EFS and OS rates for patients with UBTF-TD were 30% and 44%, respectively. These values were lower than those for non–UBTF-TD patients enrolled in AAML1031 (45% and 64%, respectively). Outcome for patients with UBTF-TD was similar to that for patients with KMT2A rearrangements.
    • In the AAML1031 trial, co-occurrence of UBTF-TD with either FLT3 ITD or WT1 variants was associated with an inferior prognosis, compared with patients with UBTF-TD alone.
  • AML with CBFB::GDXY insertions. CBFB encodes the CBFB protein that is part of the multiprotein, core-binding transcription factor complex, which master regulates a gene expression program critical for hematopoiesis. CBFB is recurrently fused with MYH11 in inv(16)/t(16;16) AML.[167]
    • In-frame insertions in exon 3 of CBFB have been identified in about 0.4% of pediatric AML cases at diagnosis. All described insertions lead to replacement of aspartic acid at position 87 (D87) with either glycine, aspartic acid, serin, and tyrosine (GDSY) or glycine, aspartic acid, threonine, and tyrosine (GDTY).
    • CBFB::GDXY insertions are associated with a gene expression profile overlapping with CBFB::MYH11–expressing AML, with the exception of increased expression of stem cell genes such as HOXA cluster genes and MEIS1.
    • CBFB::GDXY insertions frequently co-occur with FLT3 tyrosine kinase domain (TKD) and BCOR1 variants, but lack KIT variants, which are frequently found in CBFB::MYH11 AML.
    • CBFB::GDXY insertions appear to be enriched among adolescents and young adults.
    • The impact of CBFB::GDXY insertions on patient outcomes are unclear due to a paucity of data. However, early analysis suggests that these patients may not have the same favorable outcome as patients with CBFB::MYH11 fusions.
  • RUNX1 variants. AML with RUNX1 variants was a provisional entity in the 2016 WHO classification. In the 5th edition of the WHO classification, it falls into the category of AML with other defined genetic alterations.[13] This subtype of AML is more common in adults than in children. In adults, the RUNX1 variant is associated with a high risk of treatment failure. A meta-analysis of outcomes for adult patients with RUNX1 variants also demonstrated high-risk disease, although this significance was lost in the context of intermediate-risk cytogenetics.[168]

    In a study of children with AML, RUNX1 variants were observed in 11 of 503 patients (approximately 2%). Six of 11 patients with AML and RUNX1 variants failed to achieve remission, and their 5-year EFS rate was 9%, suggesting that the RUNX1 variant confers a poor prognosis in both children and adults.[169] However, a second study in which 23 children were found to have RUNX1 variants among 488 children with AML found no significant impact of RUNX1 variants on response or outcome. Additionally, analysis identified that children with RUNX1 variants were more frequently male, adolescents, and had a greater incidence of co-occurring FLT3 ITD and other variants. However, in each of these groups, univariable and multivariable analyses found no survival differences based on the presence of RUNX1 variants.[170] Genetic variants of RUNX1 result in a familial platelet disorder with associated myeloid malignancy (FPD-MM).[13]

  • WT1 variants. WT1, a zinc-finger protein regulating gene transcription, is altered in approximately 10% of cytogenetically normal cases of AML in adults.[171-174] The WT1 variant has been shown in some,[171,172,174] but not all, studies [173] to be an independent predictor of worse DFS, EFS, and OS in adult patients.

    In children with AML, WT1 variants are observed in approximately 10% of cases.[175,176] Cases with WT1 variants are enriched among children with normal cytogenetics and FLT3 ITD but are less common among children younger than 3 years.[175,176] AML cases with NUP98::NSD1 fusions are enriched for both FLT3 ITD and WT1 variants.[128] In univariate analyses, WT1 variants are predictive of poorer outcome in pediatric patients, but the independent prognostic significance of WT1 variant status is unclear because of its strong association with FLT3 ITD and its association with NUP98::NSD1 fusions.[128,175,176] The largest study of WT1 variants in children with AML observed that children with WT1 variants in the absence of FLT3 ITD had outcomes similar to that of children without WT1 variants, while children with both WT1 variants and FLT3 ITD had survival rates less than 20%.[175]

    In a study of children with refractory AML, WT1 was overrepresented, compared with a cohort who did achieve remission (54% [15 of 28 patients] vs. 15%).[133]

  • DNMT3A variants. Variants of the DNMT3A gene have been identified in approximately 20% of adult patients with AML. These variants are uncommon in patients with favorable cytogenetics but occur in one-third of adult patients with intermediate-risk cytogenetics.[177] Variants in this gene are independently associated with poor outcome.[177-179] DNMT3A variants are virtually absent in children.[180]
  • IDH1 and IDH2 variants. Variants in IDH1 and IDH2, which code for isocitrate dehydrogenase, occur in approximately 20% of adults with AML,[44,181-185] and they are enriched in patients with NPM1 variants.[182,183,186] The specific variants that occur in IDH1 and IDH2 create a novel enzymatic activity that promotes conversion of alpha-ketoglutarate to 2-hydroxyglutarate.[187,188] This novel activity appears to induce a DNA hypermethylation phenotype similar to that observed in AML cases with loss-of-function variants in TET2.[186]

    Variants in IDH1 and IDH2 are rare in pediatric AML, occurring in 0% to 4% of cases.[44,180,189-193] There is no indication of a negative prognostic effect for IDH1 and IDH2 variants in children with AML.[44,189]

  • CSF3R variants. CSF3R is the gene encoding the granulocyte colony-stimulating factor (G-CSF) receptor, and activating variants in CSF3R are observed in 2% to 3% of pediatric AML cases.[194] These variants lead to enhanced signaling through the G-CSF receptor. They are primarily observed in AML with either CEBPA variants or with CBF abnormalities (RUNX1::RUNX1T1 and CBFB::MYH11 fusions).[194] In a study of 2,150 pediatric patients with AML, 35 patients (1.6%) were found to have CSF3R variants; 30 (89%) of these cases were in patients with either RUNX1::RUNX1T1 fusions (n = 18) or with CEBPA variants (n = 12).[83] Risk of relapse was significantly higher for patients with co-occurring CSF3R and CEBPA variants, compared with patients with RUNX1::RUNX1T1 fusions and CSF3R variants.[83] Although relapse rates are higher in patients with AML who have co-occurring CSF3R and CEBPA variants, OS is not adversely impacted, reflecting a high salvage rate with reinduction therapy and HSCT.[74]

    Activating variants in CSF3R are also observed in patients with severe congenital neutropenia. These variants are not the cause of severe congenital neutropenia, but rather arise as somatic variants and can represent an early step in the pathway to AML.[195] In one study of patients with severe congenital neutropenia, 34% of patients who had not developed a myeloid malignancy had CSF3R variants detectable in peripheral blood neutrophils and mononuclear cells, while 78% of patients who had developed a myeloid malignancy showed CSF3R variants.[195] A study of 31 patients with severe congenital neutropenia who developed AML or MDS observed CSF3R variants in approximately 80% of patients. The study also observed a high frequency of RUNX1 variants (approximately 60%), suggesting cooperation between CSF3R and RUNX1 variants for leukemia development within the context of severe congenital neutropenia.[196]

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Treatment Option Overview for Childhood AML

Diagnostic Criteria

Childhood acute myeloid leukemia (AML) is diagnosed when the bone marrow has 20% or greater blasts or when a lower blast percentage is present but molecular evaluation reveals an AML-defining genetic abnormality.[1] For information about the defining abnormalities, see the World Health Organization (WHO) Classification System for Childhood AML section.

Leukemia is considered to be disseminated in the hematopoietic system at diagnosis, even in children with AML who present with isolated chloromas (also called granulocytic or myeloid sarcomas). These children invariably develop AML in months to years if they do not receive systemic chemotherapy. 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.[2] In one retrospective analysis, leukemia cutis did not have an adverse impact on outcomes of infants when they were treated with traditional chemotherapy.[3]

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.[4] This incidence was also seen in the NOPHO-AML 2004 (NCT00476541) trial.[5]

Patients with isolated granulocytic sarcoma have a good prognosis if treated with current AML therapy.[4]

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 patients with marrow disease and granulocytic sarcoma at other sites and AML patients without any extramedullary disease.[5,6] 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. However, radiation therapy may be necessary if the site(s) of granulocytic sarcoma do not show complete response to chemotherapy or for disease that recurs locally.[4]

CNS involvement is often described as extramedullary disease and included in overall summaries of extramedullary disease. However, it has a distinct prognostic impact and requires therapeutic alterations. It is therefore discussed in detail in sections for both prognosis and treatment.

Remission Criteria

The first goal in the treatment of AML is to eradicate all identifiable evidence of leukemia, also known as complete remission (CR).

CR has traditionally been defined in the United States using morphological 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 CNS or at other extramedullary sites.[7]

Alternative definitions of remission using morphology are used in AML because of the prolonged myelosuppression caused by intensive chemotherapy. These definitions include CR with incomplete platelet recovery (CRp) and CR with incomplete marrow recovery (typically absolute neutrophil count) (CRi). Whereas the use of CRp provides a clinically meaningful response in studies of adults with AML, the traditional CR definition remains the gold standard because patients in CR were more likely to survive longer than those in CRp.[8]

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]). In APL, a hypoplastic marrow phase is often not necessary before the achievement of remission. 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.[9] If the findings are in doubt, a bone marrow aspirate should be repeated in 1 to 2 weeks.[2]

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. These methods have proven to be of greater prognostic significance than morphology. For more information about these methodologies, see the Prognosis and Prognostic Factors section.

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).

Induction therapy

Induction therapy typically involves several (usually 2–4) cycles of intensive chemotherapy. Past approaches often had four cycles of chemotherapy comprising the entire induction course. Contemporary protocols have combined the first two and the last two cycles into two more intensified cycles of overall induction, which has improved event-free survival (EFS) and overall survival (OS).

Postremission therapy

Postremission therapy may consist of varying numbers of courses of intensive chemotherapy and/or allogeneic hematopoietic stem cell transplant (HSCT). For example, 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.[10-12]

Maintenance chemotherapy is no longer part of pediatric AML protocols because two randomized clinical trials failed to show a benefit for maintenance therapy when given after modern intensive chemotherapy.[13,14] Contemporary APL therapy also does not use maintenance chemotherapy. A tretinoin- and arsenic trioxide–based treatment is used instead.[15] Maintenance therapy with targeted therapies is gaining interest. Treatment of patients with AML and FLT3 internal tandem duplication (ITD) using sorafenib (a FLT3 inhibitor) during chemotherapy cycles and maintenance (following completion of chemotherapy or HSCT) significantly improved survival.[16]

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.[10] Two COG trials reported an 11% to 13% incidence of remission failure, mainly because of resistant disease. Only 2% to 3% resulted from toxic death during the two induction courses.[12,17]

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, including total-body irradiation with HSCT, have declined because of increased risk of growth failure, gonadal and thyroid dysfunction, cataract formation, and second malignancies.[18] For more information, see the Survivorship and Adverse Late Sequelae of Treatment for AML section and Late Effects of Treatment for Childhood Cancer.

Prognosis and Prognostic Factors

Dramatic improvements in survival have been achieved for children and adolescents with cancer.[19] Between 1975 and 2020, childhood cancer mortality decreased by more than 50%.[19-21] For AML, the 5-year survival rate increased over the same time, from less than 20% to 69% for children younger than 15 years and from less than 20% to 72% for adolescents aged 15 to 19 years.[19,21]

Most contemporary comparisons also show that OS rates have improved over the past three decades for children with AML, with 5-year survival rates now in the 55% to 70% range.[21-25] Overall remission-induction rates are approximately 85% to 90%, and EFS rates from the time of diagnosis are in the 45% to 55% range.[23-26] There is, however, a wide range in outcomes for different biological subtypes of AML. 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. For more information, see the sections on Genomics of AML and Risk Classification Systems.

