Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment (PDQ®): Treatment - Health Professional Information [NCI]

General Information About Childhood Acute Myeloid Leukemia (AML)

Dramatic improvements in survival have been achieved for children and adolescents with cancer.[1] Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. For acute myeloid leukemia (AML), the 5-year survival rate increased over the same time from less than 20% to 68% for children younger than 15 years and from less than 20% to 57% for adolescents aged 15 to 19 years.[1]

Characteristics of Myeloid Leukemias and Other Myeloid Malignancies in Children

Approximately 20% of childhood leukemias are of myeloid origin and they represent a spectrum of hematopoietic malignancies.[2] Most myeloid leukemias are acute, and the remainder include chronic and/or subacute myeloproliferative disorders such as chronic myelogenous leukemia and juvenile myelomonocytic leukemia. Myelodysplastic syndromes occur much less frequently in children than in adults and almost invariably represent clonal, preleukemic conditions that may evolve from congenital marrow failure syndromes such as Fanconi anemia and Shwachman-Diamond syndrome.

The general characteristics of myeloid leukemias and other myeloid malignancies are described below:

• Acute myeloid leukemia (AML). AML is defined as a clonal disorder caused by malignant transformation of a bone marrow–derived, self-renewing stem cell or progenitors, leading to accumulation of immature, nonfunctional myeloid cells. These events lead to increased accumulation in the bone marrow and other organs by these malignant myeloid cells. To be called acute, the bone marrow usually must include greater than 20% immature leukemic blasts, with some exceptions as noted in subsequent sections. (Refer to the Treatment Option Overview for Childhood AML and Treatment of Childhood AML sections of this summary for more information.)
• Transient abnormal myelopoiesis (TAM). TAM is also termed transient myeloproliferative disorder or transient leukemia. The TAM observed in infants with Down syndrome represents a clonal expansion of myeloblasts that can be difficult to distinguish from AML. Most importantly, TAM spontaneously regresses in most cases within the first 3 months of life. TAM occurs in 4% to 10% of infants with Down syndrome.[3,4,5]

  TAM blasts most commonly have megakaryoblastic differentiation characteristics and distinctive mutations involving the GATA1 gene in the presence of trisomy 21.[6,7] TAM may occur in phenotypically normal infants with genetic mosaicism in the bone marrow for trisomy 21. While TAM is generally not characterized by cytogenetic abnormalities other than trisomy 21, the presence of additional cytogenetic findings may predict an increased risk of developing subsequent AML.[8] Approximately 20% of infants with TAM of Down syndrome eventually develop AML, with most cases diagnosed within the first 3 years of life.[7,8]

  Early death from TAM-related complications occurs in 10% to 20% of affected infants.[8,9] Infants with progressive organomegaly, visceral effusions, high blast count (>100,000 cells/μL) and laboratory evidence of progressive liver dysfunction are at a particularly high risk of early mortality.[8,9] (Refer to the Myeloid Proliferations Associated with Down Syndrome section of this summary for more information.)

• Myelodysplastic syndrome (MDS). MDS in children represents a heterogeneous group of disorders characterized by ineffective hematopoiesis, impaired maturation of myeloid progenitors with dysplastic morphologic features, and cytopenias. Although the underlying cause of MDS in children is unclear, there is often an association with marrow failure syndromes. Most patients with MDS may have hypercellular bone marrows without increased numbers of leukemic blasts, but some patients may present with a very hypocellular bone marrow, making the distinction between severe aplastic anemia and MDS difficult.[10,11]

  The presence of a karyotype abnormality in a hypocellular marrow is consistent with MDS and transformation to AML should be expected. Given the high association of MDS evolving into AML, patients with MDS are typically referred for stem cell transplantation before transformation to AML. (Refer to the Myelodysplastic Syndromes [MDS] section of this summary for more information.)

• Juvenile myelomonocytic leukemia (JMML). JMML represents the most common myeloproliferative syndrome observed in young children. JMML occurs at a median age of 1.8 years.

  JMML characteristically presents with hepatosplenomegaly, lymphadenopathy, fever, and skin rash along with an elevated white blood cell (WBC) count and increased circulating monocytes.[12] In addition, patients often have an elevated hemoglobin F, hypersensitivity of the leukemic cells to granulocyte-macrophage colony-stimulating factor (GM-CSF), monosomy 7, and leukemia cell mutations in a gene involved in RAS pathway signaling (e.g., NF1, KRAS/NRAS, PTPN11, or CBL).[12,13,14] (Refer to the Juvenile Myelomonocytic Leukemia [JMML] section of this summary for more information.)

• Chronic myelogenous leukemia (CML). CML is primarily an adult disease but represents the most common of the chronic myeloproliferative disorders in childhood, accounting for approximately 10% of childhood myeloid leukemia.[2] Although CML has been reported in very young children, most patients are aged 6 years and older.

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

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

Conditions Associated With Myeloid Malignancies

Genetic abnormalities (cancer predisposition syndromes) are associated with the development of AML. There is a high concordance rate of AML in identical twins; however, this is not believed to be related to genetic risk, but rather to shared circulation and the inability of one twin to reject leukemic cells from the other twin during fetal development.[15,16,17] There is an estimated twofold to fourfold increased risk of developing leukemia for the fraternal twin of a pediatric leukemia patient up to about age 6 years, after which the risk is not significantly greater than that of the general population.[18,19]

The development of AML has also been associated with a variety of inherited/familial syndromes, which are recognized as a unique category within the 2016 World Health Organization (WHO) Classification of Myeloid Neoplasms and Acute Leukemia. There are also several acquired conditions that increase the risk of developing AML. 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.[20,21]

Inherited syndromes

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

Acquired syndromes

• Severe aplastic anemia.
• Paroxysmal nocturnal hemoglobinuria.
• Amegakaryocytic thrombocytopenia.
• Acquired monosomy 7.

The 2016 WHO classification system has categorized the myeloid neoplasms with germline predisposition as follows:

• Myeloid neoplasms with germline predisposition without a pre-existing disorder or organ dysfunction.[22]
  • AML with germline CEBPA mutations.
  • Myeloid neoplasms with germline DDX41 mutations.
• Myeloid neoplasms with germline predisposition and pre-existing platelet disorders.[22]
  • Myeloid neoplasms with germline RUNX1 mutations.
  • Myeloid neoplasms with germline ANKRD26 mutations.
  • Myeloid neoplasms with germline ETV6 mutations.
• Myeloid neoplasms with germline predisposition and other organ dysfunction.[22]
  • Myeloid neoplasms with germline GATA2 mutations.
  • Myeloid neoplasms associated with bone marrow failure syndromes (including Fanconi anemia, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome).
  • Myeloid neoplasms associated with telomere biology disorders (including dyskeratosis congenita).
  • JMML associated with neurofibromatosis, Noonan syndrome or Noonan syndrome–like disorders (including germline CBL mutations).
  • Myeloid neoplasms associated with Down syndrome.

Nonsyndromic genetic susceptibility to AML is also being studied. For example, homozygosity for a specific IKZF1 polymorphism has been associated with an increased risk of infant AML.[23]

References:

1. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014.
2. Smith MA, Ries LA, Gurney JG, et al.: Leukemia. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649, pp 17-34. Also available online. Last accessed October 09, 2020.
3. 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.
4. Zipursky A: Transient leukaemia--a benign form of leukaemia in newborn infants with trisomy 21. Br J Haematol 120 (6): 930-8, 2003.
5. 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.
6. Hitzler JK, Cheung J, Li Y, et al.: GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome. Blood 101 (11): 4301-4, 2003.
7. Mundschau G, Gurbuxani S, Gamis AS, et al.: Mutagenesis of GATA1 is an initiating event in Down syndrome leukemogenesis. Blood 101 (11): 4298-300, 2003.
8. Massey GV, Zipursky A, Chang MN, et al.: A prospective study of the natural history of transient leukemia (TL) in neonates with Down syndrome (DS): Children's Oncology Group (COG) study POG-9481. Blood 107 (12): 4606-13, 2006.
9. Gamis AS, Alonzo TA, Gerbing RB, et al.: Natural history of transient myeloproliferative disorder clinically diagnosed in Down syndrome neonates: a report from the Children's Oncology Group Study A2971. Blood 118 (26): 6752-9; quiz 6996, 2011.
10. Hasle H, Niemeyer CM: Advances in the prognostication and management of advanced MDS in children. Br J Haematol 154 (2): 185-95, 2011.
11. Schwartz JR, Ma J, Lamprecht T, et al.: The genomic landscape of pediatric myelodysplastic syndromes. Nat Commun 8 (1): 1557, 2017.
12. 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.
13. Loh ML: Recent advances in the pathogenesis and treatment of juvenile myelomonocytic leukaemia. Br J Haematol 152 (6): 677-87, 2011.
14. Stieglitz E, Taylor-Weiner AN, Chang TY, et al.: The genomic landscape of juvenile myelomonocytic leukemia. Nat Genet 47 (11): 1326-33, 2015.
15. Zuelzer WW, Cox DE: Genetic aspects of leukemia. Semin Hematol 6 (3): 228-49, 1969.
16. Miller RW: Persons with exceptionally high risk of leukemia. Cancer Res 27 (12): 2420-3, 1967.
17. Inskip PD, Harvey EB, Boice JD, et al.: Incidence of childhood cancer in twins. Cancer Causes Control 2 (5): 315-24, 1991.
18. Kurita S, Kamei Y, Ota K: Genetic studies on familial leukemia. Cancer 34 (4): 1098-101, 1974.
19. Greaves M: Pre-natal origins of childhood leukemia. Rev Clin Exp Hematol 7 (3): 233-45, 2003.
20. Puumala SE, Ross JA, Aplenc R, et al.: Epidemiology of childhood acute myeloid leukemia. Pediatr Blood Cancer 60 (5): 728-33, 2013.
21. 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.
22. Arber DA, Orazi A, Hasserjian R, et al.: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127 (20): 2391-405, 2016.
23. 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.

Classification of Pediatric Myeloid Malignancies

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

The first comprehensive morphologic-histochemical classification system for acute myeloid leukemia (AML) was developed by the FAB Cooperative Group.[1,2,3,4,5] This classification system, which has been replaced by the World Health Organization (WHO) system described below, categorized AML into major subtypes primarily on the basis of morphology and immunohistochemical detection of lineage markers.

The major subtypes of AML include the following:

• 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. (Refer to the Acute Promyelocytic Leukemia [APL] section of this summary for more information.)
• M3v: APL, microgranular variant. Cytoplasm of promyelocytes demonstrates a fine granularity, and nuclei are often folded. M3v has the same clinical, cytogenetic, and therapeutic implications as FAB M3.
• M4: Acute myelomonocytic leukemia (AMML).
• M4Eo: AMML with eosinophilia (abnormal eosinophils with dysplastic basophilic granules).
• M5: Acute monocytic leukemia (AMoL).
  • M5a: AMoL without differentiation (monoblastic).
  • M5b: AMoL with differentiation.
• M6: Acute erythroid leukemia (AEL).
  • M6a: Erythroleukemia.
  • M6b: Pure erythroid leukemia (myeloblast component not apparent).
  • M6c: Presence of myeloblasts and proerythroblasts.
• M7: Acute megakaryocytic leukemia (AMKL).

Other extremely rare subtypes of AML include acute eosinophilic leukemia and acute basophilic leukemia.

The FAB classification was superseded by the WHO classification described below but remains relevant as it forms the basis of the WHO's subcategory of AML, not otherwise specified (AML, NOS).

World Health Organization (WHO) Classification System for Childhood AML

In 2001, the WHO proposed a new classification system that incorporated diagnostic cytogenetic information and that more reliably correlated with outcome. In this classification, patients with t(8;21), inv(16), t(15;17), or KMT2A (MLL) translocations, which collectively constituted nearly half of the cases of childhood AML, were classified as AML with recurrent cytogenetic abnormalities. This classification system also decreased the bone marrow percentage of leukemic blast requirement for the diagnosis of AML from 30% to 20%; an additional clarification was made so that patients with recurrent cytogenetic abnormalities did not need to meet the minimum blast requirement to be considered an AML patient.[8,9,10]

In 2008, the WHO expanded the number of cytogenetic abnormalities linked to AML classification and, for the first time, included specific gene mutations (CEBPA and NPM) in its classification system.[11] In 2016, the WHO classification underwent revisions to incorporate the expanding knowledge of leukemia biomarkers that are significantly important to the diagnosis, prognosis, and treatment of leukemia.[12] With emerging technologies aimed at genetic, epigenetic, proteomic, and immunophenotypic classification, AML classification will certainly continue to evolve and provide informative prognostic and biologic guidelines to clinicians and researchers.

2016 WHO classification of AML and related neoplasms

• AML with recurrent genetic abnormalities:
  • AML with t(8;21)(q22;q22), RUNX1-RUNX1T1.
  • AML with inv(16)(p13.1;q22) or t(16;16)(p13.1;q22), CBFB-MYH11.
  • APL with PML-RARA.
  • AML with t(9;11)(p21.3;q23.3), MLLT3-KMT2A.
  • AML with t(6;9)(p23;q34.1), DEK-NUP214.
  • AML with inv(3)(q21.3;q26.2) or t(3;3)(q21.3;q26.2), GATA2, MECOM.
  • AML (megakaryoblastic) with t(1;22)(p13.3;q13.3), RBM15-MKL1.
  • AML with BCR-ABL1 (provisional entity).
  • AML with mutated NPM1.
  • AML with biallelic mutations of CEBPA.
  • AML with mutated RUNX1 (provisional entity).
• AML with myelodysplasia-related features.
• Therapy-related myeloid neoplasms.
• AML, NOS:
  • AML with minimal differentiation.
  • AML without maturation.
  • AML with maturation.
  • Acute myelomonocytic leukemia.
  • Acute monoblastic/monocytic leukemia.
  • Pure erythroid leukemia.
  • Acute megakaryoblastic leukemia.
  • Acute basophilic leukemia.
  • Acute panmyelosis with myelofibrosis.
• Myeloid sarcoma.
• Myeloid proliferations related to Down syndrome:
  • Transient abnormal myelopoiesis (TAM).
  • Myeloid leukemia associated with Down syndrome.

2016 WHO classification of acute leukemias of ambiguous lineage

For the group of acute leukemias that have characteristics of both AML and acute lymphoblastic leukemia (ALL), the acute leukemias of ambiguous lineage, the WHO classification system is summarized in Table 1.[13,14] The criteria for lineage assignment for a diagnosis of mixed phenotype acute leukemia (MPAL) are provided in Table 2.[12,15]

Table 1. Acute Leukemias of Ambiguous Lineage According to the World Health Organization Classification of Tumors of Hematopoietic and Lymphoid Tissues^a

Condition	Definition
NOS = not otherwise specified.
a Béné MC: Biphenotypic, bilineal, ambiguous or mixed lineage: strange leukemias! Haematologica 94 (7): 891-3, 2009.[13]Obtained from Haematologica/the Hematology Journal websitehttp://www.haematologica.org.
Acute undifferentiated leukemia	Acute leukemia that does not express any marker considered specific for either lymphoid or myeloid lineage
Mixed phenotype acute leukemia with t(9;22)(q34;q11.2);BCR-ABL1	Acute leukemia meeting the diagnostic criteria for mixed phenotype acute leukemia in which the blasts also have the (9;22) translocation or theBCR-ABL1rearrangement
Mixed phenotype acute leukemia with t(v;11q23);KMT2A(MLL) rearranged	Acute leukemia meeting the diagnostic criteria for mixed phenotype acute leukemia in which the blasts also have a translocation involving theKMT2Agene
Mixed phenotype acute leukemia, B/myeloid, NOS	Acute leukemia meeting the diagnostic criteria for assignment to both B and myeloid lineage, in which the blasts lack genetic abnormalities involvingBCR-ABL1orKMT2A
Mixed phenotype acute leukemia, T/myeloid, NOS	Acute leukemia meeting the diagnostic criteria for assignment to both T and myeloid lineage, in which the blasts lack genetic abnormalities involvingBCR-ABL1orKMT2A
Mixed phenotype acute leukemia, B/myeloid, NOS—rare types	Acute leukemia meeting the diagnostic criteria for assignment to both B- and T-lineage
Other ambiguous lineage leukemias	Natural killer–cell lymphoblastic leukemia/lymphoma

Table 2. Lineage Assignment Criteria for Mixed Phenotype Acute Leukemia According to the 2016 Revision to the World Health Organization Classification of Myeloid Neoplasms and Acute Leukemia^a

Lineage	Criteria
a Adapted from Arber et al.[12]
b Strong defined as equal to or brighter than the normal B or T cells in the sample.
Myeloid Lineage	Myeloperoxidase (flow cytometry, immunohistochemistry, or cytochemistry);or monocytic differentiation (at least two of the following: nonspecific esterase cytochemistry, CD11c, CD14, CD64, lysozyme)
T Lineage	Strongb cytoplasmic CD3 (with antibodies to CD3 epsilon chain);or surface CD3
B Lineage	Strongb CD19 with at least one of the following strongly expressed: CD79a, cytoplasmic CD22, or CD10;or weak CD19 with at least two of the following strongly expressed: CD79a, cytoplasmic CD22, or CD10

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.[16] B-myeloid biphenotypic leukemias lacking the TEL-AML1 fusion have a lower rate of complete remission (CR) and a significantly worse event-free survival (EFS) compared with patients with precursor B-cell ALL.[16] Some studies suggest that patients with biphenotypic leukemia may fare better with a lymphoid, as opposed to a myeloid, treatment regimen.[17,18,19,20]; [21][Level of evidence: 3iiiA] A large retrospective study from the international Berlin-Frankfurt-Münster (BFM) group demonstrated that initial therapy with an ALL-type regimen was associated with a superior outcome compared with AML-type or combined ALL/AML regimens, particularly in cases with CD19 positivity or other lymphoid antigen expression. In this study, hematopoietic stem cell transplantation (HSCT) in first CR was not beneficial, with the possible exception of cases with morphologic evidence of persistent marrow disease (≥5% blasts) after the first month of treatment.[20]

WHO Classification of Bone Marrow and Peripheral Blood Findings for Myelodysplastic Syndromes

The FAB classification of myelodysplastic syndromes (MDS) was not completely applicable to children.[22,23] Traditionally, MDS classification systems have been divided into several distinct categories on the basis of the presence of the following:[23,24,25,26]

• Myelodysplasia.
• Types of cytopenia.
• Specific chromosomal abnormalities.
• Percentage of myeloblasts.

A modified classification schema for MDS and myeloproliferative disorders (MPDs) was published by the WHO in 2008 and included subsections that focused on pediatric MDS and MPD.[27] This pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases was initially proposed in 2003.[10] The 2016 revision to the WHO classification has removed focus on the specific lineage (anemia, thrombocytopenia, or neutropenia) and now distinguishes cases with dysplasia in single versus multiple lineages. The category of MDS with excess blasts (MDS-EB) now encompasses the pediatric cases previously classified as refractory anemia with excess blasts (RAEB) or RAEB in transformation (RAEB-T).[28] The category of refractory cytopenia of childhood is retained as a provisional entity. The bone marrow and peripheral blood findings for MDS according to the 2008 WHO classification schema are summarized in Tables 3 and 4.[12,27] When MDS-EB is associated with the recurrent cytogenetic abnormalities that are usually associated with AML, a diagnosis of AML is made and patients are treated accordingly.

Distinguishing MDS from similar-appearing, reactive causes of dysplasia and/or cytopenias is noted to be difficult. In general, the finding of more than 10% dysplasia in a cell lineage is a diagnostic criteria for MDS; however, the 2016 WHO guidelines caution that reactive etiologies, rather than clonal, may have more than 10% dysplasia and should be excluded especially when dysplasia is subtle and/or restricted to a single lineage.[12]

The International Prognostic Scoring System is used to determine the risk of progression to AML and the outcome in adult patients with MDS. When this system was applied to children with MDS or juvenile myelomonocytic leukemia (JMML), only a blast count of less than 5% and a platelet count of more than 100 × 10⁹ /L were associated with a better survival in MDS, and a platelet count of more than 40 × 10⁹ /L predicted a better outcome in JMML.[29] These results suggest that MDS and JMML in children may be significantly different disorders than adult-type MDS.

Pediatric MDS can be grouped into several general categories, each with distinctive clinical and biological characteristics, as follows:[28]

• MDS arising from an inherited bone marrow failure syndrome, such as Fanconi anemia, severe congenital neutropenia, and Shwachman-Diamond syndrome.
• MDS arising from severe aplastic anemia.
• Secondary MDS arising from cytotoxic insults, such as high-dose alkylating chemotherapy.
• Primary MDS includes cases of MDS beyond those listed above, acknowledging that some of the cases characterized as primary MDS are also associated with predisposition syndromes.

Genomic characterization of pediatric primary MDS has identified specific subsets defined by alterations in selected genes (refer to the Molecular Abnormalities subsection of this summary for more information about MDS). For example, germline mutations in either GATA2[30] or SAMD9/SAMD9L[31,32,33] are especially common in children with deletions of all or part of chromosome 7. Genomic characterization has also shown that primary MDS in children differs from adult MDS at the molecular level.[32,34]

Table 3. World Health Organization (WHO) Classification of Bone Marrow and Peripheral Blood Findings for Myelodysplastic Syndromes (MDS)^a

Type of MDS		Bone Marrow	Peripheral Blood
a Adapted from Arber et al.[12]
b Note that cases with pancytopenia would be classified as MDS-U.
c When the marrow has <5% myeloblasts, but the peripheral blood has 2%–4% myeloblasts, the diagnosis is MDS-EB-1.
d The diagnosis of MDS-EB-2 should be made if any one of the following criteria are met: marrow with 10%–19% blasts, peripheral blood with 5%–19% blasts, or presence of Auer rods.
e Recurring chromosomal abnormalities in MDS: Unbalanced: +8, -7 or del(7q), -5 or del(5q), del(20q), -Y, i(17q) or t(17p), -13 or del(13q), del(11q), del(12p) or t(12p), del(9q), idic(X)(q13); Balanced: t(11;16)(q23;p13.3), t(3;21)(q26.2;q22.1), t(1;3)(p36.3;q21.2), t(2;11)(p21;q23), inv(3)(q21q26.2), t(6;9)(p23;q34). The WHO classification notes that the presence of these chromosomal abnormalities in presence of persistent cytopenias of undetermined origin should be considered to support a presumptive diagnosis of MDS when morphological characteristics are not observed.
f The diagnostic criteria for childhood MDS (refractory cytopenia of childhood-provisional entry) include: 1) persistent cytopenia of 1–3 cell lines with <5% bone marrow blasts, <2% peripheral blood blasts, and no ringed sideroblasts and 2) dysplastic changes in 1–3 lineages should be present.
MDS with single lineage dysplasia		Unilineage dysplasia: ≥10% in one myeloid lineage	1–2 cytopeniasb
		<5% blasts	Blasts <1%c
		<15% ring sideroblasts
MDS with ring sideroblasts (MDS-RS)		Erythroid dysplasia only
		<5% blasts	No blasts
		≥15% ring sideroblasts
MDS with multilineage dysplasia		Dysplasia in ≥10% of cells in ≥2 myeloid lineages	1–3 cytopenias
		<5% blasts	Blasts (none or <1%)c
		±15% ring sideroblasts
		No Auer rods	No Auer rods
			<1×109 monocytes/L
MDS with excess blasts-1 (MDS-EB-1)		Single lineage or multilineage dysplasia	Cytopenia(s)
		5%–9% blastsc	<5% blastsc
		No Auer rods	No Auer rods
			<1×109 monocytes/L
MDS with excess blasts-2 (MDS-EB-2)		Single lineage or multilineage dysplasia	Cytopenia(s)
		10%–19% blastsd	5%–19% blastsd
		Auer rods ±d	Auer rods ±d
			<1×109 monocytes/L
MDS with isolated del(5q)		Normal to increased megakaryocytes (hypolobulated nuclei)	Anemia
		<5% blasts	Blasts (none or <1%)
		No Auer rods	Normal to increased platelet count
		Isolated del(5q)
MDS-unclassifiable (MDS-U)		Dysplasia in <10% of cells in ≥1 myeloid cell lineage	Cytopenias
		Cytogenetic abnormality associated with diagnosis of MDSe	≤1% blastsc
		<5% blasts
Provisional entity: Refractory cytopenia of childhoodf		Refer to Table 4for more information.