Prognostic factors in childhood AML can be categorized as follows:

Prognostic factors associated with patient characteristics

  • Age: Several reports have identified older age as an adverse prognostic factor.[11,24,25,27-29] The age effect is not large with regard to OS, but in general, the adverse outcomes seen in adolescents (≥16 years) compared with younger children appear to be primarily caused by increases in toxic mortality.[30] In the COG AAML1031 (NCT01371981) trial, age older than 11 years was an independent predictor of more favorable EFS on multivariable analysis.[31]

    While outcome for infants with acute lymphoblastic leukemia (ALL) remains inferior to that of older children, outcome for infants (<12 months) with AML is similar to that of older children when they are treated with standard AML regimens.[27,32-34] Infants have been reported to have a 5-year survival rate of 60% to 70%, but with increased treatment-associated toxicity, particularly during induction.[27,32-35]

  • Race and ethnicity: In both the Children's Cancer Group (CCG) CCG-2891 and COG-2961 (NCT00002798) studies, White children had higher OS rates than Black and Hispanic children.[24,36,37] Black children also experienced lower survival rates than White children in St. Jude Children’s Research Hospital AML clinical trials.[38]
  • Down syndrome: For children with Down syndrome who develop AML, survival is generally favorable when diagnosed at a young age.[39-41] The prognosis is particularly good (EFS rate exceeding 80%) for children younger than 4 years at diagnosis, the age group that accounts for the vast majority of patients with Down syndrome and AML. Children older than 4 years have similar outcomes to patients without Down syndrome.[41-45]
  • Body mass index: Obesity (body mass index more than the 95th percentile for age) is predictive of inferior survival.[24,46] Inferior survival was attributable to early treatment-related mortality that was primarily caused by infectious complications.[46,47]

Prognostic factors associated with leukemia characteristics

  • WBC count: WBC count at diagnosis has been consistently noted to be inversely related to survival.[11,31,48,49] Patients with high presenting leukocyte counts have a higher risk of developing pulmonary and CNS complications and, historically, have a higher risk of death during induction.[50]
  • FAB subtype: Associations between FAB non-M3 subtypes and prognosis have been more variable.
    • M0 subtype. The M0, or minimally differentiated subtype, has been associated with a poor outcome.[51]
    • M6 subtype. In the 2016 WHO classification system, the M6 subtype was limited to pure erythroid leukemia. The combined COG AAML0531 and AAML1031 studies demonstrated that it is a rare subtype (5 of 1,934 cases; 0.2%), occurs in younger patients (median age, 2.3 years), and is associated with a poor outcome (5-year EFS and OS rates, 20% ± 36%).[52]
    • M7 subtype. Some studies have indicated a relatively poor outcome for M7 (megakaryocytic leukemia) in patients without Down syndrome,[39] although reports suggest an intermediate prognosis for this group of patients when contemporary treatment approaches are used.[10,53,54]

      In a retrospective study of non–Down syndrome M7 patients with samples available for molecular analysis, the presence of specific genetic abnormalities (CBFA2T3::GLIS2 [cryptic inv(16)(p13q24)], NUP98::KDM5A, t(11;12)(p15;p13), KMT2A [MLL] rearrangements, monosomy 7) was associated with a significantly worse outcome than for other M7 patients.[55,56] By contrast, the 10% of patients with AMKL and GATA1 variants without Down syndrome appeared to have a favorable outcome if there were no prognostically unfavorable fusion genes also present, as did patients with HOX rearrangement.[56]

  • CNS disease: CNS involvement at diagnosis is categorized on the basis of the presence or absence of blasts in cerebrospinal fluid (CSF). European cooperative groups have applied ALL definitions of various degrees of CNS involvement to AML, as follows:
    • CNS1: CSF negative for blasts on cytospin, regardless of CSF WBC count.
    • CNS2 is divided into the following three subgroups, which are defined as follows:
      • CNS2a: CSF with fewer than 5 WBC/μL and cytospin positive for blasts in an atraumatic tap (<10 red blood cells [RBC]/μL).
      • CNS2b: CSF with fewer than 5 WBC/μL and cytospin positive for blasts in a traumatic tap (≥10 RBC/μL).
      • CNS2c: CSF with 5 or more WBC/μL and cytospin positive for blasts in a traumatic tap (≥10 RBC/μL) in which the WBC/RBC ratio in the CSF is less than twice that in the peripheral blood.
    • CNS3 includes the following three subgroups, which are defined as follows:
      • CNS3a: CSF with 5 or more WBC/μL and cytospin positive for blasts in an atraumatic tap (<10 RBC/μL).
      • CNS3b: CSF with 5 or more WBC/μL and cytospin positive for blasts in a traumatic tap (≥10 RBC/μL) in which the WBC/RBC ratio in the CSF is more than or equal to twice the ratio in the peripheral blood.
      • CNS3c: Clinical signs of CNS leukemia (e.g., cranial nerve palsy, brain/eye involvement, or radiographic evidence of an intracranial, intradural chloroma).

      COG trials (including AAML03P1 [NCT00070174], AAML0531 [NCT00372593], and AAML1031 [NCT01371981]) used a modified version of the CNS disease definitions, in which patients were dichotomously classified for treatment purposes as CNS positive or negative. The CNS-positive group included all patients with blasts on cytospin (regardless of CSF WBC) unless there were more than 100 RBC/μL in the CSF. Patients with 100 RBC/μL in the CSF were CNS positive only if the WBC/RBC ratio in the CSF was greater than or equal to twice the ratio in the peripheral blood. CNS outcomes on COG studies were analyzed using the more traditional CNS1/2/3 definitions.[57]

      In children with AML, CNS2 disease has been observed in approximately 13% to 16% of cases, and CNS3 disease has been observed in approximately 11% to 17% of cases.[57,58] Studies have variably shown that patients with CNS2/CNS3 disease were younger, more often had hyperleukocytosis, and had higher incidences of t(9;11), t(8;21), or inv(16).[57,58]

      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 disease was associated with inferior outcomes, including decreased CR rate, EFS, and disease-free survival (DFS), and an increased risk of relapse involving the CNS.[57] Another trial showed it to be associated with an increased risk of isolated CNS relapse.[59] The COG study did not find traumatic lumbar punctures at diagnosis to have an adverse impact on OS.[57] From an analysis of patients enrolled in the AAML0531 and AAML1031 trials, using the COG definition of CNS involvement, peripheral blood contamination increased the number of patients who were classified as CNS positive and guided to additional intrathecal therapy.[60] In these trials, following past precedence, diagnostic CSF examinations and initial intrathecal administration were done on or before day 1 of induction therapy. Beginning with the COG AAML1831 (NCT04293562) trial, to minimize the contamination risk, the newer guidance is to delay the diagnostic lumbar puncture to day 8, when most patients have cleared their peripheral blood of leukemic blasts. Additionally, a definition of CNS involvement that is more similar to the ALL definition is now in use.

  • Cytogenetic and molecular characteristics: Cytogenetic and molecular characteristics are also associated with prognosis. For detailed information, see the Genomics of AML section. Cytogenetic and molecular characteristics that are currently used in the COG clinical trials for treatment assignment are shown in Table 5:
    Table 5. Cytogenetic and Molecular Prognostic Findingsa
    Favorable Unfavorable
    aAdapted from the COG AAML1831 (NCT04293562) trial.
    t(8;21)(q22;q22); RUNX1::RUNX1T1 inv(3)(q21.3q26.2)/t(3;3)(q21.3q26.2); RPN1::MECOM and t(3;21)(26.2;q22); RUNX1::MECOM
    AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB::MYH11 t(3;5)(q25;q34.1); NPM1::MLF1
    NPM1 variants t(6;9)(p22.3;q34.1); DEK::NUP214
    Variants in the bZIP domain of CEBPA t(8;16)(p11.2;p13.3); KAT6A::CREBBP (if 90 days or older at diagnosis)
     t(16;21)(p11.2;q22.2); FUS::ERG
      inv(16)(p13.3q24.3); CBFA2T3::GLIS2
     KMT2A rearrangement with high-risk partners:
      t(4;11)(q21;q23.3) KMT2A::AFF1
      t(6;11)(q27;q23.3) KMT2A::AFDN
      t(10;11)(p12.3;q23.3) KMT2A::MLLT10
      t(10;11)(p12.1;q23.3) KMT2A::ABI1
      t(11;19)(q23.3;p13.3) KMT2A::MLLT1
     11p15; NUP98 rearrangement with any partner gene
     12p13.2; ETV6 rearrangement with any partner gene
     Deletion 12p to include 12p13.2 loss of ETV6
     Monosomy 5/Del(5q) to include 5q31 loss of EGR1
     Monosomy 7
     10p12.3; MLLT10 rearrangement with any partner gene
     FLT3 ITD+ with allelic ratio >0.1%
  • Immunophenotype:
    • A distinctive immunophenotype (initially reported as the RAM phenotype), with high CD56 levels, dim or negative expression of CD45 and CD38, and a lack of HLA-DR expression was associated with a poor prognosis (5-year EFS rate of approximately 20%).[61,62] Most patients with the RAM phenotype have the CBFA2T3::GLIS2 fusion gene.[62,63]
    • High CD123 expression (quartile 4 vs. quartiles 1–3), in Cox multivariable regression, was shown to be an independent adverse prognostic risk factor for OS, EFS, and relapse risk (RR), although it did not impact remission success. High CD123 expression occurred more frequently in patients with many high-risk cytogenetic and molecular characteristics. High CD123 expression also adversely impacted OS and EFS, but not RR. In patients with low-risk cytogenetic and molecular characteristics, those with high CD123 expression (quartile 4) had significantly worse OS, EFS, and RR.[64]

Prognostic factors associated with therapeutic response

  • 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 morphological examination of bone marrow,[48,65] cytogenetic analysis, fluorescence in situ hybridization, or more sophisticated techniques to identify MRD (e.g., multiparameter flow cytometry, quantitative RT-PCR).[66-68] Multiple groups have shown that the level of MRD after one course of induction therapy is an independent predictor of prognosis.[66-71]

    Molecular approaches to assessing MRD in AML: Molecular approaches (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. Results have shown the following:

    • Quantitative RT-PCR detection of RUNX1::RUNX1T1 fusion transcripts can effectively predict higher risk of relapse for patients in clinical remission.[72-74]
    • Other molecular alterations such as NPM1 variants [75] and CBFB::MYH11 fusion transcripts [76] have also been successfully employed as leukemia-specific molecular markers in MRD assays. For these alterations, the level of MRD has shown prognostic significance.
    • The presence of FLT3 ITD 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.[77]

    Flow cytometric methods: Flow cytometry has 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.

    • In a COG analysis (AAML0531 [NCT00372593]) of 784 patients, the following results were reported:[71]
      • Sixty-nine percent of patients (n = 544) were MRD negative (defined as <0.02%) in their bone marrow at the end of induction 1 (EOI1).
      • Those patients had better DFS rates (57%; 95% CI, 53%–61%; P < .001) and OS rates (73%; 95% CI, 69%–76%; P < .001) than patients who were MRD positive (DFS rate, 30%; 95% CI, 25%–36% and OS rate, 48%; 95% CI, 42%–54%).
      • Additionally, in the 76% of patients who were in morphological remission at EOI1, 20% were MRD positive and had a significantly worse outcome than patients who were MRD negative/morphology negative.
      • In the 24% of patients who were not in morphological remission, 36% were actually MRD negative and had significantly better outcomes than patients who were MRD positive/morphology positive.
      • This was also true in patients with marrow blast percentages in excess of 15%, 27% of whom had MRD-negative bone marrow and significantly better outcomes.
    • A CCG study of 252 pediatric patients with AML in morphological remission demonstrated the following:[78]
      • MRD, 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.[66,67,69]

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.[65] Classification is further applied based on the ability of the pediatric patient to undergo reinduction to obtain a second complete remission and their subsequent OS after first relapse.[79]

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

  1. In COG AAML0531 (NCT00372593), the first COG trial to stratify therapy by risk group, patients were stratified into three risk groups on the basis of diagnostic cytogenetics and response after induction 1.[12]
    • Low-risk patients included those diagnosed with a core-binding factor AML (either t(8;21) or inv(16)).
    • High-risk patients had either monosomy 7, monosomy 5 or del(5q), chromosome 3 abnormalities, or a poor response to induction 1 therapy with morphological marrow leukemic blasts (>15%).
    • All other patients fell into the intermediate-risk category.
    • This resulted in a risk distribution of 24% low risk, 59% intermediate risk, and 17% high risk.
  2. In the subsequent COG-AAML1031 (NCT01371981) trial, the risk groups were reduced to two on the basis of the finding that those in the intermediate category could be more specifically and prognostically defined by adding the use of MRD by multiparameter flow cytometry.[31,80]
    • Patients whose cytogenetics and/or molecular genetics were noninformative (i.e., traditional intermediate risk) and were negative for MRD (<0.1%) were placed in the low-risk category.
    • Patients who were positive for MRD (≥0.1%) were placed in the high-risk category.
  3. In the COG-AAML1031 trial, the study stratification was further based on cytogenetics, molecular markers, and MRD at bone marrow recovery postinduction 1, with patients being divided into a low-risk or high-risk group as follows:[31]
    1. The low-risk group represented 78% of patients, had a 3-year OS rate from the end of induction 1 of 74.1% (±3.4%), and was defined by the following:
      • Inv(16), t(8;21), NPM1 variants, or CEBPA variants, regardless of MRD and other cytogenetics.
      • Intermediate-risk cytogenetics (defined by the absence of either low-risk or high-risk cytogenetic characteristics) with negative MRD (<0.1% by flow cytometry) at end of induction 1.
    2. The high-risk group represented the remaining 22% of patients, had a 3-year OS rate from the end of induction 1 of 36.9% (± 7.6%), and was defined by the following:
      • High-allelic ratio FLT3 ITD positive with any MRD status.
      • Monosomy 7 with any MRD status.
      • Monosomy 5/del(5q) with any MRD status.
      • Intermediate-risk cytogenetics with positive MRD at end of induction 1.

      Where risk factors contradicted each other, the following evidence-based table was used (see Table 6).

      Table 6. Risk Assignment in the AAML1031 Studya,b
      Risk Assignment:Low RiskHigh Risk
       Low-Risk Group 1Low-Risk Group 2High-Risk Group 1High-Risk Group 2High-Risk Group 3
      ITD = internal tandem duplications.
      aGroups are based on combinations of risk factors, which may be found in any individual patient.
      bBold indicates the overriding risk factor in risk-group assignment.
      cNPM1, CEBPA, t(8;21), inv(16).
      d"Any" indicates any status and thus the marker's presence/absence or minimal residual disease status does not impact risk classification in the particular Risk Group.
      eMonosomy 7, monosomy 5, del(5q).
      FLT3 ITD allelic ratioLow/negativeLow/negativeHighLow/negativeLow/negative
      Good-risk molecular markerscPresentAbsentAnydAbsentAbsent
      Poor-risk cytogenetic markerseAnydAbsentAnydPresentAbsent
      Minimal residual diseaseAnydNegativeAnydAnydPositive

The high-risk group of patients was guided to transplant in first remission with the most appropriate available donor. Patients in the low-risk group were instructed to pursue transplant if they relapsed.[67,81]

The COG AAML1831 (NCT04293562) trial for patients with newly diagnosed AML uses a more complex risk-stratification system. This system incorporates more genetic lesions into the high-risk group and builds on the use of MRD as a strong prognostic marker.[82]

Risk factors used for stratification vary by pediatric and adult cooperative clinical trial groups. 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.