Table 4. Definitions for Minimal Diagnostic Criteria for Childhood Myelodysplastic Syndrome (MDS) (Provisional Entity: Refractory Cytopenia of Childhood)^a

​	Erythroid Lineage	Myeloid Lineage	Megakaryocyte Lineage
a Adapted from Baumann et al.[35]
b Bone marrow trephine/biopsy may be required as bone marrow in childhood refractory cytopenia of childhood is often hypocellular.
c Characteristics include abnormal nuclear lobulation, multinuclear cells, presence of nuclear bridges.
d Presence of pseudo–Pelger-Huet cells, hypo- or agranular cytoplasm, giantband forms.
e Megakaryocytes have variable size and often round or separated nuclei; the absence of megakaryocytes does not exclude the diagnosis of refractory cytopenia of childhood.
Bone Marrow Aspirateb	Dysplasia and/or megablastoid changes in ≥10% of erythroid precursorsc	Dysplasia in ≥10% of granulocytic precursors and neutrophils	Micromegakaryocytes plus other dysplastic featurese
		<5% blastsd
Bone Marrow Biopsy	Presence of erythroid precursors	No additional criteria	Micromegakaryocytes plus other dysplastic featurese
	Increased proerythroblasts		Immunohistochemistry positive for CD61 and CD41
	Increased number of mitoses
Peripheral Blood		Dysplasia in ≥10% of neutrophils
		<2% blasts

References:

1. Bennett JM, Catovsky D, Daniel MT, et al.: Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol 33 (4): 451-8, 1976.
2. Bennett JM, Catovsky D, Daniel MT, et al.: Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group. Ann Intern Med 103 (4): 620-5, 1985.
3. Bennett JM, Catovsky D, Daniel MT, et al.: Criteria for the diagnosis of acute leukemia of megakaryocyte lineage (M7). A report of the French-American-British Cooperative Group. Ann Intern Med 103 (3): 460-2, 1985.
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5. Cheson BD, Bennett JM, Kopecky KJ, et al.: Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 21 (24): 4642-9, 2003.
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14. Borowitz MJ, Béné MC, Harris NL: Acute leukaemias of ambiguous lineage. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer, 2008, pp 150-5.
15. Alexander TB, Gu Z, Iacobucci I, et al.: The genetic basis and cell of origin of mixed phenotype acute leukaemia. Nature 562 (7727): 373-379, 2018.
16. Gerr H, Zimmermann M, Schrappe M, et al.: Acute leukaemias of ambiguous lineage in children: characterization, prognosis and therapy recommendations. Br J Haematol 149 (1): 84-92, 2010.
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20. Hrusak O, de Haas V, Stancikova J, et al.: International cooperative study identifies treatment strategy in childhood ambiguous lineage leukemia. Blood 132 (3): 264-276, 2018.
21. Orgel E, Alexander TB, Wood BL, et al.: Mixed-phenotype acute leukemia: A cohort and consensus research strategy from the Children's Oncology Group Acute Leukemia of Ambiguous Lineage Task Force. Cancer 126 (3): 593-601, 2020.
22. Bennett JM, Catovsky D, Daniel MT, et al.: Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51 (2): 189-99, 1982.
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24. Bennett JM: World Health Organization classification of the acute leukemias and myelodysplastic syndrome. Int J Hematol 72 (2): 131-3, 2000.
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26. Nösslinger T, Reisner R, Koller E, et al.: Myelodysplastic syndromes, from French-American-British to World Health Organization: comparison of classifications on 431 unselected patients from a single institution. Blood 98 (10): 2935-41, 2001.
27. Brunning RD, Porwit A, Orazi A, et al.: Myelodysplastic syndromes/neoplasms overview. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer, 2008, pp 88-93.
28. Wlodarski MW, Sahoo SS, Niemeyer CM: Monosomy 7 in Pediatric Myelodysplastic Syndromes. Hematol Oncol Clin North Am 32 (4): 729-743, 2018.
29. Hasle H, Baumann I, Bergsträsser E, et al.: The International Prognostic Scoring System (IPSS) for childhood myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML). Leukemia 18 (12): 2008-14, 2004.
30. Wlodarski MW, Hirabayashi S, Pastor V, et al.: Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents. Blood 127 (11): 1387-97; quiz 1518, 2016.
31. Narumi S, Amano N, Ishii T, et al.: SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7. Nat Genet 48 (7): 792-7, 2016.
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33. Davidsson J, Puschmann A, Tedgård U, et al.: SAMD9 and SAMD9L in inherited predisposition to ataxia, pancytopenia, and myeloid malignancies. Leukemia 32 (5): 1106-1115, 2018.
34. Pastor V, Hirabayashi S, Karow A, et al.: Mutational landscape in children with myelodysplastic syndromes is distinct from adults: specific somatic drivers and novel germline variants. Leukemia 31 (3): 759-762, 2017.
35. Baumann I, Niemeyer CM, Bennett JM, et al.: Childhood myelodysplastic syndrome. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer, 2008, pp 104-7.

Histochemical, Immunophenotypic, and Molecular Evaluation for Childhood AML

Histochemical Evaluation

The treatment for children with acute myeloid leukemia (AML) differs significantly from that for acute lymphoblastic leukemia (ALL). As a consequence, it is critical to distinguish AML from ALL. Special histochemical stains performed on bone marrow specimens of children with acute leukemia can be helpful to confirm their diagnosis. The stains most commonly used include myeloperoxidase, periodic acid-Schiff, Sudan Black B, and esterase. In most cases, the staining pattern with these histochemical stains will distinguish AML from acute myelomonocytic leukemia (AMML) and ALL (refer to Table 5). Histochemical stains have been mostly replaced by flow cytometric immunophenotyping.

Table 5. Histochemical Staining Patterns^a

​		M0	AML, APL (M1-M3)	AMML (M4)	AMoL (M5)	AEL (M6)	AMKL (M7)	ALL
AEL = acute erythroid leukemia; ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; AMKL = acute megakaryocytic leukemia; AMML = acute myelomonocytic leukemia; AMoL = acute monocytic leukemia; APL = acute promyelocytic leukemia; PAS = periodic acid-Schiff.
a Refer to the French-American-British (FAB) Classification for Childhood Acute Myeloid Leukemiasection of this summary for more information about the morphologic-histochemical classification system for AML.
b These reactions are inhibited by fluoride.
Myeloperoxidase		-	+	+	-	-	-	-
Nonspecific esterases
	Chloracetate	-	+	+	±	-	-	-
	Alpha-naphthol acetate	-	-	+b	+b	-	±b	-
Sudan Black B		-	+	+	-	-	-	-
PAS		-	-	±	±	+	-	+

Immunophenotypic Evaluation

The use of monoclonal antibodies to determine cell-surface antigens of AML cells is helpful to reinforce the histologic diagnosis. Various lineage-specific monoclonal antibodies that detect antigens on AML cells should be used at the time of initial diagnostic workup, along with a battery of lineage-specific T-lymphocyte and B-lymphocyte markers to help distinguish AML from ALL and acute leukemias of ambiguous lineage. The expression of various cluster determinant (CD) proteins that are relatively lineage-specific for AML include CD33, CD13, CD14, CDw41 (or platelet antiglycoprotein IIb/IIIa), CD15, CD11B, CD36, and antiglycophorin A. Lineage-associated B-lymphocytic antigens CD10, CD19, CD20, CD22, and CD24 may be present in 10% to 20% of AML cases, but monoclonal surface immunoglobulin and cytoplasmic immunoglobulin heavy chains are usually absent; similarly, CD2, CD3, CD5, and CD7 lineage-associated T-lymphocytic antigens are present in 20% to 40% of AML cases.[1,2,3] The aberrant expression of lymphoid-associated antigens by AML cells is relatively common but generally has no prognostic significance.[1,2]

Immunophenotyping can also be helpful in distinguishing the following French-American-British (FAB) classification subtypes of AML:

• Testing for the presence of HLA-antigen D related (HLA-DR) can be helpful in identifying acute promyelocytic leukemia (APL). Overall, HLA-DR is expressed on 75% to 80% of AML cells but rarely expressed on APL cells.[4,5] In addition, APL is characterized by bright CD33 expression and by CD117 (c-KIT) expression in most cases, heterogeneous expression of CD13 with CD34, CD11a, and CD18 often negative or low.[4,5] The APL microgranular variant M3v more commonly expresses CD34 along with CD2.[4,6]
• Testing for the presence of glycoprotein Ib, glycoprotein IIb/IIIa, or Factor VIII antigen expression is helpful in making the diagnosis of M7 (megakaryocytic leukemia).
• Glycophorin expression is helpful in making the diagnosis of M6 (erythroid leukemia).

Less than 5% of cases of acute leukemia in children are of ambiguous lineage, expressing features of both myeloid and lymphoid lineage.[7,8,9] 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 World Health Organization (WHO) criteria.[10,11,12] In the WHO classification, the presence of myeloperoxidase (MPO) is required to establish myeloid lineage. This is not the case for the EGIL classification. The 2016 revision to the WHO classification also denotes that in some cases, leukemia with otherwise classic B-cell ALL immunophenotype may also express low-intensity MPO without other myeloid features, and the clinical significance of that finding is unclear such that one should be cautious before designating these cases as mixed phenotype acute leukemia (MPAL).[13]

Molecular Evaluation

Molecular features of acute myeloid leukemia

Comprehensive molecular profiling of pediatric and adult AML has shown that AML is a disease demonstrating both commonalities and differences across the age spectrum.[14,15]

• Pediatric AML, in contrast to AML in adults, is typically a disease of recurring chromosomal alterations (refer to Table 6 for a list of common gene fusions).[14,16] Within the pediatric age range, certain gene fusions occur primarily in children younger than 5 years (e.g., NUP98 gene fusions, KMT2A gene fusions, and CBFA2T3-GLIS2), while others occur primarily in children aged 5 years and older (e.g., RUNX1-RUNX1T1, CBFB-MYH11, and NPM1-RARA).
• Pediatric patients with AML have low rates of mutations, with most cases showing less than one somatic change in protein-coding regions per megabase.[15] This mutation rate is somewhat lower than that observed in adult AML and is much lower than the mutation rate for cancers that respond to checkpoint inhibitors (e.g., melanoma).[15]
• The pattern of gene mutations differs between pediatric and adult AML cases. For example, IDH1/IDH2, TP53, RUNX1, and DNMT3A mutations are more common in adult AML than in pediatric AML, while NRAS and WT1 mutations are significantly more common in pediatric AML.[14,15]

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.[16,17,18,19,20] 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, mutations of NPM and CEBPA are associated with favorable outcomes while certain mutations of FLT3 portend a high risk of relapse, and identifying the latter mutations may allow for targeted therapy.[21,22,23,24]

The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia emphasizes that recurrent chromosomal translocations in pediatric AML may be unique or have a different prevalence than in adult AML.[13] The pediatric AML chromosomal translocations that are found by conventional chromosome analysis and those that are cryptic (identified only with fluorescence in situ hybridization or molecular techniques) occur at higher rates than in adults. These recurrent translocations are summarized in Table 6.[13,15] Table 6 also shows, in the bottom three rows, additional relatively common recurrent translocations observed in children with AML.[15,18,19,25]

Table 6. Common Pediatric Acute Myeloid Leukemia (AML) Chromosomal Translocations

Gene Fusion Product	Chromosomal Translocation	Prevalence in Pediatric AML (%)
a Cryptic chromosomal translocation.
KMT2A(MLL) translocated	11q23.3	25.0
NUP98-NSD1a	t(5;11)(q35.3;p15.5)	7.0
CBFA2T3-GLIS2a	inv(16)(p13.3;q24.3)	3.0
NUP98-KDM5Aa	t(11;12)(p15.5;p13.5)	3.0
DEK-NUP214	t(6;9)(p22.3;q34.1)	1.7
RBM15(OTT)-MKL1(MAL)	t(1;22)(p13.3;q13.1)	0.8
MNX1-ETV6	t(7;12)(q36.3;p13.2)	0.8
KAT6A-CREBBP	t(8;16)(p11.2;p13.3)	0.5
RUNX1-RUNX1T1	t(8;21)(q22;q22)	13–14
CBFB-MYH11	inv(16)(p13.1;q22) or t(16;16)(p13.1;q22)	4–9
PML-RARA	t(15;17)(q24;q21)	6–11

The genomic landscape of pediatric AML cases can change from diagnosis to relapse, with mutations detectable at diagnosis dropping out at relapse and, conversely, with new mutations 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 mutations at relapse.[26] 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 mutation in the FLT3 gene resulting from internal tandem duplications (ITD) predicted for poor prognosis only when there was a high FLT3 ITD allelic ratio.

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

Genetic abnormalities associated with a favorable prognosis

Genetic abnormalities associated with a favorable prognosis include the following:

• Core-binding factor (CBF) AML includes cases with RUNX1-RUNX1T1 and CBFB-MYH11 fusion genes that disrupt the activity of CBF, which contains RUNX1 and CBFB. These are specific entities in the 2016 revision to the WHO classification of myeloid neoplasms and acute leukemia.
  • AML with t(8;21)(q22;q22.1); RUNX1-RUNX1T1: In leukemias with t(8;21), the RUNX1 (AML1) gene on chromosome 21 is fused with the RUNX1T1 (ETO) 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.[17] Children with t(8;21) have a more favorable outcome than do children with AML characterized by normal or complex karyotypes,[17,27,28,29] with 5-year overall survival (OS) rates of 74% to 90%.[18,19,30] The t(8;21) translocation occurs in approximately 12% of children with AML.[18,19,30]
  • AML with inv(16)(p13.1;q22) or t(16;16)(p13.1;q22); CBFB-MYH11: 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. Inv(16) confers a favorable prognosis for both adults and children with AML,[17,27,28,29] with a 5-year OS rate of about 85%.[18,19] Inv(16) occurs in 7% to 9% of children with AML.[18,19,30] As noted above, cases with CBFB-MYH11 and cases with RUNX1-RUNX1T1 have distinctive secondary mutations; CBFB-MYH11 secondary mutations are primarily restricted to genes that activate receptor tyrosine kinase signaling (NRAS, FLT3, and KIT).[31,32]
  • AML with t(16;21)(q24;q22); RUNX1-CBFA2T3: 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.[33] These patients present at a median age of 7 years and are rare, representing approximately 0.1% to 0.3% of pediatric AML cases. Among 23 patients with RUNX1-CBFA2T3, five presented with secondary AML, including two patients who had a primary diagnosis of Ewing sarcoma. Outcome for the cohort of 23 patients was favorable, with a 4-year EFS rate of 77% and a cumulative incidence of relapse rate of 0%.[33]

  Both RUNX1-RUNX1T1 and CBFB-MYH11 subtypes commonly show mutations in genes that activate receptor tyrosine kinase signaling (e.g., NRAS, FLT3, and KIT); NRAS and KIT are the most commonly mutated genes for both subtypes. The prognostic significance of activating KIT mutations in adults with CBF AML has been studied with conflicting results. A meta-analysis found that KIT mutations appear to increase the risk of relapse without an impact on OS for adults with RUNX1-RUNX1T1 AML.[34]KIT mutations are often subclonal in children and adults with CBF AML;[35,36] and in adults with RUNX1-RUNX1T1 AML, higher KIT-mutant allele ratio appears to be associated with higher risk of treatment failure.[31,35] The prognostic significance of KIT mutations in pediatric CBF AML remains unclear; some studies have found no impact of KIT mutations on outcome,[37,38,39] while other studies have reported a higher risk of treatment failure when KIT mutations are present.[36,40,41,42,43]

  Although both RUNX1-RUNX1T1 and CBFB-MYH11 fusion genes disrupt the activity of CBF, cases with these genomic alterations have distinctive secondary mutations.[31,32]

  • RUNX1-RUNX1T1 cases also have frequent mutations in genes regulating chromatin conformation (e.g., ASXL1 and ASXL2) (40% of cases) and genes encoding members of the cohesin complex (20% of cases). Mutations in ASXL1 and ASXL2 and mutations in members of the cohesin complex are rare in CBFB-MYH11 leukemias.[31,32]
  • A study of 204 adults with RUNX1-RUNX1T1 AML found that ASXL2 mutations (present in 17% of cases) and ASXL1 or ASXL2 mutations (present in 25% of cases) lacked prognostic significance.[44] Similar results, albeit with smaller numbers, were reported for children with RUNX1-RUNX1T1 AML and ASXL1 and ASXL2 mutations.[45]
• Acute promyelocytic leukemia (APL) with PML-RARA: APL represents about 7% of children with AML.[19,46] AML with t(15;17) is invariably associated with APL, a distinct subtype of AML that is treated differently than other types of AML because of its marked sensitivity to arsenic trioxide and the differentiating effects of tretinoin. The t(15;17) translocation or other more complex chromosomal rearrangements may lead to the production of a fusion protein involving the retinoid acid receptor alpha and PML. The 2016 revision to the WHO classification does not include the t(15;17) cytogenetic designation to stress the significance of the PML-RARA fusion, which may be cryptic or result from complex karyotypic changes.[13]

  Utilization of quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) for PML-RARA transcripts has become standard practice.[47] Quantitative RT-PCR allows identification of the three common transcript variants and is used for monitoring response on treatment and early detection of molecular relapse. Other much less common translocations involving the retinoic acid receptor alpha can also result in APL (e.g., t(11;17)(q23;q21) involving the PLZF gene).[48,49] Identification of cases with the t(11;17)(q23;q21) is important because of their decreased sensitivity to tretinoin.[48]

• AML with mutated NPM1: 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 mutations by the demonstration of cytoplasmic localization of NPM. Mutations in the NPM1 protein that diminish its nuclear localization are primarily associated with a subset of AML with a normal karyotype, absence of CD34 expression, and an improved prognosis in the absence of FLT3 ITD mutations in adults and younger adults.[50,51,52,53,54,55]

  Studies of children with AML suggest a lower rate of occurrence of NPM1 mutations in children compared with adults with normal cytogenetics. NPM1 mutations occur in approximately 8% of pediatric patients with AML and are uncommon in children younger than 2 years.[21,22,56,57]NPM1 mutations are associated with a favorable prognosis in patients with AML characterized by a normal karyotype.[21,22,57] For the pediatric population, conflicting reports have been published regarding the prognostic significance of an NPM1 mutation when a FLT3 ITD mutation is also present. One study reported that an NPM1 mutation did not completely abrogate the poor prognosis associated with having a FLT3 ITD mutation,[21,58] but other studies showed no impact of a FLT3 ITD mutation on the favorable prognosis associated with an NPM1 mutation.[15,22,57]

• AML with biallelic mutations of CEBPA: Mutations in the CEBPA gene occur in a subset of children and adults with cytogenetically normal AML.[59] In adults younger than 60 years, approximately 15% of cytogenetically normal AML cases have mutations in CEBPA.[54] Outcomes for adults with AML with CEBPA mutations appear to be relatively favorable and similar to that of patients with CBF leukemias.[54,60] Studies in adults with AML have demonstrated that CEBPA double-mutant, but not single-mutant, AML is independently associated with a favorable prognosis,[61,62,63,64] leading to the WHO 2016 revision that requires biallelic mutations for the disease definition.[13]

  CEBPA mutations occur in 5% to 8% of children with AML and have been preferentially found in the cytogenetically normal subtype of AML with FAB M1 or M2; 70% to 80% of pediatric patients have double-mutant alleles, which is predictive of a significantly improved survival, similar to the effect observed in adult studies.[23,65] Although both double-mutant and single-mutant alleles of CEBPA were associated with a favorable prognosis in children with AML in one large study,[23] a second study observed inferior outcome for patients with single CEBPA mutations.[65] However, very low numbers of children with single-allele mutants were included in these two studies (only 13 total patients), which makes a conclusion regarding the prognostic significance of single-allele CEBPA mutations in children premature.[23] In newly diagnosed patients with double-mutant CEBPA AML, germline screening should be considered in addition to usual family history queries, because 5% to 10% of these patients are reported to have a germline CEBPA mutation.[59]CSF3R mutations commonly occur in a subset of patients with mutant CEBPA AML, and when present, may be associated with increased risk of treatment failure but without an impact on OS.[66]

• Myeloid leukemia associated with Down syndrome (GATA1 mutations): GATA1 mutations are present in most, if not all, Down syndrome children with either transient abnormal myelopoiesis (TAM) or acute megakaryoblastic leukemia (AMKL).[67,68,69,70]GATA1 mutations were also observed in 9% of non–Down syndrome children and 4% of adults with AMKL (with coexistence of amplification of the RCAN1 [DSCR1] gene on chromosome 21 in 9 of 10 cases).[71]GATA1 is a transcription factor that is required for normal development of erythroid cells, megakaryocytes, eosinophils, and mast cells.