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Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence has slowly increased since 1975.[1] 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.[2] This multidisciplinary team approach incorporates the skills of the following pediatric specialists and others to ensure that children receive treatment, supportive care, and rehabilitation to achieve optimal survival and quality of life:

  • Primary care physicians.
  • Pediatric surgeons.
  • Pathologists.
  • Pediatric radiation oncologists.
  • Pediatric medical oncologists and hematologists.
  • Rehabilitation specialists.
  • Pediatric oncology nurses.
  • Social workers.
  • Child-life professionals.
  • Psychologists.
  • Nutritionists.

For specific information about supportive care for children and adolescents with cancer, see the summaries on Supportive and Palliative Care.

The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of children and adolescents with cancer.[3] At these centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate is offered to most patients and their families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with current standard therapy. Other types of clinical trials test novel therapies when there is no standard therapy for a cancer diagnosis. Most of the progress in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.

References
  1. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010. [PUBMED Abstract]
  2. Wolfson J, Sun CL, Wyatt L, et al.: Adolescents and Young Adults with Acute Lymphoblastic Leukemia and Acute Myeloid Leukemia: Impact of Care at Specialized Cancer Centers on Survival Outcome. Cancer Epidemiol Biomarkers Prev 26 (3): 312-320, 2017. [PUBMED Abstract]
  3. American Academy of Pediatrics: Standards for pediatric cancer centers. Pediatrics 134 (2): 410-4, 2014. Also available online. Last accessed August 23, 2024.

Treatment of Childhood AML

The general principles of therapy for children and adolescents with acute myeloid leukemia (AML) are discussed below. For information about the treatment of children with Down syndrome, see Childhood Myeloid Proliferations Associated With Down Syndrome Treatment. For information about the treatment of children with acute promyelocytic leukemia (APL), see Childhood Acute Promyelocytic Leukemia Treatment.

Induction Therapy

Contemporary pediatric AML protocols result in 85% to 90% complete remission (CR) rates.[1-3] 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. Approximately 2% to 3% of patients die during the induction phase, most often caused by treatment-related complications.[1-4]

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

  1. Chemotherapy.
  2. Immunotherapeutic approaches (e.g., gemtuzumab ozogamicin).
  3. Targeted therapy (e.g., FLT3 inhibitors).
  4. Supportive care.

Chemotherapy

Common induction therapy regimens in children with AML use cytarabine and an anthracycline in combination with other agents such as etoposide and/or thioguanine.[5-7]

Evidence (induction chemotherapy regimen):

  1. The United Kingdom Medical Research Council (MRC) AML10 trial compared induction with cytarabine, daunorubicin, and etoposide (ADE) versus induction with cytarabine, daunorubicin, and thioguanine.[8]
    • There was no difference in remission rate or disease-free survival (DFS) between the thioguanine and etoposide arms, although the thioguanine-containing regimen was associated with increased toxicity.
  2. The MRC AML15 trial demonstrated the following results:[9]
    • Induction with daunorubicin and cytarabine resulted in equivalent survival rates when compared with ADE induction.

The anthracycline that has been most used in induction regimens for children with AML is daunorubicin,[5-7] although idarubicin and the anthracenedione mitoxantrone have also been used.[1,10,11] 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 (daunorubicin vs. other anthracyclines):

  1. The German Berlin-Frankfurt-Münster (BFM) Group AML-BFM 93 study evaluated cytarabine plus etoposide with either daunorubicin or idarubicin (ADE or AIE).[6,10]
    • Similar event-free survival (EFS) and overall survival (OS) rates were observed for both induction treatments.
  2. The MRC-LEUK-AML12 (NCT00002658) clinical trial studied induction with cytarabine, mitoxantrone, and etoposide (MAE) in children and adults with AML compared with ADE.[1,12]
    • For all patients, the MAE regimen produced a reduction in relapse risk, but the increased rate of treatment-related mortality observed for patients receiving MAE led to no significant difference in DFS or OS rates when compared with ADE.[12]
    • Similar results were noted when analyses were restricted to pediatric patients.[1]
  3. The AML-BFM 2004 (NCT00111345) clinical trial compared liposomal daunorubicin (L-DNR) with idarubicin at a higher-than-equivalent dose (80 mg/m2 vs. 12 mg/m2 per day for 3 days) during induction.[13]
    • Five-year OS and EFS rates were similar in both treatment arms.
    • Treatment-related mortality was significantly lower with L-DNR than with idarubicin (2 of 257 patients vs. 10 of 264 patients).
  4. The COG AAML1031 (NCT01371981) trial used mitoxantrone with high-dose cytarabine in its second cycle of induction, following a first cycle of ADE for patients with high-risk AML.[14]
    • In a planned comparison with the AAML0531 (NCT00372593) trial, which used a standard ADE regimen in the second induction cycle for similar patients, neither response nor survival was improved, whereas toxicity was increased in patients who received mitoxantrone.

Although the combination of an anthracycline and cytarabine is the basis of initial standard induction therapy for adults and children, there is evidence that alternative drugs can be used to reduce the use of anthracyclines when necessary.

Evidence (reduced-anthracycline induction regimen):

  1. In the St. Jude Children's Research Hospital (SJCRH) AML08 (NCT00703820) protocol, patients were randomly assigned to receive either clofarabine/cytarabine (CA) or high-dose cytarabine combined with daunorubicin and etoposide (HD-ADE) for induction I. All patients then received the anthracycline-containing, standard-dose ADE regimen for induction II.[15]
    • Despite a higher rate of minimal residual disease (MRD) in the CA group at day 22 of induction I (47% vs. 35%; P = .04), 3-year EFS and OS rates were similar between the two groups.

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).[16] The MRC has intensified induction therapy by prolonging the duration of cytarabine treatment to 10 days.[5]

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/m2/dose) compared with standard-dose cytarabine,[17] a benefit for the use of high-dose cytarabine in children was not observed using a cytarabine dose of 1 g/m2 given twice daily for 7 days with daunorubicin and thioguanine.[18] A second pediatric study also failed to detect a benefit for high-dose cytarabine over standard-dose cytarabine when used during induction therapy.[19]

Immunotherapeutic approaches

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.

Antibody-drug conjugate therapy (gemtuzumab ozogamicin)

Gemtuzumab ozogamicin is a CD33-directed monoclonal antibody linked to a calicheamicin, a cytotoxic agent.

Evidence (gemtuzumab ozogamicin during induction):

  1. The Children's Oncology Group (COG) completed two trials—AAML03P1 (NCT00070174), a pilot study, and AAML0531 (NCT00372593), a randomized trial—that examined the incorporation of gemtuzumab ozogamicin into induction therapy.[3,4]
    • With the use of gemtuzumab ozogamicin during induction cycle 1, dosed at 3 mg/m2 on day 6, the randomized trial identified an improvement in EFS but not in OS; this was likely impacted by postremission toxicity mortality. Patients had a reduction in postremission relapse overall and specifically in the following distinct subsets of patients:[4]
      • Patients with low-risk cytogenetics.
      • Patients with KMT2A-rearranged AML, both overall and in the context of high-risk and non–high-risk fusions. These patients had improvement in outcome from treatment with gemtuzumab.[20]
      • Patients with high-risk high-allelic ratio (>0.4) FLT3 internal tandem duplication (ITD) AML who then received a hematopoietic stem cell transplant (HSCT) from any donor.[21]
    • The efficacy and safety of gemtuzumab ozogamicin in children, which included infants as young as 1 month,[22] were established in these trials.
  2. A meta-analysis of five randomized clinical trials that evaluated gemtuzumab ozogamicin in adults with AML observed the following:[23]
    • The greatest OS benefit was for patients with low-risk cytogenetics (t(8;21)(q22;q22) and inv(16)(p13;q22)/t(16;16)(p13;q22)).
    • Adult patients with AML and intermediate-risk cytogenetics who received gemtuzumab ozogamicin had a significant but more modest improvement in OS.
    • There was no evidence of benefit for patients with adverse cytogenetics.
    • The evidence for a benefit in patients with FLT3 ITD variants was mixed; the French ALFA-0701 (NCT00927498) trial showed a trend toward a benefit, whereas the five-trial meta-analysis study did not find a benefit.[23,24] These trials did not examine the outcomes specifically for the combination of gemtuzumab ozogamicin followed by HSCT, as was reported by the COG.[21]

    Fractionated gemtuzumab ozogamicin dosing (3 mg/m2 per dose on days 1, 4, and 7; maximum dose, 5 mg), which has been shown to be safe and effective in adult patients with de novo AML, is an alternative option to single-dose administration during induction.[24] Because this is the recommended dosing method for adults, this schedule is now being evaluated in the MyeChild 01 (NCT02724163) phase III study for pediatric patients with de novo AML in the United Kingdom.

    The characteristics of CD33, the target of gemtuzumab ozogamicin, have been examined to further identify the patients who will benefit most from this agent.

  3. The expression intensity of CD33 on leukemic cells appeared to predict which patients benefited from gemtuzumab ozogamicin on the COG AAML0531 clinical trial.[20][Level of evidence B1]
    • Patients whose CD33 intensity fell into the highest three population quartiles benefited from treatment with gemtuzumab ozogamicin (i.e., improved relapse risk, DFS, and EFS), whereas those in the lowest quartile had no reduction in relapse risk, EFS, or OS.
    • This impact was seen for low-, intermediate-, and high-risk patients.
  4. In a retrospective analysis of the ALFA-0701 (NCT00927498) trial of older adults, higher CD33 expression corresponded with greater benefit from treatment with gemtuzumab ozogamicin.[25]
  5. The CD33 receptor on AML cells exhibited architectural variability (polymorphism) that resulted in 51% of patients expressing the single nucleotide polymorphism (SNP) rs12459419 (designated CC). The alteration of this SNP resulted in a CD33 isoform lacking the CD33 IgV domain to which gemtuzumab ozogamicin binds and that is used in diagnostic immunophenotyping.[26]
    • The patients with this SNP had a significant reduction in relapse with the use of gemtuzumab ozogamicin, compared with patients who were not treated with this drug (26% vs. 49%; P < .001).
    • For patients with either a one or two allele C>T variant (CT and TT phenotypes, respectively) at this SNP, there was no reduction in relapse when adding gemtuzumab ozogamicin therapy (5-year cumulative incidence of relapse, 39% vs. 40%; P = .85).

Targeted therapy

Similar to immunotherapeutic approaches, the use of targeted therapy attempts to circumvent the severe toxicity of traditional chemotherapy by employing agents that target leukemia-specific variants and/or their abnormal present or missing byproducts. While randomized clinical trials have not yet demonstrated that targeted therapies improve outcomes in children with newly diagnosed AML, single-arm trials have demonstrated a survival benefit, such as the sorafenib trial described below. Because most data on the use of targeted agents are from adult clinical trials, the adult experience is initially described, followed by a description of the more limited experience in children.

FLT3 inhibitors in de novo AML

Because of the high prevalence of FLT3 variants in adult AML and the adverse impact in patients with AML of all ages, the FLT3 target has received the greatest attention for target-specific drug development in AML. Among the various FLT3 inhibitors developed and clinically studied, midostaurin, a multikinase inhibitor, is the only one with U.S. Food and Drug Administration (FDA) approval for adult de novo AML. It was approved in 2017 for use with conventional backbone chemotherapy but not as a single agent.[27]

Midostaurin

Evidence (midostaurin for adults with de novo AML):

  1. In a randomized, placebo-controlled, phase III study (CALGB10603/RATIFY [NCT00651261]) of 717 adults aged 18 to 59 years with AML and FLT3 ITD or TKD variants, standard chemotherapy was given with or without midostaurin (50 mg/dose twice daily) followed by maintenance midostaurin or placebo for patients who did not proceed to HSCT.[28]
    • OS (the primary end point) and EFS were significantly better for patients who received midostaurin.
    • The median OS was 74.7 months (95% confidence interval [CI], 31.5–not reached) for patients in the midostaurin arm versus 25.6 months (95% CI, 18.6–42.9) for patients in the control arm (hazard ratio [HR], 0.78; 95% CI, 0.63–0.96; P = .009).
    • The median EFS was 8.2 months (95% CI, 5.4–10.7) for patients in the midostaurin arm versus 3.0 months (95% CI, 1.9–5.9) for patients in the control arm (HR, 0.78; 95% CI, 0.66–0.93; P = .002).
    • This benefit was seen across all FLT3 subgroups regardless of whether allogeneic HSCT was used in consolidation.
  2. A second single-arm trial in 284 adults (aged 18–70 years) with FLT3 ITD AML added midostaurin (50 mg/dose twice daily) to intensive chemotherapy followed by allogeneic HSCT or consolidation, and all patients had a subsequent midostaurin maintenance phase.[29]
    • The 2-year EFS rate was 37.7% (95% CI, 32%–44.3%), and the OS rate was 50.9% (95% CI, 44.9%–57.6%).
    • Using a historical-control comparison, significant improvement in EFS was reported (HR, 0.58; 95% CI, 0.48–0.70; P < .001).

Midostaurin has been studied in children with relapsed/refractory AML,[30] but there is no experience with midostaurin in children with newly diagnosed AML. For more information, see the Targeted therapy (FLT3 inhibitors) section.

Sorafenib

Sorafenib, another multikinase inhibitor, has been approved for the treatment of other malignancies, but it has not been approved for use in patients with AML. This agent has been evaluated for use in adult and pediatric patients with de novo AML and FLT3 variants.