  GATA1 mutations confer increased sensitivity to cytarabine by down-regulating cytidine deaminase expression, possibly providing an explanation for the superior outcome of children with Down syndrome and M7 AML when treated with cytarabine-containing regimens.[72]

Genetic abnormalities associated with an unfavorable prognosis

Genetic abnormalities associated with an unfavorable prognosis include the following:

• Chromosomes 5 and 7: Chromosomal abnormalities associated with poor prognosis in adults with AML include those involving chromosome 5 (del(5q)) and chromosome 7 (monosomy 7).[17,73,74] These cytogenetic subgroups represent approximately 2% and 4% of pediatric AML cases, respectively, and are also associated with poor prognosis in children.[18,73,74,75,76,77]

  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.[20] However, outcome for children with del(7q), but not monosomy 7, appears comparable to that of other children with AML.[19,76] The presence of del(7q) does not abrogate the prognostic significance of favorable cytogenetic characteristics (e.g., inv(16) and t(8;21)).[17,76]

  Chromosome 5 and 7 abnormalities appear to lack prognostic significance in AML patients with Down syndrome who are aged 4 years and younger.[78]

• AML with inv(3)(q21.3;q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM: 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.[79,80] These abnormalities are associated with poor prognosis in adults with AML,[17,73,81] but are very uncommon in children (<1% of pediatric AML cases).[18,28,82]

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

• FLT3 mutations: Presence of a FLT3 ITD mutation appears to be associated with poor prognosis in adults with AML,[83] particularly when both alleles are mutated or there is a high ratio of the mutant allele to the normal allele.[84]FLT3 ITD mutations also convey a poor prognosis in children with AML.[24,58,85,86,87] The frequency of FLT3 ITD mutations in children is lower than that observed in adults, especially for children younger than 10 years, for whom 5% to 10% of cases have the mutation (compared with approximately 30% in adults).[86,87]

  The prognostic significance of FLT3 ITD is modified by the presence of other recurring genomic alterations. The prevalence of FLT3 ITD is increased in certain genomic subtypes of pediatric AML, including those with the NUP98-NSD1 fusion gene, of which 80% to 90% have FLT3 ITD.[88,89] Approximately 15% of patients with FLT3 ITD have NUP98-NSD1, and patients with both FLT3 ITD and NUP98-NSD1 have a poorer prognosis than do patients who have FLT3 ITD without NUP98-NSD1.[89] For patients who have FLT3 ITD, the presence of either WT1 mutations or NUP98-NSD1 fusions is associated with poorer outcome (EFS rates below 25%) than for patients who have FLT3 ITD without these alterations.[15] Conversely, when FLT3 ITD is accompanied by NPM1 mutations, the outcome is relatively favorable and is similar to that of pediatric AML cases without FLT3 ITD.[15]

  For APL, FLT3 ITD and point mutations occur in 30% to 40% of children and adults.[84,86,90,91] Presence of the FLT3 ITD mutation is strongly associated with the microgranular variant (M3v) of APL and with hyperleukocytosis.[90,92,93,94] It remains unclear whether FLT3 mutations are associated with poorer prognosis in patients with APL who are treated with modern therapy that includes tretinoin and arsenic trioxide.[91,93,95,96,97,98]

  Activating point mutations of FLT3 have also been identified in both adults and children with AML, although the clinical significance of these mutations is not clearly defined. Some of these point mutations appear to be specific to pediatric patients.[15]

• AML with t(16;21)(p11;q22); FUS-ERG: 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.[33] These patients present at a median age of 8 to 9 years and are rare, representing approximately 0.3% to 0.5% of pediatric AML cases. For a cohort of 31 patients with FUS-ERG AML, outcome was poor, with a 4-year EFS rate of 7% and a cumulative incidence of relapse rate of 74%.[33]

Other genetic abnormalities observed in pediatric AML

Other genetic abnormalities observed in pediatric AML include the following:

• KMT2A (MLL) gene rearrangements: KMT2A gene rearrangement occurs in approximately 20% of children with AML.[18,19] These cases, including most AMLs secondary to epipodophyllotoxin exposure,[99] are generally associated with monocytic differentiation (FAB M4 and M5). KMT2A rearrangements are also reported in approximately 10% of FAB M7 (AMKL) patients (see below).[71,100]

  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 MLLT3 gene.[101] The 2016 revision to the WHO classification defined AML with t(9;11)(p21.3;q23.3); MLLT3-KMT2A as a distinctive disease entity. However, more than 50 different fusion partners have been identified for the KMT2A gene in patients with AML.

  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.[101] 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).[101]

  Outcome for patients with de novo AML and KMT2A gene rearrangement is generally reported as being similar to that for other patients with AML.[17,18,101,102] However, as the KMT2A gene can participate in translocations with many different fusion partners, the specific fusion partner appears to influence prognosis, as demonstrated by a large international retrospective study evaluating outcome for 756 children with 11q23- or KMT2A-rearranged AML.[101] For example, cases with t(1;11)(q21;q23), representing 3% of all 11q23/KMT2A-rearranged AML, showed a highly favorable outcome, with a 5-year event-free survival (EFS) rate of 92%.

  While reports from single clinical trial groups have variably described more favorable prognosis for patients with AML who have t(9;11)(p21.3;q23.3)/MLLT3-KMT2A, the international retrospective study did not confirm the favorable prognosis for this subgroup.[17,18,101] An international collaboration evaluating pediatric AMKL patients observed that the presence of t(9;11), which was seen in approximately 5% of AMKL cases, was associated with an inferior outcome compared with other AMKL cases.[100]

  KMT2A-rearranged AML subgroups that appear to be associated with poor outcome include the following:

  • Cases with the t(10;11) translocation are a group at high risk of relapse in bone marrow and the CNS.[17,19] Some cases with the t(10;11) translocation have fusion of the KMT2A gene with the MLLT10 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 year, have a 5-year EFS rate of 20% to 30%.[101]
  • Patients with t(6;11)(q27;q23) have a poor outcome, with a 5-year EFS rate of 11%.
  • Patients with t(4;11)(q21;q23) also have a poor outcome, with a 5-year EFS rate of 29%.[101]
  • A follow-up study by the international collaborative group demonstrated that additional cytogenetic abnormalities further influenced outcome of children with KMT2A translocations, with complex karyotypes and trisomy 19 predicting poor outcome and trisomy 8 predicting a more favorable outcome.[103]
• AML with t(6;9)(p23;q34.1); DEK-NUP214: t(6;9) leads to the formation of a leukemia-associated fusion protein DEK-NUP214.[104,105] This subgroup of AML has been associated with a poor prognosis in adults with AML,[104,106,107] and occurs infrequently in children (less than 1% of AML cases). The median age of children with DEK-NUP214 AML is 10 to 11 years, and approximately 40% of pediatric patients have FLT3 ITD.[108,109]

  t(6;9) AML appears to be associated with a high risk of treatment failure in children, particularly for those not proceeding to allogeneic stem cell transplantation.[18,105,108,109]

• Molecular subgroups of non–Down syndrome acute megakaryoblastic leukemia (AMKL): AMKL accounts for approximately 10% of pediatric AML and includes substantial heterogeneity at the molecular level. Molecular subtypes of AMKL are listed below.
  • CBFA2T3-GLIS2: CBFA2T3-GLIS2 is a fusion resulting from a cryptic chromosome 16 inversion (inv(16)(p13.3;q24.3)).[110,111,112,113,114] It occurs commonly in non–Down syndrome AMKL, representing 16% to 27% of pediatric AMKL and presenting with a median age of 1 year.[71,112,115,116] It appears to be associated with unfavorable outcome.[71,110,114,115,116]

    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, and with all cases observed in children younger than 3 years.[117] 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). The CBFA2T3-GLIS2 fusion was an independent prognostic factor for both OS and EFS. The OS rate at 5 years was 22% for patients with CBFA2T3-GLIS2 versus 63% for fusion-negative patients. CBFA2T3-GLIS2 leukemia cells have a distinctive immunophenotype (initially reported as the RAM phenotype),[118,119] with high CD56, dim or negative expression of CD45 and CD38, and a lack of HLA-DR expression.

  • KMT2A-rearranged: Cases with KMT2A translocations represent 10% to 17% of pediatric AMKL, with MLLT3 being the most common KMT2A fusion partner.[71,100,115]KMT2A-rearranged cases appear to be associated with inferior outcome among children with AMKL, with OS rates at 4 to 5 years of approximately 30%.[71,100,115] An international collaboration evaluating pediatric AMKL observed that the presence of t(9;11)/MLLT3-KMT2A, which was seen in approximately 5% of AMKL cases (n = 21), was associated with an inferior outcome (5-year OS rate, approximately 20%) compared with other AMKL cases and other KMT2A-rearrangements (n = 17), each with a 5-year OS rate of 50% to 55%.[100] Inferior outcome was not observed for patients (n = 17) with other KMT2A-rearrangements.
  • NUP98-KDM5A: NUP98-KDM5A is observed in approximately 10% of pediatric AMKL cases [71,115] and is observed at lower rates in non-AMKL cases,[116] although approximately two-thirds of children with NUP98-KDM5A have a non-AMKL FAB subtype (see below).[120]NUP98-KDM5A cases showed a trend towards inferior prognosis, although the small number of cases studied limits confidence in this assessment.[71,115]
  • RBM15-MKL1: The t(1;22)(p13;q13) translocation that produces RBM15-MKL1 is uncommon (<1% of pediatric AML) and is restricted to acute megakaryocytic leukemia (AMKL).[18,116,121,122,123,124] Studies have found that t(1;22)(p13;q13) is observed in 10% to 18% of children with AMKL who have evaluable cytogenetics or molecular genetics.[71,100,115] Most AMKL cases with t(1;22) occur in infants, with the median age at presentation (4–7 months) being younger than that for other children with AMKL.[100,112,125] 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.[122]

    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.[100] 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 AMKL patients with other specific genetic abnormalities (CBFA2T3/GUS2, NUP98/KDM5A, KMT2A rearrangements, monosomy 7).[115]

  • HOX-rearranged: Cases with a gene fusion involving a HOX cluster gene represented 15% of pediatric AMKL in one report.[71] 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 mutated: GATA1-truncating mutations in non–Down syndrome AMKL arise in young children (median age, 1–2 years) and are associated with amplification of the RCAN1 (DSCR1) gene on chromosome 21.[71] 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).[71]
• t(8;16) (MYST3-CREBBP): The t(8;16) translocation fuses the MYST3 gene on chromosome 8p11 to CREBBP on chromosome 16p13. t(8;16) AML rarely occurs in children. In an International Berlin-Frankfurt-Münster (iBFM) AML study of 62 children, presence of this translocation was associated with younger age at diagnosis (median, 1.2 years), FAB M4/M5 phenotype, erythrophagocytosis, leukemia cutis, and disseminated intravascular coagulation.[126] Outcome for children with t(8;16) AML appears similar to other types of AML.

  A substantial proportion of infants diagnosed with t(8;16) AML in the first month of life show spontaneous remission, although AML recurrence may occur months to years later.[126,127,128,129] These observations suggest that a watch and wait policy could be considered in cases of t(8;16) AML diagnosed in the neonatal period if close long-term monitoring can be ensured.[126]

• t(7;12)(q36;p13): The t(7;12)(q36;p13) translocation involves ETV6 on chromosome 12p13 and variable breakpoints on chromosome 7q36 in the region of MNX1. The translocation may be cryptic by conventional karyotyping and in some cases may be confirmed only by FISH.[130,131] This alteration occurs virtually exclusively in children younger than 2 years, is mutually exclusive with the KMT2A rearrangement, and is associated with a high risk of treatment failure.[18,19,57,130,132,133]
• NUP98 gene fusions: NUP98 has been reported to form leukemogenic gene fusions with more than 20 different partners.[134] In the pediatric AML setting, the two most common fusion genes are NUP98-NSD1 and NUP98-KDM5A, with the former observed in one report in approximately 15% of cytogenetically normal pediatric AML and the latter observed in approximately 10% of pediatric AMKL (see above).[71,88,112] AML cases with either NUP98 fusion gene show high expression of HOXA and HOXB genes, indicative of a stem cell phenotype.[105,112]

  The NUP98-NSD1 fusion gene, which is often cytogenetically cryptic, results from the fusion of NUP98 (chromosome 11p15) with NSD1 (chromosome 5q35).[88,89,105,135] This alteration occurs in approximately 4% to 7% of pediatric AML cases.[13,25,88,105,136]

  • The highest frequency of NUP98-NSD1 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).
  • NUP98-NSD1 cases present with a high white blood cell (WBC) count (median, 147 × 10⁹ /L in one study).[88,89] Most NUP98-NSD1 AML cases do not show cytogenetic aberrations.[88,105]
  • A high percentage of NUP98-NSD1 cases (74%–90%) have FLT3 ITD.[25,88,89]
  • A study that included 12 children with NUP98-NSD1 AML reported that although all patients achieved a complete response (CR), the presence of NUP98-NSD1 independently predicted poor prognosis, and children with NUP98-NSD1 AML had a high risk of relapse, with a resulting 4-year EFS rate of approximately 10%.[88] In another study that included children (n = 38) and adults (n = 7) with NUP98-NSD1 AML, presence of both NUP98-NSD1 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%).[89]
  • 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%).[137]

  The NUP98-KDM5A fusion gene results from the fusion of the NUP98 gene with the KDM5A gene, which results from a cytogenetically cryptic translocation, t(11;12)(p15;p13).[138] Approximately 2% of pediatric AML patients have NUP98-KDM5A, and these cases tend to present at a young age (median age, 3 years).[120]

  • Cases with NUP98-KDM5A tend to be AMKL (34%), followed by FAB M5 (21%), and FAB M6 (17%).[120]NUP98-KDM5A is observed in approximately 10% of pediatric AMKL cases.[71,115]
  • Other genetic aberrations associated with pediatric AML, including FLT3 mutations, are uncommon in NUP98-KDM5A cases.[120]
  • Prognosis for children with NUP98-KDM5A is inferior to that of other children with AML (5-year EFS rate of 29.6% ± 14.6% and an OS rate of 34.1% ± 16.1%).[120]
• RUNX1 mutations: AML with mutated RUNX1, which is a provisional entity in the 2016 WHO classification of AML and related neoplasms, is more common in adults than in children. In adults, the RUNX1 mutation is associated with a high risk of treatment failure. In a study of children with AML, RUNX1 mutations were observed in 11 of 503 patients (approximately 2%). Six of 11 patients with RUNX1-mutated AML failed to achieve remission and their 5-year EFS rate was 9%, suggesting that the RUNX1 mutation confers a poor prognosis in both children and adults.[139]
• RAS mutations: Although mutations in RAS have been identified in 20% to 25% of patients with AML, the prognostic significance of these mutations has not been clearly shown.[57,140] Mutations in NRAS are observed more commonly than mutations in KRAS in pediatric AML cases.[57,141]RAS mutations occur with similar frequency for all Type II alteration subtypes, with the exception of APL, for which RAS mutations are seldom observed.[57]
• KIT mutations: Mutations in KIT occur in approximately 5% of AML, but in 10% to 40% of AML with CBF abnormalities.[43,57,141,142]

  The prognostic significance of activating KIT mutations in adults with CBF AML has been studied with conflicting results. A meta-analysis found that KIT mutations appear to increase the risk of relapse without an impact on OS for adults with RUNX1-RUNX1T1 AML.[34]KIT mutations are often subclonal in children and adults with CBF AML;[35,36] in adults with RUNX1-RUNX1T1 AML, higher KIT mutant–allele ratio appears to be associated with higher risk of treatment failure in adults with RUNX1-RUNX1T1 AML.[31,35] The prognostic significance of KIT mutations in pediatric CBF AML remains unclear; some studies found no impact of KIT mutations on outcome,[37,38,39] while other studies reported a higher risk of treatment failure when KIT mutations were present.[36,40,41,42,43]

• WT1 mutations: WT1, a zinc-finger protein regulating gene transcription, is mutated in approximately 10% of cytogenetically normal cases of AML in adults.[143,144,145,146] The WT1 mutation has been shown in some,[143,144,146] but not all studies [145] to be an independent predictor of worse disease-free survival, EFS, and OS of adults.

  In children with AML, WT1 mutations are observed in approximately 10% of cases.[147,148] Cases with WT1 mutations are enriched among children with normal cytogenetics and FLT3 ITD, but are less common among children younger than 3 years.[147,148] AML cases with NUP98-NSD1 are enriched for both FLT3 ITD and WT1 mutations.[88] In univariate analyses, WT1 mutations are predictive of poorer outcome in pediatric patients, but the independent prognostic significance of WT1 mutation status is unclear because of its strong association with FLT3 ITD and its association with NUP98-NSD1.[88,147,148] The largest study of WT1 mutations in children with AML observed that children with WT1 mutations in the absence of FLT3 ITD had outcomes similar to that of children without WT1 mutations, while children with both WT1 mutation and FLT3 ITD had survival rates less than 20%.[147]

  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%).[137]

• DNMT3A mutations: Mutations of the DNMT3A gene have been identified in approximately 20% of adult AML patients and are uncommon in patients with favorable cytogenetics but occur in one-third of adult patients with intermediate-risk cytogenetics.[149] Mutations in this gene are independently associated with poor outcome.[149,150,151]DNMT3A mutations are virtually absent in children.[152]
• IDH1 and IDH2 mutations: Mutations in IDH1 and IDH2, which code for isocitrate dehydrogenase, occur in approximately 20% of adults with AML,[153,154,155,156,157] and they are enriched in patients with NPM1 mutations.[154,155,158] The specific mutations that occur in IDH1 and IDH2 create a novel enzymatic activity that promotes conversion of alpha-ketoglutarate to 2-hydroxyglutarate.[159,160] This novel activity appears to induce a DNA hypermethylation phenotype similar to that observed in AML cases with loss of function mutations in TET2.[158]

  Mutations in IDH1 and IDH2 are rare in pediatric AML, occurring in 0% to 4% of cases.[152,161,162,163,164,165] There is no indication of a negative prognostic effect for IDH1 and IDH2 mutations in children with AML.[161]

• CSF3R mutations: CSF3R is the gene encoding the granulocyte colony-stimulating factor (G-CSF) receptor, and activating mutations in CSF3R are observed in 2% to 3% of pediatric AML cases.[166] These mutations lead to enhanced signaling through the G-CSF receptor, and they are primarily observed in AML with either CEBPA mutations or with CBF abnormalities (RUNX1-RUNX1T1 and CBFB-MYH11).[166] In a study of 2,150 pediatric patients with AML, 35 patients (1.6%) were found to have CSF3R mutations; 30 (89%) of these cases were in patients with either RUNX1-RUNX1T1 (n = 18) or with CEBPA mutations (n = 12).[66] Risk of relapse was significantly higher for patients with co-occurring CSF3R and CEBPA mutations compared with patients with RUNX1-RUNX1T1 AML and CSF3R mutations.

  Activating mutations in CSF3R are also observed in patients with severe congenital neutropenia. These mutations are not the cause of severe congenital neutropenia, but rather arise as somatic mutations and can represent an early step in the pathway to AML.[167] In one study of patients with severe congenital neutropenia, 34% of patients who had not developed a myeloid malignancy had CSF3R mutations detectable in peripheral blood neutrophils and mononuclear cells, while 78% of patients who had developed a myeloid malignancy showed CSF3R mutations.[167] A study of 31 patients with severe congenital neutropenia who developed AML or MDS observed CSF3R mutations in approximately 80% of patients, and also observed a high frequency of RUNX1 mutations (approximately 60%), suggesting cooperation between CSF3R and RUNX1 mutations for leukemia development within the context of severe congenital neutropenia.[168]

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Treatment Option Overview for Childhood AML

Leukemia is considered to be disseminated in the hematopoietic system at diagnosis, even in children with acute myeloid leukemia (AML) who present with isolated chloromas (also called granulocytic or myeloid sarcomas). If these children do not receive systemic chemotherapy, they invariably develop AML in months or years. AML may invade nonhematopoietic (extramedullary) tissue such as meninges, brain parenchyma, testes or ovaries, or skin (leukemia cutis). Extramedullary leukemia is more common in infants than in older children with AML.[1]

Childhood AML is diagnosed when bone marrow has 20% or greater blasts. The blasts have the morphologic and histochemical characteristics of one of the French-American-British (FAB) subtypes of AML. It can also be diagnosed by biopsy of a chloroma. For treatment purposes, patients with clonal cytogenetic abnormalities typically associated with AML, such as t(8;21)(RUNX1-RUNX1T1), inv(16)(CBFB-MYH11), t(9;11)(MLLT3-KMT2A) or t(15;17)(PML-RARA) and who have less than 20% bone marrow blasts, are considered to have AML rather than a myelodysplastic syndrome.[2]

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

• Peripheral blood counts (white blood cell [WBC] count, differential [absolute neutrophil count >1,000/μL], and platelet count >100,000/μL) rising toward normal.
• Mildly hypocellular to normal cellular marrow with fewer than 5% blasts.
• No clinical signs or symptoms of the disease, including in the central nervous system (CNS) or at other extramedullary sites.[3]

Alternative definitions of remission using morphology are used in AML because of the prolonged myelosuppression caused by intensive chemotherapy and include CR with incomplete platelet recovery (CRp) and CR with incomplete marrow recovery (typically absolute neutrophil count) (CRi). Whereas the use of CRp provides a clinically meaningful response, the traditional CR definition remains the gold standard because patients in CR were found to be more likely to survive longer than those in CRp.[4]

Achieving a hypoplastic bone marrow (using morphology) is usually the first step in obtaining remission in AML with the exception of the M3 subtype (acute promyelocytic leukemia [APL]); a hypoplastic marrow phase is often not necessary before the achievement of remission in APL. Additionally, early recovery marrows in any of the subtypes of AML may be difficult to distinguish from persistent leukemia, although the application of flow cytometric immunophenotyping and cytogenetic/molecular testing have made this less problematic. Correlation with blood cell counts and clinical status is imperative in passing final judgment on the results of early bone marrow findings in AML.[5] If the findings are in doubt, the bone marrow aspirate should be repeated in 1 to 2 weeks.[1]

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

Treatment Approach

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

Treatment is ordinarily divided into the following two phases:

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

Postremission therapy may consist of varying numbers of courses of intensive chemotherapy and/or allogeneic hematopoietic stem cell transplantation (HSCT). For example, ongoing trials of the Children's Oncology Group (COG) and the United Kingdom Medical Research Council (MRC) use similar chemotherapy regimens consisting of two courses of induction chemotherapy followed by two to three additional courses of intensification chemotherapy.[6,7,8]

Maintenance therapy is not part of most pediatric AML protocols because two randomized clinical trials failed to show a benefit for maintenance therapy when given after modern intensive chemotherapy.[9,10] The exception to this generalization is made for APL, because maintenance therapy was shown to improve event-free survival (EFS) and overall survival (OS) when tretinoin was combined with chemotherapy.[11] Some studies of adult APL patients, including studies incorporating arsenic trioxide treatment, have shown no benefit to maintenance.[12,13]

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.[6] The most recent COG trials reported an 11% to 13% incidence of remission failure because of resistant disease and only 2% to 3% resulted from toxic death during the two induction courses.[8,14]