Evidence (sorafenib):

  1. Sorafenib was shown to improve EFS in the COG AAML1031 (NCT01371981) study of pediatric patients with de novo AML and high-allelic ratio (HAR) (i.e., >0.4) FLT3 ITD variants. Seventy-two patients who received sorafenib were evaluable for response. The patients in this study were compared with patients with AML and HAR FLT3 ITD (N = 76) in the AAML1031 and the COG AAML0531 trials who did not receive sorafenib.[31]
    • The morphological CR rate after induction cycle I was significantly improved for patients who received sorafenib (75% vs. 57%; P = .028).
    • However, there was similar prevalence of MRD in both groups of patients (48% vs. 45%; P = .724).
    • Patients who received sorafenib had significantly improved 3-year EFS rates (55.9% vs. 31.9%, P = .001), DFS rates (70.9% vs. 49.4%, P = .032), and relapses after CR (17.6% vs. 44.1%, P = .012).
    • The OS rate did not improve after treatment with sorafenib (65.8% vs. 55.3%, P = .244).
    • Although similar trends were seen in patients with AML harboring both HAR FLT3 ITD variants and NPM1 variants, they did not approach a significant level of benefit.
    • Statistics showed that a benefit of sorafenib treatment remained in multivariable analyses controlling for both NPM1 status and HSCT, a time-varying covariate.

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%.[32-34] Several approaches have been examined to reduce the morbidity and mortality from infection in children with AML.

Antimicrobial prophylaxis

The use of antibacterial prophylaxis in children undergoing treatment for AML has been supported by several studies. Studies, including one prospective randomized trial, suggest a benefit to the use of antibiotic prophylaxis.

Evidence (antimicrobial prophylaxis):

  1. A retrospective study from SJCRH in patients with AML reported the following:[35]
    • The use of intravenous cefepime or vancomycin in conjunction with oral ciprofloxacin or a cephalosporin significantly reduced the incidence of bacterial infection and sepsis, compared with patients receiving only oral or no antibiotic prophylaxis.
  2. A subsequent study confirmed the results of the SJCRH study.[36]
  3. A retrospective report from the COG AAML0531 (NCT00372593) trial demonstrated the following results:[37]
    • There were significant reductions in sterile-site bacterial infections and particularly gram-positive, sterile-site infections with the use of antibacterial prophylaxis.
    • This study also reported that prophylactic use of granulocyte colony-stimulating factor (G-CSF) reduced bacterial and Clostridium difficile (C. difficile) infections.
  4. A study compared the percentage of bloodstream infections or invasive fungal infections in children with acute lymphoblastic leukemia (ALL) or AML who underwent chemotherapy and received antibacterial and antifungal prophylaxis.[38]
    • Both variables were significantly reduced with the use of prophylaxis, compared with a historical control group that did not receive any prophylaxis.
  5. In the prospective COG ACCL0934 trial for children receiving intensive chemotherapy, patients were enrolled in two separate groups—patients with acute leukemia (consisting of AML or relapsed ALL) and patients undergoing HSCT. Patients with acute leukemia were randomly assigned to receive levofloxacin (n = 96) or no prophylactic antibiotic (n = 99) during the period of neutropenia in one to two cycles of chemotherapy.[39]
    • Analysis of the 195 children with acute leukemia revealed a significant reduction in bacteremia (43.4% to 21.9%, P = .001) and neutropenic fever (82.1% to 71.2%, P = .002) in the levofloxacin prophylaxis group compared with the control group, without increases in fungal infections, C. difficile–associated diarrhea, or musculoskeletal toxicities.
    • There was no significant decrease in severe infections (3.6% vs. 5.9%, P = .20), and no bacterial infection–related deaths occurred in either group.
    • Levofloxacin prophylaxis is consistent with the guidelines published by the American Society of Clinical Oncology and Infectious Diseases Society of America in 2018 for adult cancer patients considered at high risk of infection by virtue of neutropenia (<100 neutrophils/µL) in excess of 7 days.[40]
Antifungal prophylaxis

Antifungal prophylaxis is important in the management of patients with AML.

Evidence (antifungal prophylaxis):

  1. Two meta-analysis reports have suggested the following result:[41,42]
    • Antifungal prophylaxis in pediatric patients with AML during treatment-induced neutropenia or during bone marrow transplant reduces the frequency of invasive fungal infections and, in some instances, nonrelapse mortality.
  2. Another study surveyed institutions that enrolled patients on the COG AAML0531 (NCT00372593) trial and investigated if these institutions routinely prescribed antifungal prophylaxis.[37]
    • The study found that antifungal prophylaxis did not reduce fungal infections or nonrelapse mortality.
    • The study was limited, however, because the investigators did not analyze whether individual patients received antifungal prophylaxis, regardless of institutional guidance.
  3. Several randomized trials in adults with AML have reported a significant benefit in reducing invasive fungal infection with the use of antifungal prophylaxis. Such studies have also balanced cost with adverse side effects. When effectiveness at reducing invasive fungal infection is balanced with these other factors, posaconazole, voriconazole, caspofungin, and micafungin are considered reasonable choices.[38,43-47]
  4. There is a single randomized study comparing two antifungal agents for prophylaxis in pediatric patients with AML. The COG ACCL0933 (NCT01307579) trial randomly assigned patients to receive prophylactic treatment with either fluconazole or caspofungin (an echinocandin with broader antiyeast and antimold activity than fluconazole).[48]
    • Caspofungin was superior to fluconazole in achieving lower 5-month cumulative incidences of both proven or probable invasive fungal disease (3.1% vs. 7.2%; P = .03) and proven or probable invasive aspergillosis (0.5% vs. 3.1%; P = .046).
Hematopoietic growth factors

Hematopoietic growth factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF) or 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.[2] 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 [49] but have not shown significant effects on treatment-related mortality or OS.[49] For more information, see the Treatment Option Overview for AML section in Acute Myeloid Leukemia Treatment.

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

Evidence (against the use of hematopoietic growth factors):

  1. A randomized study in children with AML that evaluated G-CSF administered after induction chemotherapy showed a reduction in duration of neutropenia but no difference in infectious complications or mortality.[50]
  2. A higher relapse rate has been reported for children with AML expressing the differentiation defective G-CSF receptor isoform IV.[51]
Cardiac monitoring

Bacteremia or sepsis and anthracycline use have been identified as significant risk factors in the development of cardiotoxicity, manifested as reduced left ventricular function.[52,53] Monitoring of cardiac function through the use of serial exams during therapy is an effective method for detecting cardiotoxicity and adjusting therapy as indicated. The use of dexrazoxane in conjunction with bolus dosing of anthracyclines can effectively reduce the risk of cardiac dysfunction during therapy.[54]

Evidence (cardiac monitoring/dexrazoxane impact):

  1. In the COG AAML0531 (NCT00372593) trial, 8.6% of enrolled patients experienced left ventricular systolic dysfunction (LVSD) during protocol therapy, with a cumulative incidence of LVSD of 12% within 5 years of completing therapy.[52]
    • Risk factors for LVSD during therapy included Black race, older age, underweight body mass, and bacteremia.
    • The occurrence of LVSD adversely impacted 5-year EFS (HR, 1.57; 95% CI, 1.16–2.14; P = .004) and OS (HR, 1.59; 95% CI, 1.15–2.19; P = .005), which was primarily a result of nonrelapse mortality.
    • In patients who experienced LVSD during therapy, there was a 12-fold greater risk of LVSD in the 5 years after the completion of therapy.
  2. The use of dexrazoxane was assessed in patients enrolled on the COG AAML1031 (NCT01371981) trial.[54]
    • This trial mandated prospective cardiac monitoring with each cycle and in follow-up and found a higher LVSD incidence (39%) occurring at a median of 3.8 months from enrollment (interquartile range, 2–6.2 months) than was seen in the preceding trial.
    • Approximately 10% of children (96 of 1,014) electively received dexrazoxane with each dose of anthracycline. The incidence of LVSD (defined as ejection fraction <55% or shortening fraction <28%) was significantly less in these patients (26.5% vs. 42.2%; HR, 0.55; 95% CI, 0.36–0.86; P = .009) than in the patients who did not elect to receive dexrazoxane. This was also evident for risk of LVSD grade 2 or higher (60% lower). Patients who received dexrazoxane also had persistently better cardiac function after therapy (median follow-up, 3.5 years).
    • Patients who received dexrazoxane had a lower treatment-related mortality (5.7% vs. 12.7%; P = .068), although the improved OS, EFS, and relapse risk outcomes did not reach statistical significance.
Hospitalization

Hospitalization until adequate granulocyte (absolute neutrophil or phagocyte count) recovery has been used to reduce treatment-related mortality.

  • The COG-2961 (NCT00002798) trial demonstrated the following:[7]
    • 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 (P < .001).
  • Another analysis of the impact of hospitalization using a survey of institutional routine practice found the following results:[37]
    • Those who mandated hospitalization had nonsignificant reduction in patients' treatment-related mortality (adjusted HR, 0.60 [0.26–1.36, P = .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.[36]

Central Nervous System (CNS) Prophylaxis for AML

Therapy with either radiation or intrathecal chemotherapy has been used to treat CNS leukemia present at diagnosis. However, the use of radiation has essentially been abandoned as a means of prophylaxis because of the lack of documented benefit and long-term sequelae.[55] Intrathecal chemotherapy is used to prevent later development of CNS leukemia. The COG has historically used single-agent cytarabine for both CNS prophylaxis and therapy. Other groups have attempted to prevent CNS relapse by using additional intrathecal agents. Similarly, the ongoing COG AAML1831 (NCT04293562) trial incorporates the use of intrathecal triples (methotrexate, cytarabine, and hydrocortisone).

CNS involvement in patients with AML and its impact on prognosis has been discussed in the Prognosis and Prognostic Factors section.

Evidence (CNS prophylaxis):

  1. The COG AAML03P1 (NCT00070174) and AAML0531 (NCT00372593) trials used single-agent cytarabine for prophylaxis.[56] The results of these trials are similar to the findings from the AAML1031 trial.[57]
    • CNS1 disease: A low relapse rate was associated with CNS1 disease (3.9%) seen in 71% of enrolled patients.
    • CNS2 disease: Sixteen percent of patients had CNS2 disease with minimal evidence of CNS leukemia at diagnosis (CNS2 or blasts present when cerebrospinal fluid [CSF] white blood cell count was <5 cells/HPF). These patients were given twice-weekly intrathecal cytarabine until the CSF cleared. Of the 16% of patients who had CNS2 disease, 95.8% had CSF cleared of leukemic blasts. Of those, 11.7% later experienced CNS relapse.
    • CNS3 disease: CNS3 involvement at diagnosis (13% of patients) conferred even worse outcomes. Despite clearing of leukemic blasts in 90.7% of children, 17.7% later experienced a CNS relapse. In a multivariate analysis, the presence of CNS3 involvement significantly worsened isolated CNS relapse risk (HR, 7.82; P = .003).
  2. Another methodology uses additional intrathecal agents, including triples, a combination of intrathecal cytarabine, hydrocortisone, and methotrexate.[58]
    • The SJCRH reported that after switching from triples (their previous standard treatment) to single-agent cytarabine, the incidence of isolated CNS relapse increased from 0% (0 of 131 patients) to 9% (3 of 33 patients), prompting them to return to triples, which then reproduced a 0% (0 of 79 patients) CNS relapse rate.

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 HSCT.

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

  1. Chemotherapy.
  2. HSCT.
  3. Targeted therapy (e.g., FLT3 inhibitors).[59] For more information, see the Induction Therapy section.

Chemotherapy

Postremission chemotherapy includes some of the drugs used in induction while 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.[60] For more information about the treatment of adults with AML, see the Treatment of AML in Remission section in Acute Myeloid Leukemia Treatment. 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.[6,61,62]

The optimal number of postremission courses of therapy remains unclear, but it appears that at least two to three courses of intensive therapy are required after induction.[7]

Evidence (number of postremission courses of chemotherapy):

  1. In a United Kingdom MRC study, adult and pediatric patients were randomly assigned to receive either four or five courses of intensive therapy.[1,12][Level of evidence A1]
    • Five courses of therapy did not show an advantage for relapse-free survival and OS.
  2. Based on this MRC data, in the COG AAML1031 (NCT01371981) trial, non–high-risk patients treated without HSCT in first CR (73% of all patients) received four cycles of chemotherapy (two induction cycles and two consolidation cycles) rather than five cycles (two induction cycles and three consolidation cycles). In the previous COG AAML0531 (NCT00372593) and AAML03P1 (NCT00070174) trials, patients who did not undergo HSCT received five cycles of chemotherapy.[63]
    • In a retrospective analysis, non–high-risk patients treated without HSCT on the COG AAML1031 trial (four chemotherapy cycles) had significantly worse outcomes than did those who had received five cycles of chemotherapy on the AAML0531 trial (four- vs. five-cycle outcomes):
      • The OS rate was 77.0% for patients who received four chemotherapy cycles, compared with 83.5% for patients who received five chemotherapy cycles (HR, 1.45; 95% CI, 0.97–2.17; P = .068).
      • The DFS rate was 56% for patients who received four cycles, compared with 67% for patients who received five cycles (HR, 1.45; 95% CI, 1.10–1.91; P = .009).
      • The relapse rate was 40.9% for patients who received four cycles, compared with 31.4% for patients who received five cycles (HR, 1.40; 95% CI, 1.06–1.85; P = .019).
    • An exception was found in the low-risk subgroup defined by favorable cytogenetics or molecular genetics who were MRD negative at the end of induction cycle 1. This subset of patients had similar outcomes regardless of whether they received four chemotherapy cycles (AAML1031) or five chemotherapy cycles (AAML0531).

    Additional study of the number of intensification courses and specific agents used will better address this issue. However, these data suggest that four chemotherapy courses should only be administered to the favorable group described above, and that all other patients who do not undergo HSCT should receive five chemotherapy courses.