Children treated for AML are living longer and require close monitoring for cancer therapy side effects that may persist or develop months or years after treatment. The high cumulative doses of anthracyclines require long-term monitoring of cardiac function. The use of some modalities have declined, including total-body irradiation with HSCT because of its increased risk of growth failure, gonadal and thyroid dysfunction, cataract formation, and second malignancies.[15] (Refer to the Survivorship and Adverse Late Sequelae section of this summary or to the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)

Prognostic Factors in Childhood AML

Prognostic factors in childhood AML can be categorized as follows:

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

Host risk factors

• Age: Several reports have identified older age as an adverse prognostic factor.[7,16,17,18,19,20] The age effect is not large with regard to OS, but in general, the adverse outcomes seen in adolescents compared with younger children appear to be primarily caused by increases in toxic mortality.[21] In the COG AAML1031 (NCT01371981) trial, age older than 11 years was an independent predictor of more favorable EFS on multivariable analysis.[22]

  While outcome for infants with ALL remains inferior to that of older children, outcome for infants with AML is similar to that of older children when they are treated with standard AML regimens.[16,23,24,25] Infants have been reported to have a 5-year survival rate of 60% to 70%, although with increased treatment-associated toxicity, particularly during induction.[16,23,24,25,26]

• Race/Ethnicity: In both the Children's Cancer Group (CCG) CCG-2891 and COG-2961 (NCT00002798) studies, white children had higher OS rates than did black and Hispanic children.[18,27] A trend for lower survival rates for black children compared with white children was also observed in children treated on St. Jude Children's Research Hospital AML clinical trials.[28]
• Down syndrome: For children with Down syndrome who develop AML, survival is generally favorable when diagnosed at a young age.[29,30,31] 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 Down syndrome patients with AML, whereas those older than 4 years have similar outcomes to those without Down syndrome.[31,32,33,34,35]
• Body mass index: Obesity (body mass index more than 95th percentile for age) is predictive of inferior survival.[18,36] Inferior survival was attributable to early treatment-related mortality that was primarily caused by infectious complications.[36,37]

Leukemia risk factors

• White blood cell (WBC) count: WBC count at diagnosis has been consistently noted to be inversely related to survival.[7,22,38,39] Patients with high presenting leukocyte counts have a higher risk of developing pulmonary and CNS complications and, historically, have a higher risk of induction death.[40]

  In patients with APL, WBC at initial diagnosis alone is used to distinguish standard-risk and high-risk APL. A WBC count of 10,000 cells/μL or more denotes high risk, and these patients have an increased risk of both early death and relapse.[41] However, more recent regimens that include arsenic trioxide result in low relapse rates that are not significantly different between the high-risk and low-risk groups.[42]

• FAB subtype: Associations between FAB subtype and prognosis have been more variable.
  • M3 subtype. The M3 (APL) subtype has a favorable outcome in studies using tretinoin in combination with chemotherapy and arsenic trioxide consolidation.[41,42,43,44]
  • M7 subtype. Some studies have indicated a relatively poor outcome for M7 (megakaryocytic leukemia) in patients without Down syndrome,[29] although reports suggest an intermediate prognosis for this group of patients when contemporary treatment approaches are used.[6,45,46]

    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.[47,48] By contrast, the 10% of non–Down syndrome AMKL patients with GATA1 mutations appeared to have a favorable outcome if there were no prognostically unfavorable fusion genes also present, as did patients with HOX-rearrangement.[48]

  • M0 subtype. The M0, or minimally differentiated subtype, has been associated with a poor outcome.[49]
• 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 acute lymphoblastic leukemia–inspired definitions to AML, as follows:
  • CNS1: CSF negative for blasts on cytospin, regardless of CSF WBC count.
  • CNS2 is divided into the following three groups and 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 and is 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 utilizing the more traditional CNS1/2/3 definitions.[50]

    CNS2 disease has been observed in approximately 13% to 16% of children with AML, and CNS3 disease has been observed in approximately 11% to 17% of children with AML.[50,51] Studies have variably shown that patients with CNS2/CNS3 were younger, more often had hyperleukocytosis, and had higher incidences of t(9;11), t(8;21), or inv(16).[50,51]

    While CNS involvement (CNS2 or CNS3) at diagnosis has not been shown to be correlated with OS in most studies, a COG analysis of children with AML enrolled from 2003 to 2010 on two consecutive and identical backbone trials found that CNS involvement, especially CNS3 status, was associated with inferior outcomes, including complete remission rate, EFS, disease-free survival, and an increased risk of relapse involving the CNS.[50] Another trial showed it to be associated with an increased risk of isolated CNS relapse.[52] Finally, the COG study did not find an adverse impact of traumatic lumbar punctures at diagnosis upon eventual outcome.[50]

• Cytogenetic and molecular characteristics: Cytogenetic and molecular characteristics are also associated with prognosis. (Refer to the Molecular Evaluation subsection in the Histochemical, Immunophenotypic, and Molecular Evaluation for Childhood AML section of this summary for detailed information.) Cytogenetic and molecular characteristics that are currently used in the COG clinical trials for treatment assignment include the following:
  • Favorable: inv(16)/t(16;16) and t(8;21), t(15;17), biallelic CEBPA mutations, and NPM1 mutations.
  • Unfavorable: monosomy 7, monosomy 5/del(5q), 3q abnormalities, FLT3 internal tandem duplications (ITD) with high-allelic ratio, KMT2A with the following partners: t(4;11)(q21;q23), t(6;11)(q27;q23), t(10;11)(p11.2;q23), t(10;11)(p12;q23), or t(11;19)(q23;p13.3), NUP98 (11p15.5), 12p (ETV6 rearrangement or loss), t(16;21)(p11;q22)(FUS-ERG), CBFA2T3-GLIS2, KAT6A (8p11.21) (if over 90 days of age), and non–KMT2A-MLLT10 fusions.[53,54]
• Immunophenotype: A distinctive immunophenotype (initially reported as the RAM phenotype), with high CD56, dim or negative expression of CD45 and CD38, and a lack of HLA-DR expression is associated with a poor prognosis (5-year EFS rate of approximately 20%).[55,56] Most cases with the RAM phenotype have the CBFA2T3-GLIS2 fusion.[56,57]

Therapeutic response risk factors

• Response to therapy/minimal residual disease (MRD): Early response to therapy, generally measured after the first course of induction therapy, is predictive of outcome and can be assessed by standard morphologic examination of bone marrow,[38,58] cytogenetic analysis, fluorescence in situ hybridization, or more sophisticated techniques to identify MRD (e.g., multiparameter flow cytometry, quantitative RT-PCR).[59,60,61,62] Multiple groups have shown that the level of MRD after one course of induction therapy is an independent predictor of prognosis.[59,60,61,62,63,64]

  Molecular approaches to assessing MRD in AML (e.g., using quantitative RT-PCR) have been challenging to apply because of the genomic heterogeneity of pediatric AML and the instability of some genomic alterations. Quantitative RT-PCR detection of RUNX1-RUNX1T1 fusion transcripts can effectively predict higher risk of relapse for patients in clinical remission.[65,66,67] Other molecular alterations such as NPM1 mutations [68] and CBFB-MYH11 fusion transcripts [69] 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.[70]

  For APL, MRD detection at the end of induction therapy lacks prognostic significance, likely related to the delayed clearance of differentiating leukemic cells destined to eventually die.[71,72] However, the kinetics of molecular remission after completion of induction therapy is prognostic, with the persistence of minimal disease after three courses of therapy portending increased risk of relapse.[72,73,74]

  Flow cytometric methods have been used for MRD detection and can detect leukemic blasts based on the expression of aberrant surface antigens that differ from the pattern observed in normal progenitors. A CCG study of 252 pediatric patients with AML in morphologic remission demonstrated that MRD as assessed by flow cytometry was the strongest prognostic factor predicting outcome in a multivariate analysis.[59] 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.[60,61,63]

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 [58] and further applied based on the ability of the pediatric patient to undergo reinduction and obtain a second complete remission and their subsequent OS after first relapse.[75]

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.[8]
   • 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 del5q, chromosome 3 abnormalities, or a poor response to induction 1 therapy with morphologic 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 trial COG-AAML1031 (NCT01371981), 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.[76]
   • 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:[22]
   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 mutations, or CEBPA mutations 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 (refer to Table 7).

      Table 7. Risk Assignment in the AAML1031 Study^a,b

      Risk Assignment:	Low Risk		High Risk
      ​	Low-Risk Group 1	Low-Risk Group 2	High-Risk Group 1	High-Risk Group 2	High-Risk Group 3
      ITD = internal tandem duplications.
      a Groups are based on combinations of risk factors, which may be found in any individual patient.
      b Bold indicates the overriding risk factor in risk-group assignment.
      c NPM1,CEBPA, t(8;21), inv(16).
      d Monosomy 7, monosomy 5, del(5q).
      FLT3ITD allelic ratio	Low/negative	Low/negative	High	Low/negative	Low/negative
      Good-risk molecular markersc	Present	Absent	Any	Absent	Absent
      Poor-risk cytogenetic markersd	Any	Absent	Any	Present	Absent
      Minimal residual disease	Any	Negative	Any	Any	Positive

The high-risk group of patients was guided to transplantation in first remission with the most appropriate available donor. Patients in the low-risk group were instructed to pursue transplantation if they relapsed.[61,77]

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

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63. Rubnitz JE, Inaba H, Dahl G, et al.: Minimal residual disease-directed therapy for childhood acute myeloid leukaemia: results of the AML02 multicentre trial. Lancet Oncol 11 (6): 543-52, 2010.
64. Tierens A, Bjørklund E, Siitonen S, et al.: Residual disease detected by flow cytometry is an independent predictor of survival in childhood acute myeloid leukaemia; results of the NOPHO-AML 2004 study. Br J Haematol 174 (4): 600-9, 2016.
65. Buonamici S, Ottaviani E, Testoni N, et al.: Real-time quantitation of minimal residual disease in inv(16)-positive acute myeloid leukemia may indicate risk for clinical relapse and may identify patients in a curable state. Blood 99 (2): 443-9, 2002.
66. Viehmann S, Teigler-Schlegel A, Bruch J, et al.: Monitoring of minimal residual disease (MRD) by real-time quantitative reverse transcription PCR (RQ-RT-PCR) in childhood acute myeloid leukemia with AML1/ETO rearrangement. Leukemia 17 (6): 1130-6, 2003.
67. Weisser M, Haferlach C, Hiddemann W, et al.: The quality of molecular response to chemotherapy is predictive for the outcome of AML1-ETO-positive AML and is independent of pretreatment risk factors. Leukemia 21 (6): 1177-82, 2007.
68. Krönke J, Schlenk RF, Jensen KO, et al.: Monitoring of minimal residual disease in NPM1-mutated acute myeloid leukemia: a study from the German-Austrian acute myeloid leukemia study group. J Clin Oncol 29 (19): 2709-16, 2011.
69. Corbacioglu A, Scholl C, Schlenk RF, et al.: Prognostic impact of minimal residual disease in CBFB-MYH11-positive acute myeloid leukemia. J Clin Oncol 28 (23): 3724-9, 2010.
70. Cloos J, Goemans BF, Hess CJ, et al.: Stability and prognostic influence of FLT3 mutations in paired initial and relapsed AML samples. Leukemia 20 (7): 1217-20, 2006.
71. Mandelli F, Diverio D, Avvisati G, et al.: Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto and Associazione Italiana di Ematologia ed Oncologia Pediatrica Cooperative Groups. Blood 90 (3): 1014-21, 1997.
72. Burnett AK, Grimwade D, Solomon E, et al.: Presenting white blood cell count and kinetics of molecular remission predict prognosis in acute promyelocytic leukemia treated with all-trans retinoic acid: result of the Randomized MRC Trial. Blood 93 (12): 4131-43, 1999.
73. Diverio D, Rossi V, Avvisati G, et al.: Early detection of relapse by prospective reverse transcriptase-polymerase chain reaction analysis of the PML/RARalpha fusion gene in patients with acute promyelocytic leukemia enrolled in the GIMEMA-AIEOP multicenter "AIDA" trial. GIMEMA-AIEOP Multicenter "AIDA" Trial. Blood 92 (3): 784-9, 1998.
74. Martinelli G, Ottaviani E, Testoni N, et al.: Disappearance of PML/RAR alpha acute promyelocytic leukemia-associated transcript during consolidation chemotherapy. Haematologica 83 (11): 985-8, 1998.
75. Webb DK, Wheatley K, Harrison G, et al.: Outcome for children with relapsed acute myeloid leukaemia following initial therapy in the Medical Research Council (MRC) AML 10 trial. MRC Childhood Leukaemia Working Party. Leukemia 13 (1): 25-31, 1999.
76. Tarlock K, Meshinchi S: Pediatric acute myeloid leukemia: biology and therapeutic implications of genomic variants. Pediatr Clin North Am 62 (1): 75-93, 2015.
77. Pui CH, Carroll WL, Meshinchi S, et al.: Biology, risk stratification, and therapy of pediatric acute leukemias: an update. J Clin Oncol 29 (5): 551-65, 2011.

Treatment of Childhood AML

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

Overall survival (OS) rates have improved over the past three decades for children with AML, with 5-year survival rates now in the 55% to 65% range.[1,2,3,4] Overall remission-induction rates are approximately 85% to 90%, and event-free survival (EFS) rates from the time of diagnosis are in the 45% to 55% range.[2,3,4,5] There is, however, a wide range in outcome for different biological subtypes of AML (refer to the Molecular Evaluation and Risk Classification Systems sections of this summary for more information); after taking specific biological factors of their leukemia into account, the predicted outcome for any individual patient may be much better or much worse than the overall outcome for the general population of children with AML.

Induction Therapy

Contemporary pediatric AML protocols result in 85% to 90% complete remission (CR) rates.[6,7,8] Approximately 2% to 3% of patients die during the induction phase, most often caused by treatment-related complications.[6,7,8,9] To achieve a CR, inducing profound bone marrow aplasia (with the exception of the M3 APL subtype) is usually necessary with currently used combination-chemotherapy regimens. Because induction chemotherapy produces severe myelosuppression, morbidity and mortality from infection or hemorrhage during the induction period may be significant.

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

1. Chemotherapy.
2. Antibody-drug conjugate therapy (e.g., gemtuzumab ozogamicin).
3. Targeted therapy (e.g., FLT3 inhibitors).
4. Supportive care.

Chemotherapy

The two most effective and essential drugs used to induce remission in children with AML are cytarabine and an anthracycline. Commonly used pediatric induction therapy regimens use cytarabine and an anthracycline in combination with other agents such as etoposide and/or thioguanine.[3,10,11]

Evidence (induction chemotherapy regimen):

1. The United Kingdom Medical Research Council (MRC) AML10 trial compared induction with cytarabine, daunorubicin, and etoposide (ADE) versus cytarabine and daunorubicin administered with thioguanine (DAT).[12]
   • The results showed 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 that induction with daunorubicin and cytarabine (DA) resulted in equivalent survival rates when compared with ADE induction.[13]

The anthracycline that has been most used in induction regimens for children with AML is daunorubicin,[3,10,11] although idarubicin and the anthracenedione mitoxantrone have also been used.[6,14,15] Randomized trials have attempted to determine whether any other anthracycline or anthracenedione is superior to daunorubicin as a component of induction therapy for children with AML. In the absence of convincing data that another anthracycline or mitoxantrone produces superior outcome over daunorubicin when given at an equitoxic dose, daunorubicin remains the anthracycline most commonly used during induction therapy for children with AML in the United States.

Evidence (anthracycline):

1. The German Berlin-Frankfurt-Münster (BFM) Group AML-BFM 93 study evaluated cytarabine plus etoposide with either daunorubicin or idarubicin (ADE or AIE).[11,14]
   • Similar EFS and 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 a similar regimen using daunorubicin (ADE).[6,16]
   • 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.[16]
   • Similar results were noted when analyses were restricted to pediatric patients.[6]
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.[17]
   • 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).

Evidence (reduced-anthracycline induction regimen):

1. 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. 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.[18]
   • 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).[19] The MRC has intensified induction therapy by prolonging the duration of cytarabine treatment to 10 days.[10]

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,[20] 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.[21] A second pediatric study also failed to detect a benefit for high-dose cytarabine over standard-dose cytarabine when used during induction therapy.[22]

Antibody-drug conjugate therapy

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.

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 a series of trials—AAML03P1 (NCT00070174), a pilot study, and AAML0531 (NCT00372593), a randomized trial—that examined the incorporation of gemtuzumab ozogamicin into induction therapy.[8,9]
   • 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 because of a reduction in postremission relapse overall and specifically in distinct subsets of patients. These subsets included patients with low-risk cytogenetics, patients with intermediate-risk AML who went on to receive stem cell transplantation (SCT) from a matched-related donor, and patients with high-risk AML (FLT3 internal tandem duplication [ITD] high-allelic ratio, >0.4) who then received a SCT from any donor.[23]
2. The characteristics of CD33, the target of gemtuzumab ozogamicin, have been examined to further identify the patients who will benefit most from this agent.
   • The expression intensity of CD33 on leukemic cells appeared to predict which patients benefited from gemtuzumab ozogamicin on the COG AAML0531 clinical trial.[24][Level of evidence: 1iiD] 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.
   • 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]
   • 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), and these patients 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). 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]
   • For patients with either a one or two allele C>T mutation (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).
3. A meta-analysis of five randomized clinical trials that evaluated gemtuzumab ozogamicin for adults with AML observed the following:[27]
   • 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 AML patients with 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 mutations was mixed; the French ALFA-0701 (NCT00927498) trial showed a trend towards a benefit, whereas the five-trial meta-analysis study did not find a benefit.[27,28] These trials did not examine the outcomes specifically for the combination of gemtuzumab ozogamicin followed by SCT, as was reported by the COG.[23]

Targeted therapy

Similar to antibody-drug conjugate therapy, the use of targeted therapy attempts to circumvent the severe toxicity of traditional chemotherapy by employing agents that target leukemia-specific mutations and/or their abnormal present or missing byproducts. As opposed to adult AML (except in APL as described in a later section), randomized clinical trials have not yet demonstrated that targeted therapies improve outcomes in children with newly diagnosed AML; therefore, targeted therapies have not been incorporated into the standard therapeutic induction regimens outside of clinical trials. 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 mutations in adult AML and adverse impact in AML patients 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.[29]

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 FLT3 ITD or TKD-mutated AML, 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 SCT.[30]
   • OS (the primary endpoint) was significantly better for patients who received midostaurin (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.63–0.96; P = .009), as was EFS (HR, 0.78; 95% CI, 0.66–0.93; P = .002).
   • This benefit was seen across all FLT3 subgroups regardless of whether allogeneic SCT was utilized 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 SCT or consolidation, and all patients had a subsequent midostaurin maintenance phase.[31]
   • In 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,[32] but there is no experience with midostaurin in children with newly diagnosed AML. (Refer to the Targeted therapy subsection in the Recurrent or Refractory Childhood AML and Other Myeloid Malignancies section of this summary for more information.)

Sorafenib

Sorafenib, another multikinase inhibitor, has been approved for the treatment of other malignancies but not AML, and has been evaluated for use in patients with de novo FLT3-mutated AML including children.

Sorafenib was evaluated in the COG AAML1031 (NCT01371981) study of pediatric patients with de novo high-allelic ratio FLT3 ITD AML. Patients received sorafenib with intensive chemotherapy, followed by allogeneic SCT and subsequent maintenance therapy with sorafenib alone. Eighty patients were evaluable and compared with historical controls from the COG AAML0531 trial. The CR rate after induction cycle II significantly improved (91% vs. 70%; P = .007), as did the 3-year EFS rate (57.5% vs. 34.3%; P = .007) and relapse risk after CR (18.2% vs. 52.5%; P = .006); however, the OS rate did not improve (63.9% vs. 54.1%; P = .375). Sorafenib was well tolerated in this young cohort, with no excess adverse events compared with the non-FLT3 ITD patients who received the same backbone therapy without sorafenib.[33]

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%.[34,35,36] Several approaches have been examined to reduce the morbidity and mortality from infection in children with AML.

Hematopoietic growth factors

Hematopoietic growth factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor (G-CSF) during AML induction therapy have been evaluated in multiple placebo-controlled studies in adults with AML in attempts to reduce the toxicity associated with prolonged myelosuppression.[7] 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 [37] but have not shown significant effects on treatment-related mortality or OS.[37] (Refer to the Treatment Option Overview for AML section in the PDQ summary on Adult Acute Myeloid Leukemia Treatment for more information.)

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

Evidence (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.[38]
2. A higher relapse rate has been reported for children with AML expressing the differentiation defective G-CSF receptor isoform IV.[39]

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 that the use of intravenous (IV) 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.[40]
2. The SJCRH results were confirmed in a subsequent study.[41]
3. A retrospective report from the COG AAML0531 (NCT00372593) trial demonstrated significant reductions in sterile-site bacterial infection and particularly gram-positive, sterile-site infections with the use of antibacterial prophylaxis.[42] This study also reported that prophylactic use of G-CSF reduced bacterial and Clostridium difficile infections.[42]
4. In a study that 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, a significant reduction in both variables was observed when compared with a historical control group that did not receive any prophylaxis.[43]
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 SCT. 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.[44]
   • 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.[45]

Antifungal prophylaxis

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

Evidence (antifungal prophylaxis):

1. Two meta-analysis reports have suggested that antifungal prophylaxis in pediatric patients with AML during treatment-induced neutropenia or during bone marrow transplantation reduces the frequency of invasive fungal infections and, in some instances, nonrelapse mortality.[46,47]
2. Several randomized trials in adults with AML have reported 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.[43,48,49,50,51,52]
3. 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).[53]
   • 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).

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.[54,55] 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 be an effective method of reducing the risk of cardiac dysfunction during therapy.[56]

Evidence (cardiac monitoring/dexrazoxane impact):

1. In the COG AAML0531 (NCT00372593) trial, 8.6% of enrolled patients experienced a reduction in left ventricular systolic dysfunction (LVSD) during protocol therapy, with a cumulative incidence of LVSD of 12% within 5 years of completing therapy.[54]
   • 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.[56]
   • 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.
   • Among the approximately 10% of children (96 of 1,014) who 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 RR 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 was the first to note a significant reduction in treatment-related mortality (19% before mandatory hospitalization was instituted in the trial along with other supportive care changes vs. 12% afterward); OS was also improved in this trial (P <.001).[3] Another analysis of the impact of hospitalization using a survey of institutional routine practice found that those who mandated hospitalization had nonsignificant reduction in patients' treatment-related mortality (adjusted HR, 0.60 [0.26–1.36, P = .22]) compared with institutions who had no set policy.[42] 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.[41]

Induction failure (refractory AML)

Induction failure (the morphologic presence of 5% or greater marrow blasts at the end of all induction courses) is seen in 10% to 15% of children with AML. Subsequent outcomes for patients with induction failure are similar to those for patients with AML who relapse early (<12 months after remission).[57,58]

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.[59] This incidence was also seen in the NOPHO-AML 2004 (NCT00476541) trial.[60]

Importantly, the patient who presents with an isolated tumor, without evidence of marrow involvement, must be treated as if there is systemic disease. Patients with isolated granulocytic sarcoma have a good prognosis if treated with current AML therapy.[59]

In a study of 1,459 children with newly diagnosed AML, patients with orbital granulocytic sarcoma and central nervous system (CNS) granulocytic sarcoma had better survival than did patients with marrow disease and granulocytic sarcoma at other sites and AML patients without any extramedullary disease.[60,61] Most patients with orbital granulocytic sarcoma have a t(8;21) abnormality, which has been associated with a favorable prognosis. The use of radiation therapy does not improve survival in patients with granulocytic sarcoma who have a complete response to chemotherapy, but may be necessary if the site(s) of granulocytic sarcoma do not show complete response to chemotherapy or for disease that recurs locally.[59]

Central Nervous System (CNS) Prophylaxis for AML

CNS involvement in patients with AML and its impact on prognosis has been discussed above in the Prognostic Factors in Childhood AML section of this summary. Therapy with either radiation or intrathecal chemotherapy has been used to treat CNS leukemia present at diagnosis and to prevent later development of CNS leukemia. The use of radiation has essentially been abandoned as a means of prophylaxis because of the lack of documented benefit and long-term sequelae.[62] The COG has used single-agent cytarabine for both CNS prophylaxis and therapy. Other groups have attempted to prevent CNS relapse by using additional intrathecal agents.

Evidence (CNS prophylaxis):

1. The COG AAML0531 (NCT00372593) trial used single-agent cytarabine for prophylaxis.[63]
   • As opposed to the low relapse rate associated with CNS1 disease (3.9%) seen in the 71% of enrolled patients, patients who had minimal evidence of CNS leukemia at diagnosis (CNS2 or blasts present when CSF WBC was <5 cells/HPF; 16% of newly diagnosed patients) were given twice-weekly intrathecal cytarabine until the CSF cleared. For the 96% of CNS2 patients whose CSF (95.8%) was cleared of leukemic blasts, 11.7% later experienced CNS relapse.
   • CNS3 involvement at diagnosis (13%) 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.[64]
   • 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 hematopoietic stem cell transplantation (HSCT).

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

1. Chemotherapy.
2. HSCT.
3. Targeted therapy (e.g., FLT3 inhibitors).[33]

Chemotherapy

Postremission chemotherapy includes some of the drugs used in induction while also introducing non–cross-resistant drugs and, commonly, high-dose cytarabine. Studies in adults with AML have demonstrated that consolidation with a high-dose cytarabine regimen improves outcome compared with consolidation with a standard-dose cytarabine regimen, particularly in patients with inv(16) and t(8;21) AML subtypes.[65] (Refer to the Adult AML in Remission section of the PDQ summary on Adult Acute Myeloid Leukemia Treatment for more information.) Randomized studies evaluating the contribution of high-dose cytarabine to postremission therapy have not been conducted in children, but studies employing historical controls suggest that consolidation with a high-dose cytarabine regimen improves outcome compared with less-intensive consolidation therapies.[11,66,67]

The optimal number of postremission courses of therapy remains unclear, but appears to require at least two to three courses of intensive therapy after induction.[3]

Evidence (number of postremission courses of chemotherapy):

1. A United Kingdom Medical Research Council (MRC) study randomly assigned adult and pediatric patients to either four or five courses of intensive therapy.[6,16][Level of evidence: 1iiA]
   • 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[68]
   • In a retrospective analysis, 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 or AAML03P1 trials; outcomes included inferior OS (HR, 1.83; 95% CI, 1.22–2.74; P = .003), inferior DFS (HR, 1.49; 95% CI, 1.13–1.97; P = .005), and higher cumulative risk of relapse (HR, 1.42; 95% CI, 1.08–1.88; P = .013).
   • 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 or AAML03P1).

   Additional study of the number of intensification courses and specific agents used will better address this issue, but 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 transplantation in children with AML suggest that overall, 60% to 70% of children with HLA-matched donors available who undergo allogeneic HSCT during their first remission experience long-term remissions,[10,69] with the caveat that outcome after allogeneic HSCT is dependent on risk-classification status.[70]

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.[10,69,71,72,73,74,75] However, the superiority of allogeneic HSCT over chemotherapy has not always been observed.[76] Several large cooperative group clinical trials for children with AML have found no benefit for autologous HSCT over intensive chemotherapy.[10,69,71,73]

Current application of allogeneic HSCT involves incorporation of risk classification to determine whether transplantation should be pursued in first remission. Because of the improved outcome in patients with favorable prognostic features (low-risk cytogenetic or molecular mutations) receiving contemporary chemotherapy regimens and the lack of demonstrable superiority for HSCT in this patient population, this group of patients typically receives matched-family donor (MFD) HSCT only after first relapse and the achievement of a second CR.[70,77,78,79]

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 mutations):

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 identified 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.[70] 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, as compared with results observed in more recent clinical trials.[6,17]
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 not a significant difference in OS.[80]
3. The AML-BFM 99 clinical trial demonstrated no significant difference in either DFS or OS for intermediate-risk patients assigned to MFD HSCT versus those assigned to chemotherapy.[76]

Given the improved outcome for patients with intermediate-risk AML in recent clinical trials and the burden of acute and chronic toxicities associated with allogeneic transplantation, many childhood AML treatment groups (including the COG) employ chemotherapy for intermediate-risk patients in first remission and reserve allogeneic HSCT for use after potential relapse.[6,80,81]

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

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

1. A retrospective analysis from the COG and Center for International Blood and Marrow Transplant Research (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.[82]
   • The analysis demonstrated no difference in the 5-year OS among the three treatment groups.
2. A Nordic Society for Pediatric Hematology and Oncology study reported that time-intensive reinduction therapy followed by transplant with best available donor for patients whose AML did not respond to induction therapy resulted in 70% survival at a median follow-up of 2.6 years.[83][Level of evidence: 2A]
3. A single-institution retrospective study of 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 morphologic first remission before allogeneic transplant.[84]
   • The investigators reported a 5-year OS rate of 72% and a leukemia-free survival 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 standard-risk AML patients who underwent transplantation during the same time period.
4. 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.[76]
5. For children with FLT3 ITD (high-allelic ratio), patients who received MFD HSCT (n = 6) had higher OS rates than did patients who received standard chemotherapy (n = 28); however, the number of cases studied limited the ability to draw conclusions.[85]
6. 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), whereas patients with low-allelic ratio did not (P = .64).[86]
7. A subset analysis of the COG phase III trial evaluated gemtuzumab ozogamicin during induction therapy in children with newly diagnosed AML.[23]
   • 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).

Many, but not all, pediatric clinical trial groups prescribe allogeneic HSCT for high-risk patients in first remission.[79] 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 and to refractory AML. This was based on results from their AML-BFM 98 study, which found no improvement in DFS or OS for high-risk patients receiving allogeneic HSCT in first CR, as well as the successful treatment using HSCT for a substantial proportion of patients who achieved a second CR.[76,87] 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.[76]

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

If transplant is chosen in first CR, the optimal preparative regimen and source of donor cells has not been determined, although alternative donor sources, including haploidentical donors, are being studied.[75,88,89] There are no data that suggest total-body irradiation (TBI) is superior to busulfan-based myeloablative regimens.[76,77] 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.[90]

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 that the former regimen was associated with less toxicity and comparable DFS and OS.[91]
2. In addition, a large prospective CIBMTR cohort study of children and adults with AML, myelodysplastic syndromes (MDS), and chronic myelogenous leukemia (CML) showed superior survival of patients with early-stage disease (chronic-phase CML, first CR AML, and MDS-refractory anemia) with busulfan-based regimens compared with TBI.[92]

Other than the APL subtype, there are no data that demonstrate that maintenance therapy given after intensive postremission therapy significantly prolongs remission duration. Maintenance chemotherapy failed to show benefit in two randomized studies that used modern intensive consolidation therapy,[66,93] and maintenance therapy with interleukin-2 also proved ineffective.[3]

Current Clinical Trials

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

Recurrent or Refractory Childhood AML and Other Myeloid Malignancies

The diagnosis of recurrent or relapsed AML according to COG criteria is essentially the same as the criteria for making the diagnosis of AML. Usually this is defined as patients having more than 5% bone marrow blasts who were in previous remission after therapy for a diagnosis of AML according to WHO classification criteria.[94,95]

Despite second remission induction in over one-half of children with AML treated with drugs similar to drugs used in initial induction therapy, the prognosis for a child with recurrent or progressive AML is generally poor.[57,96]

Recurrent childhood AML

Approximately 50% to 60% of relapses occur within the first year after diagnosis, with most relapses occurring by 4 years from diagnosis.[96] The vast majority of relapses occur in the bone marrow, and CNS relapse is very uncommon.[96]

Prognosis and prognostic factors

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

• Length of first remission. Length of first remission is an important factor affecting the ability to attain a second remission; children with a first remission of less than 1 year have substantially lower rates of second remission (50%–60%) than children whose first remission is greater than 1 year (70%–90%).[57,97,98] Survival for children with shorter first remissions is also substantially lower (approximately 10%) than that for children with first remissions exceeding 1 year (approximately 40%).[57,97,98,99] The Therapeutic Advances in Childhood Leukemia and Lymphoma Consortium also identified duration of previous remission as a powerful prognostic factor, with 5-year OS rates of 54% (± 10%) for patients with greater than 12 months first remission duration and 19% (± 6%) for patients with shorter periods of first remission.[100] In this same analysis, outcomes, primarily in early relapsing patients, declined with each attempt to reinduce remission (56% ± 5%, 25% ± 8%, and 17% ± 7% for each consecutive attempt).
• Molecular alterations. In addition, specific molecular alterations at the time of relapse have been reported to impact subsequent survival. For instance, the presence of either WT1 or FLT3 ITD mutations at first relapse were associated, as independent risk factors, with worse OS in patients achieving a second remission.[101]

Additional prognostic factors were identified in the following studies:

• In a report of 379 children with AML who relapsed after initial treatment on the German BFM group protocols, a second complete remission rate was 63% and the OS rate was 23%.[102][Level of evidence: 3iiiA] The most significant prognostic factors associated with a favorable outcome after relapse included achieving second complete remission, a relapse greater than 12 months from initial diagnosis, no allogeneic bone marrow transplant in first remission, and favorable cytogenetics (t(8;21), t(15;17), and inv(16)).
• The international Relapsed AML 2001/01 (NCT00186966) trial also found that early response to salvage therapy was highly prognostic.[103][Level of evidence: 3iiD]
• A retrospective study of 71 patients with relapsed AML from Japan reported a 5-year OS rate of 37%. Patients who had an early relapse had a 27% second remission rate compared with 88% for patients who had a late relapse. The 5-year OS rate was higher in patients who underwent HSCT after achieving a second complete remission (66%) than in patients not in remission (17%).[99]
• Patients who relapsed on two consecutive Nordic Society of Pediatric Hematology and Oncology (NOPHO) AML trials between 1993 to 2012 were analyzed for survival (208 patients relapsed of 543 children initially treated). Second remissions were achieved in 146 children (70%) with a variety of reinduction regimens. 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).[104]

Treatment of recurrent AML

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

1. Chemotherapy.
2. Antibody-drug conjugate therapy.
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.[57]
• Fludarabine and idarubicin.[105]
• L-asparaginase.[106]
• Etoposide.
• Liposomal daunorubicin. A study by the International BFM group compared fludarabine, cytarabine, and G-CSF (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 mutations (82%, FLAG plus liposomal daunorubicin vs. 58%, FLAG; P = .04).[107][Level of evidence: 1iiA]
• CPX-351. The liposomal combination agent CPX-351, which utilizes a fixed combination of daunorubicin and cytarabine, has been evaluated in the phase I/II COG trial AAML1421 (NCT02642965) 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/CRp/CRi response after the CPX-351 cycle, with 21 of 25 CR/CRp patients having no MRD after cycle 2, and 20 of 25 patients without MRD before HSCT.[108][Level of evidence: 2Div]
• Venetoclax. The 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. 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.

Regimens built upon clofarabine and[109,110,111][Level of evidence: 2Div] 2-chloroadenosine have been used.[112] The COG AAML0523 (NCT00372619) trial evaluated the combination of clofarabine plus high-dose cytarabine in patients with relapsed AML; the response rate was 48% and the OS rate, with 21 of 23 responders undergoing HSCT, was 46%. MRD before HSCT was a strong predictor of survival.[113][Level of evidence: 2Di]

The standard-dose cytarabine regimens used in the United Kingdom MRC AML10 study for newly diagnosed children with AML (cytarabine and daunorubicin plus either etoposide or thioguanine) have, when used in the setting of relapse, produced remission rates similar to those achieved with high-dose cytarabine regimens.[98] In a COG phase II study, the addition of bortezomib to idarubicin plus low-dose cytarabine resulted in an overall CR rate of 57%, and the addition of bortezomib to etoposide and high-dose cytarabine resulted in an overall CR rate of 48%.[114]

Antibody-drug conjugate therapy

Before its FDA approval for use in children with de novo AML in 2020, gemtuzumab ozogamicin was approved for children with relapsed or refractory AML in patients aged 2 years and older.

• The COG AAML00P2 (NCT00028899) study established the maximum tolerated dose of gemtuzumab ozogamicin, when combined with mitoxantrone and high-dose cytarabine, as 3 mg/m²; the maximum tolerated dose of gemtuzumab ozogamicin, when combined with Capizzi II based high-dose cytarabine, was 2 mg/m². These regimens produced an overall remission response rate of 45% (±15%), a 1-year EFS rate of 38% (±14%), and a 1-year OS rate of 53% (±15%). Sinusoidal occlusion syndrome was seen in one patient with a previous SCT during the cycle containing gemtuzumab ozogamicin and in 4 of 28 patients during subsequent SCT (grade 1 in two patients, grade 3 in 1 patient, and grade 4 in 1 patient), all of whom recovered.[58]
• 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 they 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. CR or CRp was seen in 37% of patients; nine patients subsequently underwent SCT, and three of these patients remained in continuous CR. All patients received prophylactic defibrotide during SCT without experiencing any sinusoidal occlusion syndrome.[115]
• 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 the relapsed adult AML setting.
  • 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 SCT.[116]
  • 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.[117] Fractionated gemtuzumab ozogamicin dosing has been shown to be safe and effective in adults with de novo AML;[28] 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 mutations) 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.[32]
  • Overall, 72.7% of patients experienced treatment-related adverse events, with only one patient experiencing a dose-limiting toxicity (grades 3–4 ALT elevation).
  • In patients with FLT3-mutated AML, 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 complete remission with incomplete count recovery who was able to proceed to SCT; this patient was the only long-term survivor in this study.
• 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. In relapsed or refractory AML, gilteritinib, a type 1 selective FLT3 inhibitor with activity against both FLT3 mutations (ITD and D835/I836 tyrosine kinase domain [TKD]), is the first and only FLT3 inhibitor that has received FDA approval for single-agent use in adults based on the ADMIRAL (NCT02421939) trial.[118]

HSCT

The selection of additional treatment after the achievement of a second complete remission depends on previous treatment and individual considerations. Consolidation chemotherapy followed by HSCT is conventionally recommended, although there are no controlled prospective data regarding the contribution of additional courses of therapy once a second complete remission is obtained.[96]

Evidence (HSCT after second complete remission):

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. This improved EFS after relapse or refractory disease was only seen in patients who received a SCT as part of their salvage therapy.[119]
2. Unrelated donor HSCT has been reported to result in 5-year probabilities of leukemia-free survival of 45%, 20%, and 12% for patients with AML transplanted in second complete remission, overt relapse, and primary induction failure, respectively.[120][Level of evidence: 3iiA]
3. A number of studies, including a large, prospective CIBMTR cohort study of children and adults with myeloid diseases, have shown similar or superior survival with busulfan-based regimens compared with TBI.[92,121,122]
4. Matched-sibling donor transplantation 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.[123] Umbilical cord outcomes are similar to other unrelated donor outcomes, but matching patients at a minimum of 7/8 alleles (HLA A, B, C, DRB1) leads to less nonrelapse mortality.[124] Haploidentical approaches are being used with increasing frequency and have shown comparable outcomes to other stem cell sources in pediatrics.[125] Direct comparison of haploidentical and other unrelated donor sources has not been performed in pediatrics, but studies in adults have shown similar outcomes.[126]
5. Reduced-intensity approaches have been used successfully in pediatrics, but mainly in children unable to undergo myeloablative approaches.[127] A randomized trial in adults showed superior outcomes with myeloablative approaches compared with reduced-intensity regimens.[128]

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. 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.[129,130,131]

CNS relapse

Isolated CNS relapse occurs in 3% to 6% of pediatric AML patients.[63,132,133] Factors associated with an increased risk of isolated CNS relapse include the following:[132]

• Age younger than 2 years at initial diagnosis.
• M5 leukemia.
• 11q23 abnormalities.
• CNS2 or CNS3 involvement at initial diagnosis.[63]

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).[63] 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%).[132] CNS relapse may also occur in the setting of bone marrow relapse and its likelihood increases with CNS involvement at diagnosis (CNS1: 2.7%, CNS2: 8.5%, CNS3: 9.2% incidence of concurrent CNS relapse, P < .001).[63]

Refractory childhood AML (induction failure)

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

1. Chemotherapy.
2. Gemtuzumab ozogamicin.

Like patients with relapsed AML, induction failure patients are typically directed towards HSCT once they attain a remission, because studies suggest a better EFS than in patients treated with chemotherapy only (31.2% vs. 5%, P < .0001). Attainment of morphologic CR for these patients is a significant prognostic factor for DFS after HSCT (46% vs. 0%; P = .02), with failure primarily resulting from relapse (relapse risk, 53.9% vs. 88.9%; P = .02).[134]

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

1. In the SJCRH trial AML02 (NCT00136084), 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 those patients with high residual MRD (1%–97%) after the first induction cycle.[135]
   • 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 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. In a phase II trial of gemtuzumab ozogamicin alone for children with relapsed/refractory AML failing previous reinduction attempts, 11 of 30 patients achieved a CR or partial CR, with a 27% versus 0% (P = .001) 3-year OS rate for responders versus nonresponders.[115]

Treatment options under clinical evaluation

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

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

1. AAML1831 (NCT04293562) (A Study to Compare Standard Chemotherapy to Therapy With CPX-351 and/or Gilteritinib for Patients With Newly Diagnosed AML With or Without FLT3 Mutations): This joint industry/COG study is a randomized trial examining whether the liposomal agent CPX-351, which contains daunomycin and cytarabine, improves EFS compared with standard daunomycin and cytarabine. An additional arm for patients with FLT3 ITD AML without favorable cytomolecular characteristics (NPM1 or CEBPA) evaluates the impact of the selective FLT3 inhibitor gilteritinib.

Current Clinical Trials

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

Current Clinical Trials

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

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Acute Promyelocytic Leukemia (APL)

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

• Clinical presentation of universal coagulopathy (disseminated intravascular coagulation) and unique morphologic characteristics (French-American-British [FAB] M3 or its variants).
• Unique molecular etiology as a result of the involvement of the RARA oncogene.
• Unique sensitivity to the differentiating agent tretinoin and to the proapoptotic agent arsenic trioxide.[1]

These unique features of APL mandate a high index of suspicion at diagnosis so as to initiate proper supportive care measures to avoid coagulopathic complications during the first days of therapy. It is also critical to institute a different induction regimen of therapy to minimize the risk of coagulopathic complications and to provide a much improved long-term relapse-free survival and overall survival (OS) than with past approaches to treating APL and compared with outcomes for patients with the other forms of AML.[2,3]

Molecular Abnormality

The characteristic chromosomal abnormality associated with APL is t(15;17). This translocation involves a breakpoint that includes the retinoic acid receptor and leads to production of the promyelocytic leukemia (PML)–retinoic acid receptor alpha (RARA) fusion protein.[1]

Patients with a suspected diagnosis of APL can have their diagnosis confirmed by detection of the PML-RARA fusion protein (e.g., through fluorescence in situ hybridization [FISH], reverse transcriptase–polymerase chain reaction [RT-PCR], or conventional cytogenetics). An immunofluorescence method using an anti-PML monoclonal antibody can rapidly establish the presence of the PML-RARA fusion protein based on the characteristic distribution pattern of PML that occurs in the presence of the fusion protein.[4,5,6]

Clinical Presentation

Clinically, APL is characterized by severe coagulopathy that is often present at the time of diagnosis.[7] This is typically manifested with thrombocytopenia, prolonged prothrombin time, partial thromboplastin time, elevated d-dimers, and hypofibrinogenemia.[8] Mortality during induction (particularly with cytotoxic agents used alone) caused by bleeding complications is more common in this subtype than in other FAB or World Health Organization (WHO) classifications.[9,10] A multicooperative group analysis of children with APL who were treated with tretinoin and chemotherapy reported that early induction coagulopathic deaths occurred in 25 of 683 children (3.7%); 23 deaths resulted from hemorrhage (19 CNS, 4 pulmonary), and 2 resulted from CNS thrombosis.[11] A lumbar puncture at diagnosis should not be performed until evidence of coagulopathy has resolved.