HSCT

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 transplants 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,[5,64] with the caveat that outcome after allogeneic HSCT is dependent on risk-classification status.[65]

In prospective trials that compared allogeneic HSCT with chemotherapy and/or autologous HSCT, superior DFS rates were observed for patients who were assigned to allogeneic HSCT on the basis of family 6/6 or 5/6 HLA-matched donors in adults and children.[5,64,66-70] However, the superiority of allogeneic HSCT over chemotherapy has not always been observed.[71] Several large cooperative group clinical trials for children with AML have found no benefit for autologous HSCT over intensive chemotherapy.[5,64,66,68]

Risk stratification for transplant

Current application of allogeneic HSCT involves incorporation of risk classification to determine whether transplant should be pursued in first remission. An analysis from the Center for International Blood and Marrow Transplant Research (CIBMTR) examined pretransplant variables to create a model for predicting leukemia-free survival (LFS) posttransplant in pediatric patients (aged <18 years). All patients were first transplant recipients who had myeloablative conditioning, and all stem cells sources were included. For patients with AML, the predictors associated with lower LFS included age younger than 3 years, intermediate-risk or poor-risk cytogenetics, and second CR or higher with MRD positivity or not in CR. A scale was established to stratify patients on the basis of risk factors to predict survival. The 5-year LFS rate was 78% for the low-risk group, 53% for the intermediate-risk group, 40% for the high-risk group, and 25% for the very high-risk group.[72]

Low-risk patients

Patients receiving contemporary chemotherapy regimens have improved outcome if they have favorable prognostic features (low-risk cytogenetic or molecular variants). This finding and the lack of demonstrable superiority for HSCT in this patient population means that such patients typically receive matched-family donor (MFD) HSCT only after first relapse and the achievement of a second CR.[65,73-75]

Intermediate-risk patients

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

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

  1. A study combining the results of the POG-8821, CCG-2891, COG-2961 (NCT00002798), and MRC AML10 studies reported the following:[65]
    • A DFS and OS advantage for allogeneic HSCT in patients with intermediate-risk AML but not favorable-risk (inv(16) and t(8;21)) or poor-risk AML (del(5q), monosomy 5 or 7, or more than 15% blasts after first induction for POG/CCG studies).
    • The MRC study included patients with 3q abnormalities and complex cytogenetics in the high-risk category.
    • Weaknesses of this study include the large percentage of patients not assigned to a risk group and the relatively low EFS and OS rates for patients with intermediate-risk AML assigned to chemotherapy, compared with results of more recent clinical trials.[1,13]
  2. The AML99 clinical trial from the Japanese Childhood AML Cooperative Study Group observed a significant difference in DFS for intermediate-risk patients assigned to MFD HSCT, but there was no significant difference in OS.[76]
  3. The AML-BFM 99 clinical trial demonstrated no significant difference in either DFS or OS for intermediate-risk patients assigned to MFD HSCT compared with patients assigned to chemotherapy.[71]

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 transplant, 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 relapses.[1,76,77]

High-risk patients

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

Many, but not all, pediatric clinical trial groups prescribe allogeneic HSCT for high-risk patients in first remission.[75] For example, the COG frontline AML clinical trial (COG-AAML1031) 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 or patients with 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.[71,78] 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.[71]

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

  1. A retrospective analysis from the COG and CIBMTR compared chemotherapy only with matched-related donor and matched-unrelated donor HSCT for patients with AML and high-risk cytogenetics, defined as monosomy 7/del(7q), monosomy 5/del(5q), abnormalities of 3q, t(6;9), or complex karyotypes.[79]
    • The analysis demonstrated no difference in the 5-year OS among the three treatment groups.
  2. A Nordic Society for Pediatric Hematology and Oncology (NOPHO) study evaluated time-intensive reinduction therapy followed by transplant with best available donor for patients whose AML did not respond to induction therapy.[80][Level of evidence B4]
    • This treatment resulted in a 70% survival rate at a median follow-up of 2.6 years.
  3. The subsequent risk-stratified NOPHO-DBH-AML2012 (NCT01828489) study reported the following:[81]
    • The 5-year EFS rate was 74.1% for patients with high-risk AML defined by flow cytometry MRD of >0.1% on day 22 of induction 1 (or any MRD for patients with FLT3 ITD), 85% of whom received HSCT in first CR. This outcome compared favorably with the 5-year EFS rate of 67.1% for patients with non–high-risk AML who received four to five courses of chemotherapy.
  4. A single-institution retrospective study included 36 consecutive patients (aged 0–30 years) with high-risk AML (FLT3 ITD, 11q23 KMT2A rearrangements, presence of chromosome 5 or 7 abnormalities, induction failure, persistent disease), who were in a morphological first remission before allogeneic transplant.[82]
    • The investigators reported a 5-year OS rate of 72% and a LFS rate (from the time of transplant) of 69% with the use of a myeloablative conditioning regimen.
    • They also reported a treatment-related mortality rate of 17%.
    • These outcomes were similar to 14 patients with standard-risk AML who underwent transplant during the same time period.
  5. A subgroup analysis from the AML-BFM 98 clinical trial demonstrated improved survival rates for patients with 11q23 aberrations allocated to allogeneic HSCT, but not for patients without 11q23 aberrations.[71]
  6. For children with FLT3 ITD (high-allelic ratio), patients who received matched family donor HSCT (n = 6) had higher OS rates than those who received standard chemotherapy (n = 28). However, the number of cases studied limited the ability to draw conclusions.[83]
  7. A subsequent retrospective report from three consecutive trials in young adults with AML found that patients with FLT3 ITD high-allelic ratio benefited from allogeneic HSCT (P = .03), but patients with low-allelic ratio did not (P = .64).[84]
  8. A subset analysis of a COG phase III trial evaluated gemtuzumab ozogamicin during induction therapy in children with newly diagnosed AML.[21]
    • For patients with FLT3 ITD high-allelic ratio who received HSCT, a lower relapse rate was observed for those who also received gemtuzumab ozogamicin (15% vs. 53%, P = .007).
    • Conversely, patients who received gemtuzumab ozogamicin had higher rates of treatment-related mortality (19% vs. 7%, P = .08), resulting in overall improved DFS (65% vs. 40%, P = .08).

Further analysis of subpopulations of patients treated with allogeneic HSCT will be an ongoing need in current and future clinical trials because of the evolving definitions of high-, intermediate-, and low-risk AML, the ongoing association of molecular characteristics of the tumor with outcome (e.g., FLT3 ITD, WT1 variants, and NPM1 variants), and response to therapy (e.g., MRD assessments postinduction therapy).

Preparative regimens

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.[70,85,86] There are no data that suggest total-body irradiation (TBI) is superior to busulfan-based myeloablative regimens.[71,73] Additionally, outstanding outcomes have been noted for patients who were treated with treosulfan-based regimens. However, trials comparing treosulfan with busulfan or TBI are lacking.[87]

Evidence (myeloablative regimen):

  1. A randomized trial that compared busulfan plus fludarabine with busulfan plus cyclophosphamide as a preparative regimen for AML in first CR demonstrated the following results:[88]
    • The busulfan plus cyclophosphamide regimen was associated with less toxicity and produced a comparable DFS and OS.
  2. A large prospective CIBMTR cohort study included children and adults with AML, myelodysplastic neoplasms (MDS), and chronic myeloid leukemia (CML).[89]
    • Patients with early-stage disease (chronic-phase CML, first CR AML, and MDS-refractory anemia) had superior survival rates with busulfan-based regimens, compared with TBI.
  3. A CIBMTR study of 624 children with de novo AML who underwent transplant between 2008 and 2016 and received either a TBI-based regimen (n = 199) or non-TBI–containing regimen (n = 425) demonstrated the following results:[90]
    • TBI recipients had a higher nonrelapse mortality (P < .0001) with lower relapse (P < .0001), culminating in equivalent LFS and OS rates.
    • TBI recipients experienced more grades 2 to 3 acute graft-versus-host disease (GVHD) (56% vs. 27%; P < .0001) but had equivalent chronic GVHD incidence.
    • TBI recipient survivors had a greater incidence of gonadal or growth deficiency (24% vs. 8%; P < .0001), but there were no differences in pulmonary, cardiac, or renal impairment.

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.[61,91] Maintenance therapy with interleukin-2 also proved ineffective.[7]

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, see the ClinicalTrials.gov 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.

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Treatment of Recurrent or Refractory Childhood AML

The diagnosis of recurrent acute myeloid leukemia (AML) is made when patients who were in previous remission after therapy develop more than 5% bone marrow blasts. The diagnosis of refractory AML is made when complete remission is not achieved by the end of induction therapy.

Recurrent Childhood AML

Approximately 50% to 60% of relapses occur within the first year after diagnosis, with most relapses occurring by 4 years after diagnosis.[1] The vast majority of relapses occur in the bone marrow, and central nervous system (CNS) relapse is very uncommon.[1]

Prognosis and prognostic factors

Factors associated with survival 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%).[2-4] Survival rates for children with shorter first remissions are also substantially lower (approximately 10%) than those for children with first remissions exceeding 1 year (approximately 40%).[2-5] The Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) Consortium also identified duration of previous remission as a powerful prognostic factor. The 5-year overall survival (OS) rates were 54% (± 10%) for patients with greater than 12 months first remission duration and 19% (± 6%) for patients with shorter periods of first remission.[6]
  • 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 WT1 or FLT3 internal tandem duplication (ITD) variants at first relapse were associated, as independent risk factors, with worse OS in patients achieving a second remission.[7]
  • Achieving a second remission.[8]
  • Early response to salvage therapy. The international Relapsed AML 2001/01 (NCT00186966) trial also found that early response to salvage therapy was a highly favorable prognostic factor.[9][Level of evidence C2]
  • No hematopoietic stem cell transplant (HSCT) in first remission.[8,10]
  • Favorable cytogenetics.[8,10]

Additional prognostic factors were identified in the following studies:

  • In a report of 379 children with AML whose disease relapsed after initial treatment on the German Berlin-Frankfurt-Muenster (BFM) group protocols, the second complete remission (CR) rate was 63% and the OS rate was 23%.[8][Level of evidence C1] The most significant prognostic factors associated with a favorable outcome after relapse included achieving a second CR, 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)).
  • 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 CR (66%) than in patients not in remission (17%).[5]
  • 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 with relapse of 543 children initially treated). Second remissions were achieved in 146 children (70%) with a variety of reinduction regimens. The 5-year OS rate 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 children in second remission who underwent HSCT, the 5-year OS rate was 61%, as opposed to a 5-year OS rate of 18% for those who did not include HSCT in their therapy (P < .001).[10]

Patients with subsequent relapses and those with refractory first relapses have declining outcomes with each event. In the TACL analysis, remission outcomes, primarily in patients with early relapses, declined with each attempt to reinduce remission (56% ± 5%, 25% ± 8%, and 17% ± 7% for each consecutive attempt).[6] An analysis by the NOPHO group found a 5-year OS rate of 17% in children who had a second relapse or in children who had a refractory first relapse and were subsequently treated with curative intent.[11]

Treatment of recurrent AML

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

  1. Chemotherapy.
  2. Immunotherapeutic approaches.
  3. Targeted therapy (FLT3 inhibitors).
  4. HSCT.
  5. Second transplant after relapse following a first transplant.
Chemotherapy

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.[4]
  • Fludarabine and idarubicin.[12]
  • L-asparaginase.[13]
  • Etoposide.
  • Liposomal daunorubicin. A study by the International BFM group compared fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG) with FLAG plus liposomal daunorubicin. The 4-year OS rate 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 variants (82%, FLAG plus liposomal daunorubicin vs. 58%, FLAG; P = .04).[14][Level of evidence A1]
  • CPX-351. The liposomal combination agent CPX-351, which uses a fixed combination of daunorubicin and cytarabine, has been evaluated in the phase I/II Children's Oncology Group (COG) AAML1421 (NCT02642965) trial for children with relapsed AML. CPX-351 (135 units/m2/day and containing 60 mg/m2 of daunorubicin) was administered without dexrazoxane in cycle 1 on days 1, 3, and 5 followed by a FLAG cycle. CPX-351 was well tolerated, with no unexpected toxicity, one dose-limiting toxicity (grade 3 ejection fraction decline that resolved), and no toxic mortality. A maculopapular rash occurred in 40% of patients. Among 37 evaluable patients, 75.7% had a CR (including CR with partial recovery of platelet count [CRp] and CR with incomplete blood count recovery [CRi]) after the CPX-351 cycle. Further, 21 of 25 CR/CRp patients had no minimal residual disease (MRD) after cycle 2, and 20 of 25 patients had no MRD before HSCT.[15][Level of evidence B4]
  • Venetoclax. The St. Jude Children's Research Hospital (SJCRH) VENAML trial (NCT03194932) evaluated venetoclax, a selective inhibitor of BCL-2, in combination with cytarabine with or without idarubicin in pediatric patients with relapsed or refractory AML.[16] The combination was well tolerated. The most common grades 3 and 4 adverse events were febrile neutropenia (66% of patients), blood stream infections (16% of patients), and invasive fungal infections (16% of patients). Among the 20 patients treated at the recommended phase II dose, 14 patients (70%) achieved a complete response with or without complete hematological recovery, and 2 patients (10%) achieved a partial response.
  • Clofarabine. Regimens built upon clofarabine have been used.[17-19][Level of evidence B4] 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 was 46%, with 21 of 23 responders undergoing HSCT. MRD before HSCT was a strong predictor of survival.[20][Level of evidence B4]
  • Cladribine. Regimens using cladribine plus idarubicin have been used.[21]

The standard-dose cytarabine regimens used in the United Kingdom Medical Research Council (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.[3] In a COG phase II study, the addition of bortezomib to idarubicin plus low-dose cytarabine resulted in an overall CR rate of 57%. The addition of bortezomib to etoposide and high-dose cytarabine resulted in an overall CR rate of 48%.[22]

Immunotherapeutic approaches

Before its U.S. Food and Drug Administration (FDA) approval for use in children with de novo AML in 2020, gemtuzumab ozogamicin was approved for children with relapsed or refractory AML who are aged 2 years and older.

Evidence (gemtuzumab ozogamicin with or without chemotherapy):

  1. The COG AAML00P2 (NCT00028899) study established the maximum tolerated dose (MTD) of gemtuzumab ozogamicin, when combined with mitoxantrone and high-dose cytarabine, as 3 mg/m2. The MTD of gemtuzumab ozogamicin, when combined with Capizzi II–based, high-dose cytarabine, was 2 mg/m2.[23]
    • These regimens produced an overall remission response rate of 45% (±15%), a 1-year event-free survival (EFS) rate of 38% (±14%), and a 1-year overall survival (OS) rate of 53% (±15%).
    • Sinusoidal occlusion syndrome was seen in one patient with a previous HSCT during the cycle containing gemtuzumab ozogamicin and in 4 of 28 patients during subsequent HSCT (grade 1 in two patients, grade 3 in 1 patient, and grade 4 in 1 patient), all of whom recovered.
    • This same MTD of gemtuzumab ozogamicin was found in the dose escalation portion of the UK MRC AML15 study in adults. In these patients, escalation beyond 3 mg/m2/dose, when given with a conventional intensive chemotherapy backbone, was not feasible because of hepatotoxicity and delayed hematopoietic recovery.[24] Gemtuzumab ozogamicin at 3 mg/m2/dose, when given with consecutive courses of intensive chemotherapy, was also not tolerated.
  2. The Relapsed AML 2001/02 study was a single-arm trial for children (n = 30) who experienced a second relapse or had refractory AML after the cancer did not respond to a second induction regimen. Gemtuzumab ozogamicin as a single agent was dosed at 7.5 mg/dose (children younger than 3 years received 0.25 mg/kg) given every 14 days for two total doses.[25]
    • CR or CRp was seen in 37% of patients. Nine patients subsequently underwent HSCT, and three of these patients remained in continuous CR.
    • All patients received prophylactic defibrotide during HSCT without experiencing any sinusoidal occlusion syndrome.
    • In a prior study of children who received single-agent gemtuzumab ozogamicin, administered at 6 to 9 mg/m2 per dose, patients did not receive defibrotide prophylaxis during subsequent HSCT. These studies demonstrated an increased risk of sinusoidal occlusion syndrome, particularly for patients who underwent HSCT less than 3.5 months after the last dose of gemtuzumab ozogamicin.[26]
  3. Two prospective studies from the Acute Leukemia French Association (ALFA) group examined fractionated gemtuzumab ozogamicin (3 mg/m2/dose on days 1, 4, and 7) in adults with relapsed AML.
    • The MYLOFRANCE 1 trial evaluated single-agent fractionated dosing in 57 adults with AML in first relapse, which resulted in a CR rate of 26% and a CRp rate of 7%. No sinusoidal occlusion syndrome occurred during or in subsequent HSCT.[27]
    • Subsequently, the MYLOFRANCE 2 trial was a phase I/II study (n = 20) that combined the same fractionated dose of gemtuzumab ozogamicin with a dose-finding backbone of daunomycin and cytarabine. Nine patients achieved CR and two patients achieved a CRp. The recommended phase II dose was found to be 60 mg/m2 per day for 3 days for daunomycin and 200 mg/m2 per day for 7 days for cytarabine. No sinusoidal occlusion syndrome was experienced.[28]
    • Fractionated gemtuzumab ozogamicin dosing has been shown to be safe and effective in adults with de novo AML;[29] it is now being evaluated in the MyeChild01 (NCT02724163) phase III study for pediatric patients with de novo AML in the United Kingdom.
Targeted therapy (FLT3 inhibitors)
Midostaurin

There is limited experience with midostaurin in pediatric patients with AML.

  • A phase I/II dose-escalation, single-agent trial in 22 children with refractory or relapsed AML (9 with FLT3 variants) was reported. Seven patients received the initial dose level of 30 mg/m2 given twice daily, and 15 patients received the higher dose level of 60 mg/m2 twice daily, with a median dose duration of 16 days.[30]
    • In patients with AML and FLT3 variants, 55.5% (21.2%–86.3%) had some clinical response at a median time of 14 days (range, 8–22 days), with one patient achieving a CR with incomplete count recovery who was able to proceed to HSCT; this patient was the only long-term survivor in this study.
    • Overall, 72.7% of patients experienced treatment-related adverse events, with only one patient experiencing a dose-limiting toxicity (grades 3–4 alanine transaminase elevation).

A phase II trial is under way in Europe, beginning with the 30 mg/m2 twice-daily dosing (NCT03591510).

Gilteritinib

As in de novo AML, most of the focus and published experience with FLT3 inhibitors is in adults with AML and this applies to the relapsed and refractory setting as well. Gilteritinib is a type 1 selective FLT3 inhibitor with activity against both FLT3 variants (ITD and D835/I836 tyrosine kinase domain [TKD]). In relapsed or refractory AML, gilteritinib is the first and only FLT3 inhibitor that has received FDA approval for single-agent use in adults. The approval was based on the ADMIRAL (NCT02421939) trial.[31]

  • The phase III ADMIRAL trial included adults (aged 18 years and older) with relapsed or refractory AML and FLT3 variants. In this study, 247 patients were randomly assigned to receive either single-agent gilteritinib (120 mg/day given once daily) or one of four salvage chemotherapy regimens.[31]
    • Median OS was significantly better in patients who received gilteritinib (9.3 months vs. 5.6 months; hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.49–0.83; P < .001), with 37.1% versus 16.7% of patients alive at 1 year.
    • Importantly, because HSCT is felt to be essential for long-term survival in patients with AML and FLT3 variants, a higher percentage of gilteritinib recipients underwent an HSCT (25.5% vs. 15.3%). It had equal efficacy in both FLT3 ITD and FLT3 TKD AML cohorts.
    • There were fewer adverse events in patients who received gilteritinib than in patients who received salvage chemotherapy regimens. However, some patients who received gilteritinib had elevated hepatic transaminase levels. The main toxic effect was myelosuppression.

Gilteritinib is now being studied in children with FLT3-positive de novo AML in the COG AAML1831 (NCT04293562) trial.

Sorafenib

Sorafenib has been evaluated in pediatric patients with relapsed and refractory AML.

  • A phase I dose de-escalation trial of oral sorafenib included pediatric patients with relapsed or refractory acute leukemia. Sorafenib was administered alone on days 1 to 7, and then in combination with clofarabine and high-dose cytarabine for 5 days, followed by single-agent sorafenib use until day 28.[32]
    • The recommended phase II dose of sorafenib was determined to be 150 mg/m2 per dose (maximum dose, 300 mg) twice daily (n = 6) after patients experienced significant hand-foot skin reactions (grades 2–3 in 4 of 4 patients; grade 3 dose-limiting toxicities [DLTs] in 2 of 4 patients) at the initial 200 mg/m2 per dose, twice daily level (n = 4).
    • Marrow blast reduction was seen in 10 of 12 total patients (4 of 5 patients with FLT3 ITD AML) at day 8.
    • Of the 11 patients with AML, 6 patients achieved CR, 2 patients achieved CRi, and 1 patient achieved a partial remission (PR) on or after day 22.
    • All five patients with FLT3 ITD achieved either CR or CRi.
  • A retrospective analysis examined 15 children with AML who received sorafenib for either prophylaxis (n = 6) or relapse (n = 9) after HSCT. Doses of sorafenib varied from 75 to 340 mg/m2 per day (median dose, 230 mg/m2) and was given alone in 11 of 15 patients.[33]
    • Toxicity was seen in 11 patients, 7 of whom received doses higher than 200 mg/m2; adverse events included count suppression (n = 6), hand-foot skin reactions (n = 6), cardiac dysfunction (n = 2), and others.
    • Of the seven patients who experienced DLTs, six patients were able to restart or continue sorafenib treatment after dose adjustments.
    • Sorafenib had the greatest efficacy in patients with MRD pre- or post-HSCT (five of five patients remained disease free), whereas only one of the six patients who began sorafenib treatment for morphological recurrence remained in CR.
    • Graft-versus-host disease (GVHD) was not exacerbated with sorafenib therapy.
HSCT

The selection of additional treatment after the achievement of a second CR 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 CR is obtained.[1]

Evidence (HSCT after second CR):

  1. The BFM group examined outcomes of children with AML over a 35-year period and found that the greatest improvement in overall outcome was the improvement in survival after relapse.[34]
    • Improved EFS after relapse or refractory disease was only seen in patients who received an HSCT as part of their salvage therapy.
  2. Unrelated-donor HSCT has been reported to result in the following:[35][Level of evidence C1]
    • The 5-year probabilities of leukemia-free survival (LFS) were 45%, 20%, and 12% for patients with AML who underwent transplants in second CR, overt relapse, and primary induction failure, respectively.
  3. A number of studies, including a large, prospective Center for International Blood and Marrow Transplant Research (CIBMTR) cohort study of children and adults with myeloid diseases, have shown similar or superior survival with busulfan-based regimens compared with total-body irradiation (TBI) for transplant.[36-39]
  4. Matched sibling-donor transplant has generally led to the best outcomes, but use of single-antigen mismatched related or matched unrelated donors results in very similar survival at the cost of increased rates of GVHD and nonrelapse mortality.[40] Outcomes for patients who received umbilical cord transplants are similar to those in patients who received other unrelated donor transplants. Matching patients at a minimum of 7/8 alleles (HLA A, B, C, DRB1) leads to less nonrelapse mortality.[41] Haploidentical approaches are being used with increasing frequency and have resulted in comparable outcomes to other stem cell sources in pediatrics.[42] Direct comparison of haploidentical and other unrelated donor sources has not been performed in pediatrics, but studies in adults have shown similar outcomes.[43]
  5. Reduced-intensity approaches have been used successfully in pediatrics, but mainly in children unable to undergo myeloablative approaches.[44] A randomized trial in adults showed superior outcomes with myeloablative approaches compared with reduced-intensity regimens.[45]
Second transplant after relapse following a first transplant

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. Improved survival was associated with late relapse (>6–12 months from first transplant), achievement of complete response before the second procedure, and use of a second myeloablative regimen if possible.[46-49]

CNS relapse

Isolated CNS relapse occurs in 3% to 6% of pediatric patients with AML.[50-52] Factors associated with an increased risk of isolated CNS relapse include the following:[50]

  • Age younger than 2 years at initial diagnosis.
  • M5 leukemia.
  • 11q23 abnormalities.
  • CNS2 or CNS3 involvement at initial diagnosis.[52]

The risk of CNS relapse increases with more CNS leukemic involvement at initial AML diagnosis (CNS1: 0.6%, CNS2: 2.6%, CNS3: 5.8% incidence of isolated CNS relapse, P < .001; multivariate HR for CNS3: 7.82, P = .0003).[52] 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 rate for a cohort of children with an isolated CNS relapse was 26% (± 16%).[50] Concurrent bone marrow and CNS relapses can occur, and the incidence increases with CNS involvement at diagnosis (CNS1: 2.7%, CNS2: 8.5%, CNS3: 9.2%, P < .001).[52]

Refractory Childhood AML (Induction Failure)

Induction failure (the morphological 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).[4,23]

Treatment of refractory AML

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

  1. Chemotherapy with HSCT.
  2. Immunotherapeutic approaches (gemtuzumab ozogamicin).
Chemotherapy with HSCT

Like patients with relapsed AML, patients with induction failure are typically directed toward HSCT once they attain a remission. Studies suggest a better EFS rate in patients treated with HSCT than in patients treated with chemotherapy only (31.2% vs. 5%; P < .0001). Attainment of morphological CR for these patients is a significant prognostic factor for disease-free survival (DFS) after HSCT (46% vs. 0%; P = .02). Failure primarily resulted from relapse (relapse risk, 53.9% vs. 88.9%; P = .02).[53]

For more information about chemotherapy to induce remission, see the Chemotherapy section in the Treatment of Recurrent AML section.

Immunotherapeutic approaches (gemtuzumab ozogamicin)

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

  1. In the SJCRH AML02 (NCT00136084) trial, gemtuzumab ozogamicin was given alone (n = 17), typically where MRD was low but still detectable (0.1%–5.6%), or in combination with chemotherapy (n = 29) to patients with high MRD (1%–97%) after the first induction cycle.[54]
    • When given alone, 13 of 17 patients became MRD negative.
    • When given in combination with chemotherapy, 13 of 29 patients became MRD negative and 28 of 29 patients had reductions in MRD.
    • Compared with a nonrandomized cohort of patients with 1% to 25% MRD after induction 1, addition of gemtuzumab ozogamicin to chemotherapy versus chemotherapy alone resulted in significant differences in MRD (P = .03); MRD was eliminated or reduced in all patients who received gemtuzumab ozogamicin versus in only 82% of patients who did not receive gemtuzumab ozogamicin. This result was seen despite higher postinduction 1 MRD levels in the cohort of patients who received gemtuzumab ozogamicin (median, 9.5% vs. 2.9% in the no gemtuzumab ozogamicin group; P < .01). There was a nonstatistically significant improvement in 5-year OS rates (55% ± 13.9% vs. 36.4% ± 9.7%; P = .28) and EFS rates (50% ± 9.3% vs. 31.8% ± 13.4%; P = .28).
    • No impact on HSCT treatment-related mortality was seen.
  2. A phase II trial of gemtuzumab ozogamicin alone for children with relapsed/refractory AML that did not respond to previous reinduction attempts demonstrated the following results:[25]
    • Of 30 patients, 11 achieved a CR or partial CR. The 3-year OS rate was 27% for responders versus 0% for nonresponders (P = .001).

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, see the ClinicalTrials.gov website.