Tretinoin therapy is initiated as soon as APL is suspected on the basis of morphological and clinical presentation,[2,12] because tretinoin has been shown to ameliorate bleeding risk for patients with APL.[13] A retrospective analysis identified an increase in early death resulting from hemorrhage in patients with APL in whom tretinoin introduction was delayed.[8] Additionally, initiation of supportive measures such as replacement transfusions directed at correction of the coagulopathy is critical during these initial days of diagnosis and therapy. Patients at greatest risk of coagulopathic complications are those presenting with high white blood cell (WBC) counts, high body mass index, hypofibrinogenemia, molecular variants of APL, and the presence of FLT3 internal tandem duplication (ITD) mutations.[8,11]

APL in children is generally similar to APL in adults, although children have a higher incidence of hyperleukocytosis (defined as WBC count higher than 10 × 10⁹ /L) and a higher incidence of the microgranular morphologic subtype.[14,15,16,17] As in adults, children with WBC counts less than 10 × 10⁹ /L at diagnosis have significantly better outcomes than do patients with higher WBC counts.[15,16,18]

Risk Classification for Treatment Stratification

The prognostic significance of WBC count is used to define high-risk and low-risk patient populations and to assign postinduction treatment, with high-risk patients most commonly defined by WBC count of 10 × 10⁹ /L or greater.[19,20]FLT3 mutations (either ITD or tyrosine kinase domain [TKD] mutations) are observed in 40% to 50% of APL cases, with the presence of FLT3 mutations correlating with higher WBC counts and the microgranular variant (M3v) subtype.[21,22,23,24,25] The FLT3 mutation has been associated with an increased risk of induction death and, in some reports, an increased risk of treatment failure.[21,22,23,24,25,26,27]

In the COG AAML0631 (NCT00866918) trial, which included treatment with chemotherapy, tretinoin, and arsenic trioxide, risk classification primarily defined early death risk rather than relapse risk (standard risk, 0 of 66 patients vs. high risk, 4 of 35 patients). Relapse risk after remission induction was 4% overall, with one relapse in a standard-risk child and two relapses in high-risk children. High-risk patients on this trial had earlier initiation of idarubicin, with first dose on day 1 rather than day 3 to reduce leukemic burden more rapidly, and one additional consolidation chemotherapy (high-dose cytarabine and idarubicin) and tretinoin cycle.[28]

The Central Nervous System (CNS) and APL

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

Overall, CNS relapse is uncommon for patients with APL, particularly for those with WBC counts of less than 10 × 10⁹ /L.[29,30] In two clinical trials enrolling more than 1,400 adults with APL in which CNS prophylaxis was not administered, the cumulative incidence of CNS relapse was less than 1% for patients with WBC counts of less than 10 × 10⁹ /L, while it was approximately 5% for those with WBC counts of 10 × 10⁹ /L or greater.[29,30] In addition to high WBC counts at diagnosis, CNS hemorrhage during induction is also a risk factor for CNS relapse.[30] A review of published cases of pediatric APL also observed low rates of CNS relapse. Because of the low incidence of CNS relapse among children with APL presenting with WBC counts of less than 10 × 10⁹ /L, CNS surveillance and prophylactic CNS therapy may not be needed for this group of patients,[31] although there is no consensus on this topic.[32]

Treatment of APL

Modern treatment programs for APL are based on the sensitivity of leukemia cells from APL patients to the differentiation-inducing and apoptotic effects of tretinoin and arsenic trioxide. APL therapy first diverged from the therapy of other non-APL subtypes of AML with the addition of tretinoin to chemotherapy. With the incorporation of arsenic trioxide into modern treatment regimens, the use of traditional chemotherapy in adults is increasingly restricted to the induction phase for high-risk patients.[33,34]

Treatment options for children with APL may include the following:

1. Chemotherapy.
2. Tretinoin.
3. Arsenic trioxide.
4. Supportive care.

Given the very high level of activity for the combination of arsenic trioxide and tretinoin for adults with APL,[33,34] and given data indicating that children with APL have a similar response to these agents,[35,36,37,38,39,40] children with APL are often treated using the adult treatment regimens.

For patients with high-risk disease, the approach begins with induction therapy using tretinoin given in combination with an anthracycline, administered with or without arsenic trioxide. For patients with standard-risk disease, induction can include tretinoin and arsenic trioxide without cytotoxic chemotherapy. Results from a completed cooperative group trial (COG AAML1331 [NCT02339740]) are pending and will provide additional data about the efficacy and toxicity of arsenic trioxide and tretinoin for children with newly diagnosed APL. The dramatic efficacy of tretinoin against APL results from the ability of pharmacologic doses of tretinoin to overcome the repression of signaling caused by the PML-RARA fusion protein at physiologic tretinoin concentrations. Restoration of signaling leads to differentiation of APL cells and then to postmaturation apoptosis.[41] Most patients with APL achieve a complete remission (CR) when treated with tretinoin, although single-agent tretinoin is generally not curative.[42,43]

A series of randomized clinical trials defined the benefit of combining tretinoin with chemotherapy during induction therapy and the utility of using tretinoin as maintenance therapy.[44,45,46] One regimen uses tretinoin in conjunction with standard-dose cytarabine and daunorubicin,[14,47] while another uses idarubicin and tretinoin without cytarabine for remission induction.[15,16] Almost all children with APL treated with one of these approaches achieves CR in the absence of coagulopathy-related mortality.[15,16,47,48,49]

Assessment of response to induction therapy in the first month of treatment using morphologic and molecular criteria may provide misleading results because delayed persistence of differentiating leukemia cells can occur in patients who will ultimately achieve CR.[2,3] Alterations in planned treatment based on these early observations are not appropriate because resistance of APL to tretinoin plus anthracycline-containing regimens is extremely rare.[20,50]

For patients with standard-risk APL, consolidation may include repeated cycles of tretinoin and arsenic trioxide without further chemotherapy, based on the adult experience.[33,34] However, for high-risk APL, consolidation therapy has typically included tretinoin given with an anthracycline with or without cytarabine. The role of cytarabine in consolidation therapy regimens is controversial. While a randomized study addressing the contribution of cytarabine to a daunorubicin-plus-tretinoin regimen in adults with low-risk APL showed a benefit for the addition of cytarabine,[51] regimens using a high-dose anthracycline appear to produce as good as or better results in low-risk patients.[52] For high-risk patients (WBC ≥10 × 10⁹ /L), a historical comparison of the Programa para el Tratamiento de Hemopatías Malignas (PETHEMA) LPA 2005 (NCT00408278) trial with the preceding LPA 99 (NCT00465933) trial suggested that the addition of cytarabine to anthracycline-tretinoin combinations can lower the relapse rate.[50] The results of the AIDA 2000 (NCT00180128) trial confirmed that the cumulative incidence of relapse for adult patients with high-risk disease can be reduced to approximately 10% with consolidation regimens that contain tretinoin, anthracyclines, and cytarabine.[20] Studies using arsenic trioxide–based consolidation have demonstrated excellent survival without cytarabine consolidation.[26,33,53]

Maintenance therapy includes tretinoin plus mercaptopurine and methotrexate; this combination has shown conflicting benefit, with some randomized trials in adults with APL showing an advantage over tretinoin alone [44,54] and other studies showing no benefit.[33,55,56] However, the utility of maintenance therapy in APL may be dependent on multiple factors (e.g., risk group, the anthracycline used during induction, the use of arsenic trioxide, and the intensity of induction and consolidation therapy).

At this time, maintenance therapy remains standard for children with high-risk APL. Maintenance therapy is likely unnecessary for patients with standard-risk APL who are treated with tretinoin and arsenic trioxide, based on data from adult trials. Because of the favorable outcomes observed with chemotherapy plus tretinoin and arsenic trioxide (event-free survival [EFS] rates of 70%–90%), hematopoietic stem cell transplantation is not recommended in first CR.

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

Evidence (arsenic trioxide therapy):

1. In adults with newly diagnosed APL treated on the CALGB-C9710 (NCT00003934) trial, the addition of two consolidation courses of arsenic trioxide to a standard APL treatment regimen resulted in the following:[53]
   • A significant improvement in EFS (80% vs. 63% at 3 years; P < .0001) and disease-free survival (DFS) rates (90% vs. 70% at 3 years; P < .0001), although the outcome of patients who did not receive arsenic trioxide was inferior to the results obtained in the Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) or PETHEMA trials.
2. In children and adolescents with newly diagnosed APL treated on the COG AAML0631 (NCT00866918) trial, two consolidation cycles of arsenic trioxide were incorporated into a chemotherapy regimen with lower cumulative anthracycline doses compared with historical controls.[28]
   • The 3-year OS rate was 94%, and the EFS rate was 91%.
   • Patients with standard-risk APL had an OS rate of 98% and an EFS rate of 95%.
   • High-risk patients had an OS rate of 86% and an EFS rate of 83%. This lower survival compared with standard-risk patients was primarily caused by early death events.
   • The relapse risk after arsenic trioxide consolidation was 4% and was similar for standard-risk and high-risk APL.
3. The concurrent use of arsenic trioxide and tretinoin in newly diagnosed patients with APL results in high rates of CR.[57,58,59] Early experience in children with newly diagnosed APL also shows high rates of CR to arsenic trioxide, either as a single agent or given with tretinoin.[37][Level of evidence: 3iiA]
   • Results of a meta-analysis of seven published studies in adult APL patients suggest that the combination of arsenic trioxide and tretinoin may be more effective than arsenic trioxide alone in inducing CR.[60]
   • The impact of arsenic induction (either alone or with tretinoin) on EFS and OS has not been well characterized in children, although early results appear promising.[35,36,37]
4. Arsenic trioxide was evaluated as a component of induction therapy with idarubicin and tretinoin in the APML4 clinical trial, which enrolled both children and adults (N = 124 evaluable patients).[26] Patients received two courses of consolidation therapy with arsenic trioxide and tretinoin (but no anthracycline) and maintenance therapy with tretinoin, mercaptopurine, and methotrexate.[61]
   • The 2-year freedom-from-relapse rate was 97.5%, the failure-free survival (FFS) rate was 88.1%, and the OS rate was 93.2%.
   • These outcome results are superior to those reported for patients who did not receive arsenic trioxide in the predecessor clinical trial (APML3).
5. A German and Italian phase III clinical trial (APL0406 [NCT00482833]) compared tretinoin plus chemotherapy with tretinoin plus arsenic trioxide in adults with APL classified as low to intermediate risk (WBC ≤10 × 10⁹ /L).[33] Patients were randomly assigned to receive either tretinoin plus arsenic trioxide for induction and consolidation therapy or standard tretinoin-idarubicin induction therapy followed by three cycles of consolidation therapy with tretinoin plus chemotherapy and maintenance therapy with low-dose chemotherapy and tretinoin.
   • All patients who received tretinoin plus arsenic trioxide (n = 77) achieved CR at the end of induction therapy, while 95% of patients who received tretinoin plus chemotherapy (n = 79) achieved CR.
   • EFS rates were 97% in the tretinoin-arsenic trioxide group compared with 86% in the tretinoin-chemotherapy group (P = .02).
   • Two-year OS probability was 99% (95% confidence interval [CI], 96%–100%) in the tretinoin-arsenic trioxide group and 91% (95% CI, 85%–97%) in the tretinoin-chemotherapy group (P = .02).
   • An updated longer-term analysis demonstrated that at 50 months, the tretinoin-arsenic trioxide arm showed even greater superiority, with OS rates of 97% versus 80% (P < .001).[33,34]
   • These results indicate that low-risk to intermediate-risk APL is curable for a high percentage of patients without conventional chemotherapy.

Numerous trials showed that for children with APL, survival rates exceeding 80% are now achievable using treatment programs that prescribe the rapid initiation of tretinoin with appropriate supportive care measures;[2,14,15,16,19,20,48,49] a rate exceeding 90% was demonstrated in a single trial that added arsenic trioxide to the treatment regimen.[28] For patients in CR for more than 5 years, relapse is extremely rare.[62][Level of evidence: 1iiDi]

Treatment options under clinical evaluation

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

Complications unique to APL therapy

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

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

  The incidence of pseudotumor cerebri has been reported to be as low as 1.7% with very strict definitions of the complication and as high as 6% to 16% in three pediatric trials.[14,15,28,63] Pseudotumor cerebri is thought to be more prevalent in children receiving tretinoin, leading to lower dosing in contemporary pediatric APL clinical trials.[14] Pseudotumor cerebri most typically occurs during induction at a median of 15 days (range, 1–35 days) after starting tretinoin, but is known to occur in other phases of therapy as well.[63] Pseudotumor cerebri incidence and severity may be exacerbated with the concurrent use of azoles via inhibition of cytochrome P450 metabolism of tretinoin.

  When a diagnosis of pseudotumor cerebri is suspected, tretinoin is held until symptoms abate and then is slowly escalated to full dose as tolerated.[63]

• Differentiation syndrome. Differentiation syndrome (also known as retinoic acid syndrome or tretinoin syndrome) is a life-threatening syndrome thought to be an inflammatory response–mediated syndrome manifested by weight gain, fever, edema, pulmonary infiltrates, pleuro-pericardial effusions, hypotension, and, in the most severe cases, acute renal failure.[64] In the contemporary COG AAML0631 (NCT00866918) study, it was present in 20% of patients during induction and was more prevalent in high-risk children (31%) than in low-risk children (13%), a risk factor also seen in adults with APL.[28,65] There is a bimodal peak with this syndrome seen in the first and third weeks of induction therapy.

  Because of the increased incidence in high-risk patients, dexamethasone is given with tretinoin and/or arsenic therapy to prevent this complication in this subset of patients.[64] Prophylaxis with dexamethasone and hydroxyurea (for cytoreduction) is also administered to standard-risk patients if their WBC count rises to greater than 10,000/uL after the start of tretinoin or arsenic. If differentiation syndrome occurs, the dexamethasone dose may be escalated with temporary holding of tretinoin and arsenic trioxide and, similar to pseudotumor cerebri, restarted at a lower dose with plans to escalate as tolerated.

• Coagulopathy. Along with differentiation syndrome, coagulopathy complications result in a higher risk of death during induction (early death in APL). APL blasts induce coagulopathy by activation of the coagulation cascade (caused by the expression of tissue factor and other procoagulants) with concomitant increase in primary and secondary fibrinolysis resulting from expression of annexin II on the APL blasts. Risk of death caused by coagulopathy is associated with an elevated WBC count, decreased platelet count, and abnormal coagulation studies (fibrinogen, prothrombin time).[12] Studies of both adult and pediatric patients have demonstrated that scoring systems using clinical characteristics and laboratory values can help predict the risk of developing severe or lethal coagulopathy.[66,67] Aggressive supportive care to correct coagulopathy, even before clinical signs and symptoms of bleeding or thrombosis occur, is important to prevent early death.
• QT interval prolongation. Arsenic trioxide is associated with QT interval prolongation that can lead to life-threatening arrhythmias (e.g., torsades de pointes).[68] It is essential to monitor electrolytes closely in patients receiving arsenic trioxide and to maintain potassium and magnesium values at midnormal ranges, as well as to be cognizant of other agents known to prolong the QT interval.[69]

Minimal disease monitoring

The induction and consolidation therapies currently employed result in molecular remission, as measured by RT-PCR for PML-RARA, in most APL patients, with 1% or fewer showing molecular evidence of disease at the end of consolidation therapy.[20,50] While two negative RT-PCR assays after completion of therapy are associated with long-term remission,[70] conversion from negative to positive RT-PCR is highly predictive of subsequent hematologic relapse.[71]

Patients with persistent or relapsing disease on the basis of PML-RARA RT-PCR measurement may benefit from intervention with relapse therapies [72,73] (refer to the Treatment of Recurrent Acute Promyelocytic Leukemia [APL] subsection of the Recurrent or Refractory Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies section of this summary for more information).

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

Uncommon molecular variants of APL produce fusion proteins that join distinctive gene partners (e.g., PLZF, NPM, STAT5B, and NuMA) to RARA.[74,75] Recognition of these rare variants is important because they differ in their sensitivity to tretinoin and to arsenic trioxide.[76]

• PLZF-RARA variant. The PLZF-RARA variant, characterized by t(11;17)(q23;q21), represents about 0.8% of APL, expresses surface CD56, and has very fine granules compared with t(15;17) APL.[77,78,79] APL with PLZF-RARA has been associated with a poor prognosis and does not usually respond to tretinoin or arsenic trioxide.[76,77,78,79]
• NPM-RARA or NuMA-RARA variant. The rare APL variants with NPM-RARA (t(5;17)(q35;q21)) or NuMA-RARA (t(11;17)(q13;q21)) translocations may still be responsive to tretinoin.[76,80,81,82,83]

Treatment of Recurrent APL

Historically, 10% to 20% of patients with APL relapse; however, more current studies that incorporated arsenic trioxide therapy showed cumulative incidence of relapse of less than 5%.[28,34]

In patients who initially received chemotherapy-based treatments, the duration of first remission is prognostic in APL, with patients who relapse within 12 to 18 months of initial diagnosis having a worse outcome.[84,85,86]

An important issue in children who relapse is the previous exposure to anthracyclines, which can range from 400 mg/m² to 750 mg/m².[2] Thus, regimens containing anthracyclines are often not optimal for children with APL who suffer relapse.

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

1. Arsenic trioxide or tretinoin.
2. Gemtuzumab ozogamicin.
3. Hematopoietic stem cell transplantation (HSCT).

Arsenic trioxide

For children with recurrent APL, the use of arsenic trioxide as a single agent or in regimens including tretinoin should be considered, depending on the therapy given during first remission. Arsenic trioxide is an active agent in patients with recurrent APL, with approximately 85% of patients achieving remission after treatment with this agent.[55,57,87,88,89] Arsenic trioxide is even capable of inducing remissions in patients who relapse after having received arsenic trioxide during initial therapy.[90] APL cells, however, may become resistant to arsenic trioxide through mechanisms including mutation of the PML domain of the PML-RARA fusion oncogene.[91]

For adults with relapsed APL, approximately 85% achieve morphologic remission after treatment with arsenic trioxide.[88,89,92] Data are limited on the use of arsenic trioxide in children, although published reports suggest that children with relapsed APL have a response to arsenic trioxide similar to that of adults.[87,89,93] Arsenic trioxide is well tolerated in children with relapsed APL. The toxicity profile and response rates in children are similar to that observed in adults.[87]

Because arsenic trioxide causes QT-interval prolongation that can lead to life-threatening arrhythmias,[68] it is essential to monitor electrolytes closely in patients receiving arsenic trioxide and to maintain potassium and magnesium values at midnormal ranges.[69]

Gemtuzumab ozogamicin

The use of gemtuzumab ozogamicin, an anti-CD33/calicheamicin monoclonal antibody, as a single agent resulted in a 91% (9 of 11 patients) molecular remission after two doses and a 100% (13 of 13 patients) molecular remission after three doses, thus, demonstrating excellent activity of this agent in patients with relapsed APL.[94]

HSCT

Retrospective pediatric studies have reported 5-year EFS rates after either autologous or allogeneic transplantation approaches to be similar, at approximately 70%.[95,96]

Evidence (autologous HSCT):

1. When considering autologous transplantation, a study in adult patients demonstrated improved 7-year EFS rates (77% vs. 50%) when both the patient and the stem cell product had negative promyelocytic leukemia/retinoic acid receptor alpha fusion transcript by polymerase chain reaction (molecular remission) before transplant.[97]
2. Another study demonstrated that among seven patients undergoing autologous HSCT and whose cells were MRD positive, all relapsed in less than 9 months after transplantation; however, only one of eight patients whose autologous donor cells were MRD negative relapsed.[98]
3. Another report demonstrated that the 5-year EFS rate was 83.3% for patients who underwent autologous HSCT in second molecular remission and was 34.5% for patients who received only maintenance therapy.[99]

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

Because of the rarity of APL in children and the favorable outcome for this disease, clinical trials in relapsed APL to compare treatment approaches are likely not feasible. However, an international expert panel provided recommendations for the treatment of relapsed APL on the basis of the reported pediatric and adult experience.[100]

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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34. Platzbecker U, Avvisati G, Cicconi L, et al.: Improved Outcomes With Retinoic Acid and Arsenic Trioxide Compared With Retinoic Acid and Chemotherapy in Non-High-Risk Acute Promyelocytic Leukemia: Final Results of the Randomized Italian-German APL0406 Trial. J Clin Oncol 35 (6): 605-612, 2017.
35. Zhang L, Zhao H, Zhu X, et al.: Retrospective analysis of 65 Chinese children with acute promyelocytic leukemia: a single center experience. Pediatr Blood Cancer 51 (2): 210-5, 2008.
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38. Creutzig U, Dworzak MN, Bochennek K, et al.: First experience of the AML-Berlin-Frankfurt-Münster group in pediatric patients with standard-risk acute promyelocytic leukemia treated with arsenic trioxide and all-trans retinoid acid. Pediatr Blood Cancer 64 (8): , 2017.
39. Yang MH, Wan WQ, Luo JS, et al.: Multicenter randomized trial of arsenic trioxide and Realgar-Indigo naturalis formula in pediatric patients with acute promyelocytic leukemia: Interim results of the SCCLG-APL clinical study. Am J Hematol 93 (12): 1467-1473, 2018.
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54. Sanz M, Martínez JA, Barragán E, et al.: All-trans retinoic acid and low-dose chemotherapy for acute promyelocytic leukaemia. Br J Haematol 109 (4): 896-7, 2000.
55. Avvisati G, Lo-Coco F, Paoloni FP, et al.: AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance. Blood 117 (18): 4716-25, 2011.
56. Powell BL, Moser BK, Stock W, et al.: Adding mercaptopurine and methotrexate to alternate week ATRA maintenance therapy does not improve the outcome for adults with acute promyelocytic leukemia (APL) in first remission: results from North American Leukemia Intergroup Trial C9710. [Abstract] Blood 118 (21): A-258, 2011. Also available online. Last accessed March 25, 2020.
57. Shen ZX, Shi ZZ, Fang J, et al.: All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A 101 (15): 5328-35, 2004.
58. Ravandi F, Estey E, Jones D, et al.: Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol 27 (4): 504-10, 2009.
59. Hu J, Liu YF, Wu CF, et al.: Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A 106 (9): 3342-7, 2009.
60. Wang H, Chen XY, Wang BS, et al.: The efficacy and safety of arsenic trioxide with or without all-trans retinoic acid for the treatment of acute promyelocytic leukemia: a meta-analysis. Leuk Res 35 (9): 1170-7, 2011.
61. Iland HJ, Collins M, Bradstock K, et al.: Use of arsenic trioxide in remission induction and consolidation therapy for acute promyelocytic leukaemia in the Australasian Leukaemia and Lymphoma Group (ALLG) APML4 study: a non-randomised phase 2 trial. Lancet Haematol 2 (9): e357-66, 2015.
62. Douer D, Zickl LN, Schiffer CA, et al.: All-trans retinoic acid and late relapses in acute promyelocytic leukemia: very long-term follow-up of the North American Intergroup Study I0129. Leuk Res 37 (7): 795-801, 2013.
63. Coombs CC, DeAngelis LM, Feusner JH, et al.: Pseudotumor Cerebri in Acute Promyelocytic Leukemia Patients on Intergroup Protocol 0129: Clinical Description and Recommendations for New Diagnostic Criteria. Clin Lymphoma Myeloma Leuk 16 (3): 146-51, 2016.
64. Sanz MA, Montesinos P: How we prevent and treat differentiation syndrome in patients with acute promyelocytic leukemia. Blood 123 (18): 2777-82, 2014.
65. Montesinos P, Bergua JM, Vellenga E, et al.: Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors. Blood 113 (4): 775-83, 2009.
66. Mitrovic M, Suvajdzic N, Bogdanovic A, et al.: International Society of Thrombosis and Hemostasis Scoring System for disseminated intravascular coagulation ≥ 6: a new predictor of hemorrhagic early death in acute promyelocytic leukemia. Med Oncol 30 (1): 478, 2013.
67. Rajpurkar M, Alonzo TA, Wang YC, et al.: Risk Markers for Significant Bleeding and Thrombosis in Pediatric Acute Promyelocytic Leukemia; Report From the Children's Oncology Group Study AAML0631. J Pediatr Hematol Oncol 41 (1): 51-55, 2019.
68. Unnikrishnan D, Dutcher JP, Varshneya N, et al.: Torsades de pointes in 3 patients with leukemia treated with arsenic trioxide. Blood 97 (5): 1514-6, 2001.
69. Barbey JT: Cardiac toxicity of arsenic trioxide. Blood 98 (5): 1632; discussion 1633-4, 2001.
70. Jurcic JG, Nimer SD, Scheinberg DA, et al.: Prognostic significance of minimal residual disease detection and PML/RAR-alpha isoform type: long-term follow-up in acute promyelocytic leukemia. Blood 98 (9): 2651-6, 2001.
71. Diverio D, Rossi V, Avvisati G, et al.: Early detection of relapse by prospective reverse transcriptase-polymerase chain reaction analysis of the PML/RARalpha fusion gene in patients with acute promyelocytic leukemia enrolled in the GIMEMA-AIEOP multicenter "AIDA" trial. GIMEMA-AIEOP Multicenter "AIDA" Trial. Blood 92 (3): 784-9, 1998.
72. Lo Coco F, Diverio D, Avvisati G, et al.: Therapy of molecular relapse in acute promyelocytic leukemia. Blood 94 (7): 2225-9, 1999.
73. Esteve J, Escoda L, Martín G, et al.: Outcome of patients with acute promyelocytic leukemia failing to front-line treatment with all-trans retinoic acid and anthracycline-based chemotherapy (PETHEMA protocols LPA96 and LPA99): benefit of an early intervention. Leukemia 21 (3): 446-52, 2007.
74. Zelent A, Guidez F, Melnick A, et al.: Translocations of the RARalpha gene in acute promyelocytic leukemia. Oncogene 20 (49): 7186-203, 2001.
75. Yan W, Zhang G: Molecular Characteristics and Clinical Significance of 12 Fusion Genes in Acute Promyelocytic Leukemia: A Systematic Review. Acta Haematol 136 (1): 1-15, 2016.
76. Rego EM, Ruggero D, Tribioli C, et al.: Leukemia with distinct phenotypes in transgenic mice expressing PML/RAR alpha, PLZF/RAR alpha or NPM/RAR alpha. Oncogene 25 (13): 1974-9, 2006.
77. Licht JD, Chomienne C, Goy A, et al.: Clinical and molecular characterization of a rare syndrome of acute promyelocytic leukemia associated with translocation (11;17). Blood 85 (4): 1083-94, 1995.
78. Guidez F, Ivins S, Zhu J, et al.: Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML- and PLZF-RARalpha underlie molecular pathogenesis and treatment of acute promyelocytic leukemia. Blood 91 (8): 2634-42, 1998.
79. Grimwade D, Biondi A, Mozziconacci MJ, et al.: Characterization of acute promyelocytic leukemia cases lacking the classic t(15;17): results of the European Working Party. Groupe Français de Cytogénétique Hématologique, Groupe de Français d'Hematologie Cellulaire, UK Cancer Cytogenetics Group and BIOMED 1 European Community-Concerted Action "Molecular Cytogenetic Diagnosis in Haematological Malignancies". Blood 96 (4): 1297-308, 2000.
80. Sukhai MA, Wu X, Xuan Y, et al.: Myeloid leukemia with promyelocytic features in transgenic mice expressing hCG-NuMA-RARalpha. Oncogene 23 (3): 665-78, 2004.
81. Redner RL, Corey SJ, Rush EA: Differentiation of t(5;17) variant acute promyelocytic leukemic blasts by all-trans retinoic acid. Leukemia 11 (7): 1014-6, 1997.
82. Wells RA, Catzavelos C, Kamel-Reid S: Fusion of retinoic acid receptor alpha to NuMA, the nuclear mitotic apparatus protein, by a variant translocation in acute promyelocytic leukaemia. Nat Genet 17 (1): 109-13, 1997.
83. Wells RA, Hummel JL, De Koven A, et al.: A new variant translocation in acute promyelocytic leukaemia: molecular characterization and clinical correlation. Leukemia 10 (4): 735-40, 1996.
84. Marjerrison S, Antillon F, Bonilla M, et al.: Outcome of children treated for relapsed acute myeloid leukemia in Central America. Pediatr Blood Cancer 61 (7): 1222-6, 2014.
85. Lengfelder E, Lo-Coco F, Ades L, et al.: Arsenic trioxide-based therapy of relapsed acute promyelocytic leukemia: registry results from the European LeukemiaNet. Leukemia 29 (5): 1084-91, 2015.
86. Holter Chakrabarty JL, Rubinger M, Le-Rademacher J, et al.: Autologous is superior to allogeneic hematopoietic cell transplantation for acute promyelocytic leukemia in second complete remission. Biol Blood Marrow Transplant 20 (7): 1021-5, 2014.
87. Fox E, Razzouk BI, Widemann BC, et al.: Phase 1 trial and pharmacokinetic study of arsenic trioxide in children and adolescents with refractory or relapsed acute leukemia, including acute promyelocytic leukemia or lymphoma. Blood 111 (2): 566-73, 2008.
88. Niu C, Yan H, Yu T, et al.: Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood 94 (10): 3315-24, 1999.
89. Shen ZX, Chen GQ, Ni JH, et al.: Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood 89 (9): 3354-60, 1997.
90. Lu J, Huang X, Bao L, et al.: Treatment outcomes in relapsed acute promyelocytic leukemia patients initially treated with all-trans retinoic acid and arsenic compound-based combined therapies. Oncol Lett 7 (1): 177-182, 2014.
91. Zhu HH, Qin YZ, Huang XJ: Resistance to arsenic therapy in acute promyelocytic leukemia. N Engl J Med 370 (19): 1864-6, 2014.
92. Soignet SL, Maslak P, Wang ZG, et al.: Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med 339 (19): 1341-8, 1998.
93. Zhang P: The use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia. J Biol Regul Homeost Agents 13 (4): 195-200, 1999 Oct-Dec.
94. Lo-Coco F, Cimino G, Breccia M, et al.: Gemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acute promyelocytic leukemia. Blood 104 (7): 1995-9, 2004.
95. Dvorak CC, Agarwal R, Dahl GV, et al.: Hematopoietic stem cell transplant for pediatric acute promyelocytic leukemia. Biol Blood Marrow Transplant 14 (7): 824-30, 2008.
96. Bourquin JP, Thornley I, Neuberg D, et al.: Favorable outcome of allogeneic hematopoietic stem cell transplantation for relapsed or refractory acute promyelocytic leukemia in childhood. Bone Marrow Transplant 34 (9): 795-8, 2004.
97. de Botton S, Fawaz A, Chevret S, et al.: Autologous and allogeneic stem-cell transplantation as salvage treatment of acute promyelocytic leukemia initially treated with all-trans-retinoic acid: a retrospective analysis of the European acute promyelocytic leukemia group. J Clin Oncol 23 (1): 120-6, 2005.
98. Meloni G, Diverio D, Vignetti M, et al.: Autologous bone marrow transplantation for acute promyelocytic leukemia in second remission: prognostic relevance of pretransplant minimal residual disease assessment by reverse-transcription polymerase chain reaction of the PML/RAR alpha fusion gene. Blood 90 (3): 1321-5, 1997.
99. Thirugnanam R, George B, Chendamarai E, et al.: Comparison of clinical outcomes of patients with relapsed acute promyelocytic leukemia induced with arsenic trioxide and consolidated with either an autologous stem cell transplant or an arsenic trioxide-based regimen. Biol Blood Marrow Transplant 15 (11): 1479-84, 2009.
100. Abla O, Kutny MA, Testi AM, et al.: Management of relapsed and refractory childhood acute promyelocytic leukaemia: recommendations from an international expert panel. Br J Haematol 175 (4): 588-601, 2016.

Myeloid Proliferations Associated With Down Syndrome

Transient Abnormal Myelopoiesis (TAM) Associated With Down Syndrome

Approximately 10% of neonates with Down syndrome develop a TAM (also termed transient myeloproliferative disorder [TMD]).[1] This disorder mimics congenital AML but typically improves spontaneously within the first 3 months of life (median, 49 days), although TAM has been reported to remit as late as 20 months.[2] The late remissions likely reflect a persistent hepatomegaly from TAM-associated hepatic fibrosis rather than active disease.[3]

Although TAM is usually a self-resolving condition, it can be associated with significant morbidity and may be fatal in 10% to 17% of affected infants.[2,3,4,5,6] Infants with progressive organomegaly, visceral effusions, preterm delivery (less than 37 weeks of gestation), bleeding diatheses, failure of spontaneous remission, laboratory evidence of progressive liver dysfunction (elevated direct bilirubin), renal failure, and very high white blood cell (WBC) count are at particularly high risk of early mortality.[3,4,6] Death has been reported to occur in 21% of these patients with high-risk TAM, although only 10% were attributable to TAM and the remaining deaths were caused by coexisting conditions known to be more prominent in neonates with Down syndrome.[3]

The following three risk groups have been identified on the basis of the diagnostic clinical findings of hepatomegaly with or without life-threatening symptoms:[3]

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

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

• Exchange transfusion.
• Leukapheresis.
• Low-dose cytarabine. Of these approaches, only cytarabine has been shown to consistently reduce TAM complications and related mortality.[3,6]; [7][Level of evidence: 2Di] Cytarabine dosing has ranged from 0.4 to 1.5 mg/kg per dose given intravenously (IV) or subcutaneously (SC) once to twice daily for 4 to 12 days,[6] with similar efficacies and less toxicity than higher, continuous 5-day infusions, which led to prolonged severe neutropenia.[3] A prospective trial that utilized cytarabine at 1.5 mg/kg per day IV or SC for 7 days for symptomatic patients reported a significant reduction in early death compared with similar historical controls (12% ± 5% vs. 33% ± 7%, respectively; P = .2).[7][Level of evidence: 2Di]

Subsequent development of myeloid leukemia associated with Down syndrome is seen in 10% to 30% of children who have a spontaneous remission of TAM and has been reported at a mean age of 16 months (range, 1–30 months).[2,3,8] While TAM is generally not characterized by cytogenetic abnormalities other than trisomy 21, the presence of additional cytogenetic findings may connote an increased risk of developing subsequent myeloid leukemia associated with Down syndrome.[4] An additional risk factor reported in two studies is the late resolution of TAM, measured by either time to complete resolution of signs of TAM (defined as resolution beyond the median, 47 days from diagnosis) or by persistence of minimal residual disease (MRD) in the peripheral blood at week 12 of follow-up.[3]; [7][Level of evidence: 2Di] The use of cytarabine for TAM symptoms or persistent MRD in TAM has failed to show a reduction in later myeloid leukemia associated with Down syndrome, as reported in large observational cohort studies.[3,6] In a prospective single-arm trial designed to assess whether cytarabine treatment for TAM could prevent the development of later myeloid leukemia associated with Down syndrome, no benefit was found when compared with historical controls (19% ± 4% vs. 22% ± 4%, respectively; P = .88).[7][Level of evidence: 2Di]

Myeloid Leukemia Associated With Down Syndrome

Children with Down syndrome have a tenfold to twentyfold increased risk of leukemia compared with children without Down syndrome; however, the ratio of acute lymphoblastic leukemia to acute myeloid leukemia (AML) is typical for childhood acute leukemia. The exception is during the first 3 years of life, when AML, particularly the megakaryoblastic subtype, predominates and exhibits a distinctive biology characterized by GATA1 mutations and increased sensitivity to cytarabine.[9,10,11,12,13,14] Importantly, these risks appear to be similar whether a child has phenotypic characteristics of Down syndrome or whether a child has only genetic bone marrow mosaicism.[15]

Prognosis and Treatment of Children With Down Syndrome and AML

Outcome is generally favorable for children with Down syndrome who develop AML (called myeloid leukemia associated with Down syndrome in the World Health Organization classification).[16,17,18]

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

• Age. The prognosis is particularly good (EFS rates exceeding 85%) in children aged 4 years or younger at diagnosis; this age group accounts for the vast majority of Down syndrome patients with AML.[17,18,19,20] Children with Down syndrome who are older than 4 years have a significantly worse prognosis and warrant therapy utilized in children with AML without Down syndrome unless a GATA1 mutation is found.[21]
• White blood cell count. A large international Berlin-Frankfurt-Münster (BFM) retrospective study of 451 children with AML and Down syndrome (aged >6 months and <5 years) observed a 7-year EFS rate of 78% and a 7-year OS rate of 79%. In multivariate analyses, WBC count (≥20 × 10⁹ /L) and age (>3 years) were independent predictors of lower EFS. The 7-year EFS rate for the older population (>3 years) and for the higher WBC-count population still exceeded 60%.[22]
• AML karyotype. Normal karyotypic AML (other than trisomy 21), which was observed in 29% of patients, independently predicted for inferior OS and EFS (7-year EFS rate of 65% compared with 82% for patients with aberrant karyotypes).[22] However, this was not seen in a later trial.[20] In this same trial, the presence of trisomy 8 was shown to adversely impact prognosis.
• MRD. MRD at the end of induction 1 was found to be a strong prognostic factor;[18] this was consistent with the BFM finding that early response correlated with improved OS.[20]

Approximately 29% to 47% of Down syndrome patients present with myelodysplastic syndromes (MDS) (<20% blasts) but their outcomes are similar to those with AML.[17,18,20]

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

1. Chemotherapy.

Appropriate therapy for younger children (aged ≤4 years) with Down syndrome and AML is less intensive than current standard childhood AML therapy. Hematopoietic stem cell transplant is not indicated in first remission.[8,11,16,17,18,19,20,21,23]

Evidence (chemotherapy):

1. In a Children's Oncology Group (COG) trial for newly diagnosed children with Down syndrome and AML (AAML0431 [NCT00369317]), 204 children were enrolled on a regimen that substituted high-dose cytarabine for the second of four induction cycles (thereby reducing cumulative anthracycline exposure from 320 mg to 240 mg), moving this cycle from intensification where it was used in the previous COG A2971 (NCT00003593) trial.[17,18] Intrathecal doses were reduced from seven to two total injections and intensification included two cycles of cytarabine/etoposide.
   • When compared with the previous trial, these changes resulted in an overall improvement of approximately 10%.
   • The EFS rate was 89.9%, and the OS rate was 93%.
   • Relapse occurred in 14 patients and there were two treatment-related deaths, both related to pneumonia, neither of which occurred during induction 2.
   • No patient had central nervous system (CNS) involvement on this trial or the preceding COG A2971 (NCT00003593) trial.[17]
   • The only prognostic factor identified was MRD using flow cytometry on day 28 of induction 1. Among those who were MRD negative (≤0.01%), the DFS rate was 92.7%; in the 14.4% of patients who were MRD positive, the DFS rate was 76.2% (P = .011).
2. In a joint trial (ML-DS 2006) from the BFM, Dutch Childhood Oncology Group (DCOG), and Nordic Society of Pediatric Hematology and Oncology (NOPHO), 170 children with Down syndrome were enrolled in a trial that focused on reducing therapy by eliminating etoposide during consolidation, reducing the number of intrathecal doses from 11 to 4, and the elimination of maintenance from the reduced therapy Down syndrome arm of AML-BFM 98.[20] As in the COG trials, no patient had CNS disease at diagnosis.
   • Outcomes were no worse despite reduction in chemotherapy. The OS rate was 89% (± 3%) and the EFS rate was 87% (± 3%), similar to that observed in AML-BFM 98 (OS rate, 90% ± 4% [P = NS]; EFS rate, 89% ± 4% [P = NS]). The cumulative incidence of relapse (CIR) rate was 6% in both trials.
   • Nine patients relapsed, and seven of those patients died.
   • Patients with a good early response (<5% blasts by morphology before induction cycle 2, n = 123 [72%]) had better outcomes (OS rate, 92% ± 3% vs. 57% ± 16%, P < .0001; EFS rate, 88% ± 3% vs. 58% ± 16%, P = .0008; and CIR rate, 3% ± 2% vs. 27% ± 18%, P = .003).
   • Less toxicity was seen in this new trial, and treatment-related mortality remained low (2.9% vs. 5%, P = .276).

   The following two prognostic factors were identified:[20]

   • Trisomy 8 was an adverse factor (n = 37; OS rate, 77% vs. 95%, P = .07; EFS rate, 73% ± 8% vs. 91% ± 4%, P = .018; CIR rate, 16% ± 7% vs. 3% ± 2%, P = .02).
   • This was confirmed in multivariate analysis, where lack of good early response and trisomy 8 maintained their adverse impact on relapse, with relative risks of 8.55 (95% confidence interval [CI], 1.96–37.29, P = .004) and 4.36 (1.24–15.39, P = .022), respectively.

Children with mosaicism for trisomy 21 are treated similarly to those children with clinically evident Down syndrome.[3,15,17] Although an optimal treatment for these children has not been defined, they are usually treated on AML regimens designed for children without Down syndrome.

Treatment options under clinical evaluation

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

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

1. COG AAML1531 (NCT02521493) (Response-Based Chemotherapy in Treating Newly Diagnosed AML or Myelodysplastic Syndrome in Younger Patients With Down Syndrome): This is a phase III, single-arm trial for newly diagnosed children with Down syndrome–associated AML that uses response to induction therapy to stratify patients to less intensive therapy if they have no MRD and more intensive therapy if they do have MRD at the end of induction cycle one. The standard-risk treatment arm was closed early because of an excess of relapses observed in the patients who did not receive a high-dose cytarabine cycle.

Refractory Disease or Relapse in Children With Down Syndrome

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

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

1. Chemotherapy, which may be followed by an allogeneic HSCT.

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

1. The Japanese Pediatric Leukemia/Lymphoma Study Group reported the outcomes of 29 patients with Down syndrome and relapsed (n = 26) or refractory (n = 3) AML. As expected with Down syndrome, the children in this cohort were very young (median age, 2 years); relapses were almost all early (median, 8.6 months; 80% <12 months from diagnosis); and 89% had M7 French-American-British classification.[24][Level of evidence: 3iiA]
   • In contrast to the excellent outcomes achieved after initial therapy, only 50% of the children attained a second remission, and the 3-year OS rate was 26%.
   • Approximately one-half of the children underwent allogeneic transplant, and no advantage was noted with transplant compared with chemotherapy, but the number of patients was small.
2. A Center for International Blood and Marrow Transplant Research study of children with Down syndrome and AML who underwent HSCT reported the following results:[25][Level of evidence: 3iiA]
   • A similarly poor outcome, with a 3-year OS rate of 19%.
   • The main cause of failure after transplant was relapse, which exceeded 60%; transplant-related mortality was approximately 20%.
3. A Japanese registry study reported better survival after transplant of children with Down Syndrome using reduced-intensity conditioning regimens compared with myeloablative approaches, but the number of patients was very small (n = 5) and the efficacy of reduced-intensity approaches in children with Down syndrome and AML requires further study.[26][Level of evidence 3iDi]

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3. Gamis AS, Alonzo TA, Gerbing RB, et al.: Natural history of transient myeloproliferative disorder clinically diagnosed in Down syndrome neonates: a report from the Children's Oncology Group Study A2971. Blood 118 (26): 6752-9; quiz 6996, 2011.
4. Massey GV, Zipursky A, Chang MN, et al.: A prospective study of the natural history of transient leukemia (TL) in neonates with Down syndrome (DS): Children's Oncology Group (COG) study POG-9481. Blood 107 (12): 4606-13, 2006.
5. Muramatsu H, Kato K, Watanabe N, et al.: Risk factors for early death in neonates with Down syndrome and transient leukaemia. Br J Haematol 142 (4): 610-5, 2008.
6. Klusmann JH, Creutzig U, Zimmermann M, et al.: Treatment and prognostic impact of transient leukemia in neonates with Down syndrome. Blood 111 (6): 2991-8, 2008.
7. Flasinski M, Scheibke K, Zimmermann M, et al.: Low-dose cytarabine to prevent myeloid leukemia in children with Down syndrome: TMD Prevention 2007 study. Blood Adv 2 (13): 1532-1540, 2018.
8. Ravindranath Y, Abella E, Krischer JP, et al.: Acute myeloid leukemia (AML) in Down's syndrome is highly responsive to chemotherapy: experience on Pediatric Oncology Group AML Study 8498. Blood 80 (9): 2210-4, 1992.
9. Ravindranath Y: Down syndrome and leukemia: new insights into the epidemiology, pathogenesis, and treatment. Pediatr Blood Cancer 44 (1): 1-7, 2005.
10. Ross JA, Spector LG, Robison LL, et al.: Epidemiology of leukemia in children with Down syndrome. Pediatr Blood Cancer 44 (1): 8-12, 2005.
11. Gamis AS: Acute myeloid leukemia and Down syndrome evolution of modern therapy--state of the art review. Pediatr Blood Cancer 44 (1): 13-20, 2005.
12. Taub JW, Ge Y: Down syndrome, drug metabolism and chromosome 21. Pediatr Blood Cancer 44 (1): 33-9, 2005.
13. Crispino JD: GATA1 mutations in Down syndrome: implications for biology and diagnosis of children with transient myeloproliferative disorder and acute megakaryoblastic leukemia. Pediatr Blood Cancer 44 (1): 40-4, 2005.
14. Ge Y, Stout ML, Tatman DA, et al.: GATA1, cytidine deaminase, and the high cure rate of Down syndrome children with acute megakaryocytic leukemia. J Natl Cancer Inst 97 (3): 226-31, 2005.
15. Kudo K, Hama A, Kojima S, et al.: Mosaic Down syndrome-associated acute myeloid leukemia does not require high-dose cytarabine treatment for induction and consolidation therapy. Int J Hematol 91 (4): 630-5, 2010.
16. Lange BJ, Kobrinsky N, Barnard DR, et al.: Distinctive demography, biology, and outcome of acute myeloid leukemia and myelodysplastic syndrome in children with Down syndrome: Children's Cancer Group Studies 2861 and 2891. Blood 91 (2): 608-15, 1998.
17. Sorrell AD, Alonzo TA, Hilden JM, et al.: Favorable survival maintained in children who have myeloid leukemia associated with Down syndrome using reduced-dose chemotherapy on Children's Oncology Group trial A2971: a report from the Children's Oncology Group. Cancer 118 (19): 4806-14, 2012.
18. Taub JW, Berman JN, Hitzler JK, et al.: Improved outcomes for myeloid leukemia of Down syndrome: a report from the Children's Oncology Group AAML0431 trial. Blood 129 (25): 3304-3313, 2017.
19. Creutzig U, Reinhardt D, Diekamp S, et al.: AML patients with Down syndrome have a high cure rate with AML-BFM therapy with reduced dose intensity. Leukemia 19 (8): 1355-60, 2005.
20. Uffmann M, Rasche M, Zimmermann M, et al.: Therapy reduction in patients with Down syndrome and myeloid leukemia: the international ML-DS 2006 trial. Blood 129 (25): 3314-3321, 2017.
21. Gamis AS, Woods WG, Alonzo TA, et al.: Increased age at diagnosis has a significantly negative effect on outcome in children with Down syndrome and acute myeloid leukemia: a report from the Children's Cancer Group Study 2891. J Clin Oncol 21 (18): 3415-22, 2003.
22. Blink M, Zimmermann M, von Neuhoff C, et al.: Normal karyotype is a poor prognostic factor in myeloid leukemia of Down syndrome: a retrospective, international study. Haematologica 99 (2): 299-307, 2014.
23. Taga T, Shimomura Y, Horikoshi Y, et al.: Continuous and high-dose cytarabine combined chemotherapy in children with down syndrome and acute myeloid leukemia: Report from the Japanese children's cancer and leukemia study group (JCCLSG) AML 9805 down study. Pediatr Blood Cancer 57 (1): 36-40, 2011.
24. Taga T, Saito AM, Kudo K, et al.: Clinical characteristics and outcome of refractory/relapsed myeloid leukemia in children with Down syndrome. Blood 120 (9): 1810-5, 2012.
25. Hitzler JK, He W, Doyle J, et al.: Outcome of transplantation for acute myelogenous leukemia in children with Down syndrome. Biol Blood Marrow Transplant 19 (6): 893-7, 2013.
26. Muramatsu H, Sakaguchi H, Taga T, et al.: Reduced intensity conditioning in allogeneic stem cell transplantation for AML with Down syndrome. Pediatr Blood Cancer 61 (5): 925-7, 2014.