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

  • NCT03934372 (An Open-Label, Single-Arm, Phase I/II Study Evaluating the Safety and Efficacy of Ponatinib for the Treatment of Recurrent or Refractory Leukemias, Lymphomas, or Solid Tumors in Pediatric Participants): This study will evaluate the safety, tolerability, pharmacokinetics, and efficacy of ponatinib in children aged 1 year to younger than 18 years.

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.

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  29. Castaigne S, Pautas C, Terré C, et al.: Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet 379 (9825): 1508-16, 2012. [PUBMED Abstract]
  30. Zwaan CM, Söderhäll S, Brethon B, et al.: A phase 1/2, open-label, dose-escalation study of midostaurin in children with relapsed or refractory acute leukaemia. Br J Haematol 185 (3): 623-627, 2019. [PUBMED Abstract]
  31. Perl AE, Martinelli G, Cortes JE, et al.: Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med 381 (18): 1728-1740, 2019. [PUBMED Abstract]
  32. Inaba H, Rubnitz JE, Coustan-Smith E, et al.: Phase I pharmacokinetic and pharmacodynamic study of the multikinase inhibitor sorafenib in combination with clofarabine and cytarabine in pediatric relapsed/refractory leukemia. J Clin Oncol 29 (24): 3293-300, 2011. [PUBMED Abstract]
  33. Tarlock K, Chang B, Cooper T, et al.: Sorafenib treatment following hematopoietic stem cell transplant in pediatric FLT3/ITD acute myeloid leukemia. Pediatr Blood Cancer 62 (6): 1048-54, 2015. [PUBMED Abstract]
  34. Rasche M, Zimmermann M, Borschel L, et al.: Successes and challenges in the treatment of pediatric acute myeloid leukemia: a retrospective analysis of the AML-BFM trials from 1987 to 2012. Leukemia 32 (10): 2167-2177, 2018. [PUBMED Abstract]
  35. Bunin NJ, Davies SM, Aplenc R, et al.: Unrelated donor bone marrow transplantation for children with acute myeloid leukemia beyond first remission or refractory to chemotherapy. J Clin Oncol 26 (26): 4326-32, 2008. [PUBMED Abstract]
  36. Woodard P, Carpenter PA, Davies SM, et al.: Unrelated donor bone marrow transplantation for myelodysplastic syndrome in children. Biol Blood Marrow Transplant 17 (5): 723-8, 2011. [PUBMED Abstract]
  37. Uberti JP, Agovi MA, Tarima S, et al.: Comparative analysis of BU and CY versus CY and TBI in full intensity unrelated marrow donor transplantation for AML, CML and myelodysplasia. Bone Marrow Transplant 46 (1): 34-43, 2011. [PUBMED Abstract]
  38. Bredeson C, LeRademacher J, Kato K, et al.: Prospective cohort study comparing intravenous busulfan to total body irradiation in hematopoietic cell transplantation. Blood 122 (24): 3871-8, 2013. [PUBMED Abstract]
  39. Dandoy CE, Davies SM, Woo Ahn K, et al.: Comparison of total body irradiation versus non-total body irradiation containing regimens for de novo acute myeloid leukemia in children. Haematologica 106 (7): 1839-1845, 2021. [PUBMED Abstract]
  40. Shaw PJ, Kan F, Woo Ahn K, et al.: Outcomes of pediatric bone marrow transplantation for leukemia and myelodysplasia using matched sibling, mismatched related, or matched unrelated donors. Blood 116 (19): 4007-15, 2010. [PUBMED Abstract]
  41. Eapen M, Klein JP, Ruggeri A, et al.: Impact of allele-level HLA matching on outcomes after myeloablative single unit umbilical cord blood transplantation for hematologic malignancy. Blood 123 (1): 133-40, 2014. [PUBMED Abstract]
  42. Locatelli F, Merli P, Pagliara D, et al.: Outcome of children with acute leukemia given HLA-haploidentical HSCT after αβ T-cell and B-cell depletion. Blood 130 (5): 677-685, 2017. [PUBMED Abstract]
  43. Rashidi A, DiPersio JF, Westervelt P, et al.: Comparison of Outcomes after Peripheral Blood Haploidentical versus Matched Unrelated Donor Allogeneic Hematopoietic Cell Transplantation in Patients with Acute Myeloid Leukemia: A Retrospective Single-Center Review. Biol Blood Marrow Transplant 22 (9): 1696-1701, 2016. [PUBMED Abstract]
  44. Pulsipher MA, Boucher KM, Wall D, et al.: Reduced-intensity allogeneic transplantation in pediatric patients ineligible for myeloablative therapy: results of the Pediatric Blood and Marrow Transplant Consortium Study ONC0313. Blood 114 (7): 1429-36, 2009. [PUBMED Abstract]
  45. Scott BL, Pasquini MC, Logan BR, et al.: Myeloablative Versus Reduced-Intensity Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes. J Clin Oncol 35 (11): 1154-1161, 2017. [PUBMED Abstract]
  46. Meshinchi S, Leisenring WM, Carpenter PA, et al.: Survival after second hematopoietic stem cell transplantation for recurrent pediatric acute myeloid leukemia. Biol Blood Marrow Transplant 9 (11): 706-13, 2003. [PUBMED Abstract]
  47. Nishikawa T, Inagaki J, Nagatoshi Y, et al.: The second therapeutic trial for children with hematological malignancies who relapsed after their first allogeneic SCT: long-term outcomes. Pediatr Transplant 16 (7): 722-8, 2012. [PUBMED Abstract]
  48. Yaniv I, Krauss AC, Beohou E, et al.: Second Hematopoietic Stem Cell Transplantation for Post-Transplantation Relapsed Acute Leukemia in Children: A Retrospective EBMT-PDWP Study. Biol Blood Marrow Transplant 24 (8): 1629-1642, 2018. [PUBMED Abstract]
  49. Uden T, Bertaina A, Abrahamsson J, et al.: Outcome of children relapsing after first allogeneic haematopoietic stem cell transplantation for acute myeloid leukaemia: a retrospective I-BFM analysis of 333 children. Br J Haematol 189 (4): 745-750, 2020. [PUBMED Abstract]
  50. Johnston DL, Alonzo TA, Gerbing RB, et al.: Risk factors and therapy for isolated central nervous system relapse of pediatric acute myeloid leukemia. J Clin Oncol 23 (36): 9172-8, 2005. [PUBMED Abstract]
  51. Abbott BL, Rubnitz JE, Tong X, et al.: Clinical significance of central nervous system involvement at diagnosis of pediatric acute myeloid leukemia: a single institution's experience. Leukemia 17 (11): 2090-6, 2003. [PUBMED Abstract]
  52. Johnston DL, Alonzo TA, Gerbing RB, et al.: Central nervous system disease in pediatric acute myeloid leukemia: A report from the Children's Oncology Group. Pediatr Blood Cancer 64 (12): , 2017. [PUBMED Abstract]
  53. Quarello P, Fagioli F, Basso G, et al.: Outcome of children with acute myeloid leukaemia (AML) experiencing primary induction failure in the AIEOP AML 2002/01 clinical trial. Br J Haematol 171 (4): 566-73, 2015. [PUBMED Abstract]
  54. O'Hear C, Inaba H, Pounds S, et al.: Gemtuzumab ozogamicin can reduce minimal residual disease in patients with childhood acute myeloid leukemia. Cancer 119 (22): 4036-43, 2013. [PUBMED Abstract]

Therapy-Related AML and Therapy-Related Myelodysplastic Neoplasms

Pathogenesis

The development of acute myeloid leukemia (AML) or myelodysplastic neoplasms (MDS) after treatment with ionizing radiation or chemotherapy, particularly alkylating agents and topoisomerase inhibitors, is termed therapy-related AML (t-AML) or therapy-related MDS (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.[1-4]

The risk of t-AML or t-MDS depends on the treatment regimen. It is often related to the cumulative doses of chemotherapy agents received and the dose and field of radiation administered.[5] 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 or t-MDS that exceeded 10% in some cases.[5,6] However, most current chemotherapy regimens that are used to treat childhood cancers have a cumulative incidence of t-AML or t-MDS no greater than 1% to 2%.

t-AML or t-MDS resulting from exposures to epipodophyllotoxins and other topoisomerase II inhibitors (e.g., anthracyclines) usually occur within 2 years of treatment and are commonly associated with chromosome 11q23 abnormalities.[7] Other subtypes of AML (e.g., acute promyelocytic leukemia) have also been reported.[8,9] 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.[1,7]

Treatment of t-AML or t-MDS

Treatment options for t-AML or t-MDS include the following:

  1. Hematopoietic stem cell transplant (HSCT).

The goal of treatment is to achieve an initial complete remission (CR) using AML-directed regimens and then, usually, to proceed directly to HSCT with the best available donor. However, treatment is challenging because of the following:[10]

  1. Increased rates of adverse cytogenetics and subsequent failure to obtain remission with chemotherapy.
  2. Comorbidities or limitations related to chemotherapy used for the previous malignancy.

Accordingly, CR rates and overall survival (OS) rates are usually lower for patients with t-AML than for patients with de novo AML.[10-12] Also, pediatric patients with t-MDS have worse survival rates than pediatric patients with MDS not related to previous therapy.[13]

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 or t-MDS):

  1. One study described the outcomes of 27 children with t-AML who received related- and unrelated-donor HSCT.[14]
    • Three-year OS rates were 18.5% (± 7.5%), and event-free survival (EFS) rates were 18.7% (± 7.5%).
    • Poor survival was mainly the result of very high transplant-related mortality (59.6% ± 8.4%).
  2. Another study reported a second retrospective single-center experience of 14 patients with t-AML or t-MDS who underwent transplant between 1975 and 2007.[11]
    • The survival rate was 29%, but in this review, only 63% of patients diagnosed with t-AML or t-MDS underwent HSCT.
  3. A multicenter study (CCG-2891) examined outcomes of 24 children with t-AML or t-MDS compared with other children enrolled on the study with de novo AML (n = 898) or MDS (n = 62). Children with t-AML or t-MDS were older and rarely had low-risk cytogenetic features.[15]
    • The rates of achieving CR and OS at 3 years were worse in the t-AML/t-MDS group (CR rate, 50% vs. 72%; P = .016; OS rate, 26% vs. 47%; P = .007). However, if patients achieved a CR, the survival was similar (OS rate, 45% vs. 53%; P = .87).
  4. The importance of obtaining remission to improve survival in these patients was further illustrated by another single-center report of 21 children who underwent HSCT for t-AML or t-MDS between 1994 and 2009. Of the 21 children, 12 had t-AML (11 in CR at the time of transplant), seven had refractory anemia (for whom induction was not done), and two had refractory anemia with excess blasts.[16]
    • The survival rate of the entire cohort was 61%. Patients in remission or with refractory anemia had a disease-free survival rate of 66%.
    • For the three patients with more than 5% blasts at the time of HSCT, the survival rate was 0% (P = .015).

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.

References
  1. Leone G, Fianchi L, Voso MT: Therapy-related myeloid neoplasms. Curr Opin Oncol 23 (6): 672-80, 2011. [PUBMED Abstract]
  2. Bolufer P, Collado M, Barragan E, et al.: Profile of polymorphisms of drug-metabolising enzymes and the risk of therapy-related leukaemia. Br J Haematol 136 (4): 590-6, 2007. [PUBMED Abstract]
  3. Ezoe S: Secondary leukemia associated with the anti-cancer agent, etoposide, a topoisomerase II inhibitor. Int J Environ Res Public Health 9 (7): 2444-53, 2012. [PUBMED Abstract]
  4. Ding Y, Sun CL, Li L, et al.: Genetic susceptibility to therapy-related leukemia after Hodgkin lymphoma or non-Hodgkin lymphoma: role of drug metabolism, apoptosis and DNA repair. Blood Cancer J 2 (3): e58, 2012. [PUBMED Abstract]
  5. Leone G, Mele L, Pulsoni A, et al.: The incidence of secondary leukemias. Haematologica 84 (10): 937-45, 1999. [PUBMED Abstract]
  6. Pui CH, Ribeiro RC, Hancock ML, et al.: Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. N Engl J Med 325 (24): 1682-7, 1991. [PUBMED Abstract]
  7. Andersen MK, Johansson B, Larsen SO, et al.: Chromosomal abnormalities in secondary MDS and AML. Relationship to drugs and radiation with specific emphasis on the balanced rearrangements. Haematologica 83 (6): 483-8, 1998. [PUBMED Abstract]
  8. Ogami A, Morimoto A, Hibi S, et al.: Secondary acute promyelocytic leukemia following chemotherapy for non-Hodgkin's lymphoma in a child. J Pediatr Hematol Oncol 26 (7): 427-30, 2004. [PUBMED Abstract]
  9. Okamoto T, Okada M, Wakae T, et al.: Secondary acute promyelocytic leukemia in a patient with non-Hodgkin's lymphoma treated with VP-16 and MST-16. Int J Hematol 75 (1): 107-8, 2002. [PUBMED Abstract]
  10. Larson RA: Etiology and management of therapy-related myeloid leukemia. Hematology Am Soc Hematol Educ Program : 453-9, 2007. [PUBMED Abstract]
  11. Aguilera DG, Vaklavas C, Tsimberidou AM, et al.: Pediatric therapy-related myelodysplastic syndrome/acute myeloid leukemia: the MD Anderson Cancer Center experience. J Pediatr Hematol Oncol 31 (11): 803-11, 2009. [PUBMED Abstract]
  12. Yokoyama H, Mori S, Kobayashi Y, et al.: Hematopoietic stem cell transplantation for therapy-related myelodysplastic syndrome and acute leukemia: a single-center analysis of 47 patients. Int J Hematol 92 (2): 334-41, 2010. [PUBMED Abstract]
  13. Xavier AC, Kutny M, Costa LJ: Incidence and outcomes of paediatric myelodysplastic syndrome in the United States. Br J Haematol 180 (6): 898-901, 2018. [PUBMED Abstract]
  14. Woodard P, Barfield R, Hale G, et al.: Outcome of hematopoietic stem cell transplantation for pediatric patients with therapy-related acute myeloid leukemia or myelodysplastic syndrome. Pediatr Blood Cancer 47 (7): 931-5, 2006. [PUBMED Abstract]
  15. Barnard DR, Lange B, Alonzo TA, et al.: Acute myeloid leukemia and myelodysplastic syndrome in children treated for cancer: comparison with primary presentation. Blood 100 (2): 427-34, 2002. [PUBMED Abstract]
  16. Kobos R, Steinherz PG, Kernan NA, et al.: Allogeneic hematopoietic stem cell transplantation for pediatric patients with treatment-related myelodysplastic syndrome or acute myelogenous leukemia. Biol Blood Marrow Transplant 18 (3): 473-80, 2012. [PUBMED Abstract]

Survivorship and Adverse Late Sequelae of Treatment for AML

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. For more information, see Late Effects of Treatment for Childhood Cancer.

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

  1. Cardiac.
    1. The Childhood Cancer Survivor Study (CCSS) examined 272 survivors of childhood AML who did not undergo an HSCT.[1]
      • This study identified second malignancies (cumulative incidence, 1.7%) and cardiac toxic effects (cumulative incidence, 4.7%) as significant long-term risks.
      • Cardiomyopathy has been reported in 4.3% of survivors of AML based on Berlin-Frankfurt-Münster studies. Of these, 2.5% showed clinical symptoms.[2]
    2. A retrospective study examined cardiac function in children treated with United Kingdom Medical Research Council–based regimens at a median of 13 months after treatment.[3]
      • There was a mean detrimental change in left ventricular stroke volume of 8.4%, compared with baseline values.
    3. A retrospective study evaluated anthracycline-related cardiomyopathy in children treated for AML.[4]
      • For pediatric patients, the risk of developing early toxicity was 13.7%, and the risk of developing late cardiac toxic effects (defined as 1 year after completing first-line therapy) was 17.4%.
      • Early cardiotoxicity was a significant predictor of late cardiac toxic effects and the development of clinical cardiomyopathy requiring long-term therapy.
    4. Retrospective analysis of a single study suggests cardiac risk may be increased in children with Down syndrome,[5] but prospective studies are required to confirm this finding.
  2. Psychosocial.
    1. A Nordic Society for Pediatric Hematology and Oncology retrospective trial evaluated children with AML who were treated with chemotherapy only. The median follow-up was 11 years.[6]
      • Based on self-reported uses of health care services, survivors demonstrated similar health care usage and marital status as their siblings.
    2. A population-based study of survivors of childhood AML who had not undergone an HSCT reported the following:[7]
      • Equivalent rates of educational achievement, employment, and marital status compared with siblings.
      • AML survivors were significantly more likely to take prescription drugs, especially for asthma, than were siblings (23% vs. 9%; P = .03).
      • Chronic fatigue has also been demonstrated to be a significantly more likely adverse late effect in survivors of childhood AML than in survivors of other malignancies.
    3. A CCSS report evaluated survivors of childhood AML treated between 1970 and 1999 (median age at the time of assessment, 30 to 32 years) and compared their outcomes to data from siblings.[8]
      • Survivors who received either intensive chemotherapy consolidation (n = 299) or underwent HSCT (n = 183) had statistically significant worse outcomes than did their siblings in somatic symptom measures (prevalence, 8.4%–12%), neurocognitive functioning (prevalence, 17.7%–25.7%), health-related quality-of-life measurements (prevalence, 8.2%–24.6%), and social attainment measures.
      • In all measures, there was no statistically significant difference in prevalence of problems identified between the two consolidation cohorts.

Renal, gastrointestinal, and hepatic late adverse effects were rare for children who received chemotherapy only for treatment of AML.[9]

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

  1. In a review from one institution, the highest frequency of adverse long-term sequelae for children treated for AML included the following:[10]
    • Growth abnormalities (51%), neurocognitive abnormalities (30%), transfusion-acquired hepatitis (28%), infertility (25%), endocrinopathies (16%), restrictive lung disease (20%), chronic graft-versus-host disease (20%), secondary malignancies (14%), and cataracts (12%).
    • Most of these adverse sequelae are the consequence of myeloablative, allogeneic HSCT. Although cardiac abnormalities were reported in 8% of patients, this issue may be particularly relevant with the current use of increased anthracyclines in clinical trials for children with newly diagnosed AML.
  2. Another study examined outcomes for children younger than 3 years with AML or acute lymphoblastic leukemia (ALL) who underwent HSCT.[11]
    • The toxicities reported include growth hormone deficiency (59%), dyslipidemias (59%), hypothyroidism (35%), osteochondromas (24%), and decreased bone mineral density (24%).
    • Two of the 33 patients developed secondary malignancies.
    • Compared with population controls, survivors had average intelligence but had frequent attention-deficit problems and fine-movement abnormalities.
  3. In contrast, the Bone Marrow Transplant Survivor Study compared childhood AML or ALL survivors with siblings using a self-reporting questionnaire.[12] The median follow-up was 8.4 years, and 86% of patients received total-body irradiation (TBI) as part of their preparative transplant regimen.
    • Survivors of leukemia who received an HSCT had significantly higher frequencies of several adverse effects than did siblings. These effects included diabetes, hypothyroidism, osteoporosis, cataracts, osteonecrosis, exercise-induced shortness of breath, neurosensory impairments, and problems with balance, tremor, and weakness.
    • The overall assessment of health was significantly decreased in survivors compared with siblings (odds ratio, 2.2; P = .03).
    • Significant differences were not observed between regimens using TBI compared with chemotherapy only, which mostly included busulfan.
    • The outcomes were similar for patients with AML and ALL, suggesting that the primary cause underlying the adverse late effects was undergoing an HSCT.
  4. A Children's Oncology Group (COG) study compared health-related quality-of-life outcomes in survivors of childhood AML.[13]
    • Of 5-year survivors, 21% had a severe or life-threatening chronic health condition. When compared by type of treatment, this percentage was 16% for the chemotherapy-only group, 21% for the autologous HSCT group, and 33% for those who received an allogeneic HSCT.
  5. A CCSS cohort analysis examined the long-term mortality and health statuses of 856 children (5-year survivors) previously treated for AML, with or without HSCT, between 1970 and 1999.[14]
    • Cumulative rates of grades 3 to 5 chronic health conditions significantly declined among HSCT recipients between the 1970s and 1990s (from 76.1% to 43.5%; P = .04) but remained stable for chemotherapy-only recipients (from 12.2% to 27.6%; P = .06).
    • There was a significant decrease in cumulative all-cause late mortality over the same time frame for HSCT recipients (from 38.9% to 8.5%; P < .0001). This decrease was primarily a result of a reduction in relapse, whereas no significant decrease in late mortality was seen in the chemotherapy-only survivors (from 38.9% to 8.5%; P < .0001).
    • In self-reports, health status among all survivors was excellent, very good, or good in 85% of HSCT recipients and in 90% of chemotherapy-only recipients. However, survivors' health status in both treatment groups was significantly worse than that of their siblings (hazard ratio [HR], 3.8; 95% confidence interval [CI], 2.7–5.4 vs. HR, 2.6; 95% CI, 1.8–3.6, respectively).

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.

References
  1. Mulrooney DA, Dover DC, Li S, et al.: Twenty years of follow-up among survivors of childhood and young adult acute myeloid leukemia: a report from the Childhood Cancer Survivor Study. Cancer 112 (9): 2071-9, 2008. [PUBMED Abstract]
  2. Creutzig U, Diekamp S, Zimmermann M, et al.: Longitudinal evaluation of early and late anthracycline cardiotoxicity in children with AML. Pediatr Blood Cancer 48 (7): 651-62, 2007. [PUBMED Abstract]
  3. Orgel E, Zung L, Ji L, et al.: Early cardiac outcomes following contemporary treatment for childhood acute myeloid leukemia: a North American perspective. Pediatr Blood Cancer 60 (9): 1528-33, 2013. [PUBMED Abstract]
  4. Temming P, Qureshi A, Hardt J, et al.: Prevalence and predictors of anthracycline cardiotoxicity in children treated for acute myeloid leukaemia: retrospective cohort study in a single centre in the United Kingdom. Pediatr Blood Cancer 56 (4): 625-30, 2011. [PUBMED Abstract]
  5. O'Brien MM, Taub JW, Chang MN, et al.: Cardiomyopathy in children with Down syndrome treated for acute myeloid leukemia: a report from the Children's Oncology Group Study POG 9421. J Clin Oncol 26 (3): 414-20, 2008. [PUBMED Abstract]
  6. Molgaard-Hansen L, Glosli H, Jahnukainen K, et al.: Quality of health in survivors of childhood acute myeloid leukemia treated with chemotherapy only: a NOPHO-AML study. Pediatr Blood Cancer 57 (7): 1222-9, 2011. [PUBMED Abstract]
  7. Jóhannsdóttir IM, Hjermstad MJ, Moum T, et al.: Increased prevalence of chronic fatigue among survivors of childhood cancers: a population-based study. Pediatr Blood Cancer 58 (3): 415-20, 2012. [PUBMED Abstract]
  8. Stefanski KJ, Anixt JS, Goodman P, et al.: Long-Term Neurocognitive and Psychosocial Outcomes After Acute Myeloid Leukemia: A Childhood Cancer Survivor Study Report. J Natl Cancer Inst 113 (4): 481-495, 2021. [PUBMED Abstract]
  9. Skou AS, Glosli H, Jahnukainen K, et al.: Renal, gastrointestinal, and hepatic late effects in survivors of childhood acute myeloid leukemia treated with chemotherapy only--a NOPHO-AML study. Pediatr Blood Cancer 61 (9): 1638-43, 2014. [PUBMED Abstract]
  10. Leung W, Hudson MM, Strickland DK, et al.: Late effects of treatment in survivors of childhood acute myeloid leukemia. J Clin Oncol 18 (18): 3273-9, 2000. [PUBMED Abstract]
  11. Perkins JL, Kunin-Batson AS, Youngren NM, et al.: Long-term follow-up of children who underwent hematopoeitic cell transplant (HCT) for AML or ALL at less than 3 years of age. Pediatr Blood Cancer 49 (7): 958-63, 2007. [PUBMED Abstract]
  12. Baker KS, Ness KK, Weisdorf D, et al.: Late effects in survivors of acute leukemia treated with hematopoietic cell transplantation: a report from the Bone Marrow Transplant Survivor Study. Leukemia 24 (12): 2039-47, 2010. [PUBMED Abstract]
  13. Schultz KA, Chen L, Chen Z, et al.: Health conditions and quality of life in survivors of childhood acute myeloid leukemia comparing post remission chemotherapy to BMT: a report from the children's oncology group. Pediatr Blood Cancer 61 (4): 729-36, 2014. [PUBMED Abstract]
  14. Turcotte LM, Whitton JA, Leisenring WM, et al.: Chronic conditions, late mortality, and health status after childhood AML: a Childhood Cancer Survivor Study report. Blood 141 (1): 90-101, 2023. [PUBMED Abstract]

Latest Updates to This Summary (09/16/2024)

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 increasing data show that the presence of monosomy 7 is associated with a higher risk of a patient having germline GATA2, SAMD9 or SAMD9L pathogenic variants. Cases associated with an underlying RUNX1-altered familial platelet disorder, telomere biology disorder, and germline ERCC6L2 pathogenic variants have also been reported (cited Wlodarski et al. as reference 149). Germline testing should be considered when monosomy 7 disease is identified.

Treatment Option Overview for Childhood AML

Added text to state that in one retrospective analysis, leukemia cutis did not have an adverse impact on outcomes of infants when they were treated with traditional chemotherapy (cited Renaud et al. as reference 3).

Added text to state that from an analysis of patients enrolled in the AAML0531 and AAML1031 trials, using the Children's Oncology Group (COG) definition of central nervous system (CNS) involvement, peripheral blood contamination increased the number of patients who were classified as CNS positive and guided to additional intrathecal therapy. In these trials, following past precedence, diagnostic cerebrospinal fluid examinations and initial intrathecal administration were done on or before day 1 of induction therapy (cited Kutny et al. as reference 60). Beginning with the COG AAML1831 trial, to minimize the risk of contamination, the newer guidance is to delay the diagnostic lumbar puncture to day 8, when most patients have cleared their peripheral blood of leukemic blasts. Additionally, a definition of CNS involvement that is more similar to the ALL definition is now in use.

Added Table 5 showing favorable and unfavorable cytogenetic and molecular prognostic findings.

Treatment of Childhood AML

Added text about the results of the NOPHO-DBH-AML2012 study (cited Tierens et al. as reference 81).

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® Cancer Information for Health Professionals 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. It is intended as a resource to inform and assist clinicians in the care of their 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 Treatment are:

  • William L. Carroll, MD (Laura and Isaac Perlmutter Cancer Center at NYU Langone)
  • Alan Scott Gamis, MD, MPH (Children's Mercy Hospital)
  • Karen J. Marcus, MD, FACR (Dana-Farber Cancer Institute/Boston Children's Hospital)
  • Jessica Pollard, MD (Dana-Farber/Boston Children's Cancer and Blood Disorders Center)
  • Michael A. Pulsipher, MD (Huntsman Cancer Institute at University of Utah)
  • Rachel E. Rau, MD (University of Washington School of Medicine, Seatle Children’s)
  • Lewis B. Silverman, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
  • Malcolm A. Smith, MD, PhD (National Cancer Institute)
  • Sarah K. Tasian, MD (Children's Hospital of Philadelphia)

Any comments or questions about the summary content should be submitted to Cancer.gov 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.

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PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Acute Myeloid Leukemia Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/leukemia/hp/child-aml-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389454]

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