Myelodysplastic Syndromes (MDS)

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

Risk Factors

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

• Fanconi anemia: Caused by germline mutations in DNA repair genes.
• Dyskeratosis congenita: Resulting from mutations in genes regulating telomere length. Genes mutated in dyskeratosis congenital include ACD, CTC1, DKC1, NHP2, NOP10, PARN, RTEL1, TERC, TERT, TINF2, and WRAP53.
• Shwachman-Diamond syndrome, Diamond-Blackfan anemia, and other bone marrow failure syndromes: Resulting from mutations in genes encoding ribosome-associated proteins.[1,2]GATA1 mutations have been linked to Diamond-Blackfan anemia and MDS predisposition.[3]
• Severe congenital neutropenia: Caused by mutations in the gene encoding elastase. The 15-year cumulative risk of MDS in patients with severe congenital neutropenia, also known as Kostmann syndrome, has been estimated to be 15%, with an annual risk of MDS/acute myeloid leukemia (AML) of 2% to 3%. It is unclear how mutations affecting this protein and how the chronic exposure of granulocyte colony-stimulating factor (G-CSF) contribute to the development of MDS.[4]
• Trisomy 21 syndrome: GATA1 mutations are nearly always present in the transient leukemia associated with Trisomy 21 and MDS in children younger than 3 years with Down syndrome.[5]
• Congenital amegakaryocytic thrombocytopenia (CAMT): Inherited mutations in the RUNX1 or CEPBA genes are associated with CAMT.[6,7] Mutations in the MPL gene are the underlying genetic cause of CAMT; there is a less than 10% risk of developing MDS/AML in patients with CAMT.[8]
• GATA2 mutations: Germline mutations of GATA2 have been reported in patients with MDS/AML in conjunction with monocytopenia, B cell and natural killer cell deficiency, pulmonary alveolar proteinosis, and susceptibility to opportunistic infections.[9,10]
• RUNX1 or CEPBA mutations: Inherited mutations in the RUNX1 or CEPBA genes are associated with familial MDS/AML.[6,7]
• SAMD9 and SAMD9L mutations: Inherited mutations in SAMD9 and SAMD9L are associated with familial MDS.[11,12,13,14,15,16]

A retrospective analysis that used a capture assay to target mutations known to predispose to marrow failure and MDS was performed on genomic DNA from peripheral blood mononuclear cell samples from patients undergoing HSCT for MDS and aplastic anemia. Among the 46 children aged 18 years and younger with MDS, 10 patients (22%) harbored constitutional predisposition genetic mutations (5 GATA2, 1 each of MPL, RTEL1, SBDS, TINF2, and TP53), of which only 2 were suspected before transplant. This is considered a high incidence of genetic mutations compared with only 8% (4 of 64) in patients aged 18 to 40 years.[17]

Clinical Presentation

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

The bone marrow is usually characterized by hypercellularity and dysplastic changes in myeloid precursors. Clonal evolution can eventually lead to the development of AML. The percentage of abnormal blasts is less than 20% and lack common AML recurrent cytogenetic abnormalities (t(8;21), inv(16), t(15;17), or KMT2A translocations).

The less common hypocellular MDS can be distinguished from aplastic anemia in part by its marked dysplasia, clonal nature, and higher percentage of CD34-positive precursors.[18,19]

Molecular Abnormalities

Molecular features of myelodysplastic syndromes (MDS)

Pediatric MDS are associated with a distinctive constellation of genetic alterations compared with MDS arising in adults. In adults, MDS often evolves from clonal hematopoiesis and is characterized by mutations in TET2, DNMT3A, and TP53. In contrast, mutations in these genes are rare in pediatric MDS, while mutations in GATA2, SAMD9/SAMD9L, SETBP1, ASXL1, and RAS/MAPK pathway genes are observed in subsets of pediatric MDS cases.[11,20]

A report of the genomic landscape of pediatric MDS described the results of whole-exome sequencing for 32 pediatric patients with primary MDS and targeted sequencing for another 14 cases.[11] These 46 cases were equally divided between refractory cytopenia of childhood and MDS with excess blasts (MDS-EB). The results from the report include the following:

• Mutations in RAS/MAPK pathway genes were observed in 43% of primary MDS cases, with mutations most commonly involving PTPN11 and NRAS but with mutations also observed in other pathway members (e.g., BRAF [non–BRAF V600E], CBL, and KRAS). RAS/MAPK mutations were more common in patients with MDS-EB (65%) than in patients with refractory cytopenia of childhood (17%).
• Germline variants in SAMD9 (n = 4) or SAMD9L (n = 4) were observed in 17% of patients with primary MDS, with seven of eight mutations occurring in patients with refractory cytopenia of childhood. These cases all showed loss of material on chromosome 7. Approximately 40% of patients with deletions of part or all of chromosome 7 had germline SAMD9 or SAMD9L variants.
• GATA2 mutations were observed in three cases (7%), and all cases were confirmed or presumed to be germline.
• Deletions involving chromosome 7 were the most common copy number alteration and were observed in 41% of cases. Loss of part or all of chromosome 7 was most commonly observed in SAMD9/SAMD9L cases (100%) and in MDS-EB patients with a RAS/MAPK mutation (71%).
• Other genes that were mutated in more than 1 of the 46 cases studied included SETBP1, ETV6, and TP53.

A second report described the application of a targeted sequencing panel of 105 genes to 50 pediatric patients with MDS (refractory cytopenia of childhood = 31 and MDS-EB = 19) and was enriched for cases with monosomy 7 (48%).[11,20]SAMD9 and SAMD9L were not included in the gene panel. The second report described the following results:

• Germline GATA2 mutations were observed in 30% of patients, and RUNX1 mutations were observed in 6% of patients.
• Somatic mutations were observed in 34% of patients and were more common in patients with MDS-EB than in patients with refractory cytopenia of childhood (68% vs. 13%).
• The most commonly mutated gene was SETBP1 (18%); less commonly mutated genes included ASXL1, RUNX1, and RAS/MAPK pathway genes (PTPN11, NRAS, KRAS, NF1). Twelve percent of cases showed mutations in RAS/MAPK pathway genes.

Patients with germline GATA2 mutations, in addition to MDS, show a wide range of hematopoietic and immune defects as well as nonhematopoietic manifestations.[21] The former defects include monocytopenia with susceptibility to atypical mycobacterial infection and DCML deficiency (loss of dendritic cells, monocytes, and B and natural killer lymphoid cells). The resulting immunodeficiency leads to increased susceptibility to warts, severe viral infections, mycobacterial infections, fungal infections, and human papillomavirus–related cancers. The nonhematopoietic manifestations include deafness and lymphedema. Germline GATA2 mutations were studied in 426 pediatric patients with primary MDS and 82 cases with secondary MDS who were enrolled in consecutive studies of the European Working Group of MDS in Childhood (EWOG-MDS).[22] The study had the following results:

• Germline GATA2 mutations were identified in 7% of pediatric patients with primary MDS. While the median age of patients presenting with GATA2 mutations was 12.3 years in the EWOG-MDS pediatric population, most cases of germline GATA2-related myeloid neoplasms occur during adulthood.[23]
• GATA2 mutations were more common in patients with MDS-EB (15%) than in patients with refractory cytopenia of childhood (4%).
• Among patients with GATA2 mutations, 46% presented with MDS-EB and 70% showed monosomy 7.
• Familial MDS/AML was identified in 12 of 53 GATA2-mutated patients for whom detailed family histories were available.
• Nonhematologic phenotypes of GATA2 deficiency were present in 51% of GATA2-mutated patients with MDS and included deafness (9%), lymphedema/hydrocele (23%), and immunodeficiency (39%).

SAMD9 and SAMD9L germline mutations are both associated with pediatric MDS cases in which there is an additional loss of all or part of chromosome 7.[12,13] In 2016, SAMD9 was identified as the cause of the MIRAGE syndrome (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy), which is associated with early-onset MDS with monosomy 7.[14] Subsequently, mutations in SAMD9L were identified in patients with ataxia pancytopenia syndrome (ATXPC; OMIM 159550). SAMD9 and SAMD9L mutations were also identified as the cause of myelodysplasia and leukemia syndrome with monosomy 7 (MLSM7; OMIM 252270),[15] a syndrome first identified in phenotypically normal siblings who developed MDS or AML associated with monosomy 7 during childhood.[16]

• Causative mutations in both SAMD9 and SAMD9L are gain-of-function mutations and enhance the growth-suppressing activity of SAMD9/SAMD9L.[14,16]
• Both SAMD9 and SAMD9L are located at chromosome 7q21.2. Cases of MDS in patients with SAMD9 or SAMD9L mutations often show monosomy 7, with the remaining chromosome 7 having wild-type SAMD9/SAMD9L. This results in the loss of the enhanced growth-suppressing activity of the mutated gene.
• Phenotypically normal patients with SAMD9/SAMD9L mutations and monosomy 7 may progress to MDS or AML or, alternatively, may show loss of their monosomy 7 with a return of normal hematopoiesis.[16] The former outcome is associated with the acquisition of mutations in genes associated with MDS/AML (e.g., ETV6 or SETBP1), while the latter is associated with genetic alterations (e.g., revertant mutations or copy-neutral loss of heterozygosity with retention of the wild-type allele) that result in normalization of SAMD9/SAMD9L activity. These observations suggest that monitoring of patients with SAMD9/SAMD9L-related monosomy 7 using clinical sequencing for acquired mutations in genes associated with progression to AML may identify patients at high risk of leukemic transformation who may benefit most from hematopoietic stem cell transplantation.[16]

(Refer to the WHO Classification of Bone Marrow and Peripheral Blood Findings for Myelodysplastic Syndromes section of this summary for more information about the WHO classification of MDS.)

Classification of MDS

The French-American-British (FAB) and World Health Organization (WHO) classification systems of MDS and MPS have been difficult to apply to pediatric patients. Alternative classification systems for children have been proposed, but none have been uniformly adopted, with the exception of the modified 2008 WHO classification system.[24,25,26,27,28] The WHO system [29] has been modified for pediatrics.[27] Refer to Table 3 and Table 4 for the WHO classification schema and diagnostic criteria. The 2016 revision to the WHO MDS classification did not affect classification in children.[30]

The refractory cytopenia subtype represents approximately 50% of all childhood cases of MDS. The presence of an isolated monosomy 7 is the most common cytogenetic abnormality, although it does not appear to portend a poor prognosis compared with its presence in overt AML. However, the presence of monosomy 7 in combination with other cytogenetic abnormalities is associated with a poor prognosis.[31,32] The relatively common abnormalities of -Y, 20q-, and 5q- in adults with MDS are rare in childhood MDS. The presence of cytogenetic abnormalities that are found in AML (t(8;21)(q22;q22.1), inv(16)(p13.1;q22) or t(16;16)(p13.1;q22), and APL with PML-RARA) defines disease that should be treated as AML and not MDS, regardless of blast percentage. The WHO notes that whether this should also apply to other recurring genetic abnormalities remains controversial.[33]

The International Prognostic Scoring System can help to distinguish low-risk from high-risk MDS, although its utility in children with MDS is more limited than in adults because many characteristics differ between children and adults.[34,35] The median survival for children with high-risk MDS remains substantially better than adults, and the presence of monosomy 7 in children has not had the same adverse prognostic impact as does the presence in adults with MDS.[36]

Treatment of Childhood MDS

Treatment options for children with MDS include the following:

1. HSCT.
2. Other therapies.

HSCT

MDS and associated disorders usually involve a primitive hematopoietic stem cell. Thus, allogeneic HSCT is considered to be the optimal approach to treatment for pediatric patients with MDS. Although matched sibling transplantation is preferred, similar survival has been noted with well-matched, unrelated cord blood and haploidentical approaches.[37,38,39,40,41]

When making treatment decisions, some data should be considered. For example, survival as high as 80% has been reported for patients with early-stage MDS who proceeded to transplant within a few months of diagnosis. Additionally, early transplant and not receiving pretransplant chemotherapy have been associated with improved survival in children with MDS.[42][Level of evidence: 3iiA] Disease-free survival (DFS) rates have been estimated to be between 50% to 70% for pediatric patients with advanced MDS using myeloablative transplant preparative regimens.[40,43,44,45,46] While nonmyeloablative preparative transplant regimens are being tested in patients with MDS and AML, such regimens are still investigational for children with these disorders, but may be reasonable in the setting of a clinical trial or when a patient's organ function is compromised in such a way that they would not tolerate a myeloablative regimen.[47,48,49,50]; [51][Level of evidence: 3iiiA]

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

Evidence (HSCT):

1. An analysis of 37 children with MDS treated on Berlin-Frankfurt-Münster AML protocols 83, 87, and 93 confirmed the induction response of 74% for patients with refractory anemia with excess blasts in transformation and suggested that transplantation was beneficial.[52]
2. Another study by the same group showed that with current approaches to HSCT, survival occurred in more than 60% of children with advanced MDS, and outcomes for patients receiving unrelated donor cells were similar to those for patients who received matched-family donor (MFD) cells.[53]
3. The Children's Cancer Group 2891 trial accrued patients between 1989 and 1995, including children with MDS.[43] There were 77 patients enrolled, including patients with refractory anemia (n = 2), refractory anemia with excess blasts (n = 33), refractory anemia with excess blasts in transformation (n = 26), or AML with antecedent MDS (n = 16). Patients were randomly assigned to receive either standard or intensively timed induction. Subsequently, patients were allocated to allogeneic HSCT if there was a suitable family donor, or randomly assigned to either autologous HSCT or chemotherapy.
   • Patients with refractory anemia or refractory anemia with excess blasts had a lower remission rate (45%), and those with refractory anemia with excess blasts in transformation (69%) or AML with history of MDS (81%) had similar remission rates compared with de novo AML (77%).
   • The 6-year survival rates were lower for those with refractory anemia or refractory anemia with excess blasts (28%) and refractory anemia with excess blasts in transformation (30%).
   • Patients with AML and antecedent MDS had a similar outcome to those with de novo AML (50% survival compared with 45%).
   • Allogeneic HSCT appeared to improve survival (P = .08).

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

Because survival after HSCT is improved in children with early forms of MDS (refractory anemia), transplantation before progression to late MDS or AML should be considered. HSCT should especially be considered when transfusions or other treatment are required, as is usually the case in patients with severe symptomatic cytopenias.[40,46] The 8-year disease-free survival (DFS) rates for children with various stages of MDS has been reported to be 65% for those treated with HLA matched donor transplants and 40% for those treated with mismatched unrelated donor transplants.[46][Level of evidence: 3iiiDii] A 3-year DFS rate of 50% was reported with the use of unrelated cord blood donor transplants for children with MDS, when the transplants were done after the year 2001.[54][Level of evidence: 3iiiDiii]

Because MDS in children is often associated with inherited predisposition syndromes, reports of transplantation in small numbers of patients with these disorders have been documented. For example, in patients with Fanconi anemia and AML or advanced MDS, the 5-year overall survival (OS) rate has been reported to be 33% to 55%.[55,56][Level of evidence: 3iiiA] Second transplants have also been used in pediatric patients with MDS/MPD who relapse or suffer graft failure. The 3-year OS rates were 33% for those retransplanted after relapse and 57% for those transplanted after initial graft failure.[57][Level of evidence: 3iiiA]

For patients with clinically significant cytopenias, supportive care that includes transfusions and prophylactic antibiotics are considered standard of care. The use of hematopoietic growth factors can improve the hematopoietic status, but concerns remain that such treatment could accelerate conversion to AML.[58]

Other therapies

Other supportive therapies that have been studied include the following:

• Steroid therapies, including glucocorticoids and androgens, have been tested with mixed results.[59]
• Treatments directed toward scavenging free oxygen radicals with amifostine [60,61] or the use of differentiation-promoting retinoids,[62] DNA methylation inhibitors (e.g., azacitidine and decitabine), and histone deacetylase inhibitors have all shown some response, but no definitive trials in children with MDS have been reported. Azacitidine has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of MDS in adults on the basis of randomized studies.[63] (Refer to the Disease-Modifying Agents section in the PDQ summary on Myelodysplastic Syndromes Treatment for more information.)
• Agents such as lenalidomide, an analog of thalidomide, have been tested based on findings that demonstrated increased activity in the bone marrow of patients with MDS. Lenalidomide has shown the most efficacy in patients with 5q- syndrome, especially those with thrombocytosis, and is now FDA approved for use in adults with this finding.[64]
• Immunosuppression with antithymocyte globulin and/or cyclosporine has also been reported in adults.[64,65]

Treatment Options Under Clinical Evaluation

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the 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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40. Parikh SH, Mendizabal A, Martin PL, et al.: Unrelated donor umbilical cord blood transplantation in pediatric myelodysplastic syndrome: a single-center experience. Biol Blood Marrow Transplant 15 (8): 948-55, 2009.
41. 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.
42. Smith AR, Christiansen EC, Wagner JE, et al.: Early hematopoietic stem cell transplant is associated with favorable outcomes in children with MDS. Pediatr Blood Cancer 60 (4): 705-10, 2013.
43. Woods WG, Barnard DR, Alonzo TA, et al.: Prospective study of 90 children requiring treatment for juvenile myelomonocytic leukemia or myelodysplastic syndrome: a report from the Children's Cancer Group. J Clin Oncol 20 (2): 434-40, 2002.
44. Andolina JR, Kletzel M, Tse WT, et al.: Allogeneic hematopoetic stem cell transplantation in pediatric myelodysplastic syndromes: improved outcomes for de novo disease. Pediatr Transplant 15 (3): 334-43, 2011.
45. Al-Seraihy A, Ayas M, Al-Nounou R, et al.: Outcome of allogeneic stem cell transplantation with a conditioning regimen of busulfan, cyclophosphamide and low-dose etoposide for children with myelodysplastic syndrome. Hematol Oncol Stem Cell Ther 4 (3): 121-5, 2011.
46. 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.
47. Champlin R: Hematopoietic stem cell transplantation for treatment of myleodysplastic syndromes. Biol Blood Marrow Transplant 17 (1 Suppl): S6-8, 2011.
48. Nelson RP, Yu M, Schwartz JE, et al.: Long-term disease-free survival after nonmyeloablative cyclophosphamide/fludarabine conditioning and related/unrelated allotransplantation for acute myeloid leukemia/myelodysplasia. Bone Marrow Transplant 45 (8): 1300-8, 2010.
49. Warlick ED: Optimizing stem cell transplantation in myelodysplastic syndromes: unresolved questions. Curr Opin Oncol 22 (2): 150-4, 2010.
50. 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.
51. Gao L, Gao L, Gong Y, et al.: Reduced-intensity conditioning therapy with fludarabine, idarubicin, busulfan and cytarabine for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia and myelodysplastic syndrome. Leuk Res 37 (11): 1482-7, 2013.
52. Creutzig U, Bender-Götze C, Ritter J, et al.: The role of intensive AML-specific therapy in treatment of children with RAEB and RAEB-t. Leukemia 12 (5): 652-9, 1998.
53. Strahm B, Nöllke P, Zecca M, et al.: Hematopoietic stem cell transplantation for advanced myelodysplastic syndrome in children: results of the EWOG-MDS 98 study. Leukemia 25 (3): 455-62, 2011.
54. Madureira AB, Eapen M, Locatelli F, et al.: Analysis of risk factors influencing outcome in children with myelodysplastic syndrome after unrelated cord blood transplantation. Leukemia 25 (3): 449-54, 2011.
55. Mitchell R, Wagner JE, Hirsch B, et al.: Haematopoietic cell transplantation for acute leukaemia and advanced myelodysplastic syndrome in Fanconi anaemia. Br J Haematol 164 (3): 384-95, 2014.
56. Ayas M, Saber W, Davies SM, et al.: Allogeneic hematopoietic cell transplantation for fanconi anemia in patients with pretransplantation cytogenetic abnormalities, myelodysplastic syndrome, or acute leukemia. J Clin Oncol 31 (13): 1669-76, 2013.
57. Kato M, Yoshida N, Inagaki J, et al.: Salvage allogeneic stem cell transplantation in patients with pediatric myelodysplastic syndrome and myeloproliferative neoplasms. Pediatr Blood Cancer 61 (10): 1860-6, 2014.
58. Zwierzina H, Suciu S, Loeffler-Ragg J, et al.: Low-dose cytosine arabinoside (LD-AraC) vs LD-AraC plus granulocyte/macrophage colony stimulating factor vs LD-AraC plus Interleukin-3 for myelodysplastic syndrome patients with a high risk of developing acute leukemia: final results of a randomized phase III study (06903) of the EORTC Leukemia Cooperative Group. Leukemia 19 (11): 1929-33, 2005.
59. Chan G, DiVenuti G, Miller K: Danazol for the treatment of thrombocytopenia in patients with myelodysplastic syndrome. Am J Hematol 71 (3): 166-71, 2002.
60. Mathew P, Gerbing R, Alonzo TA, et al.: A phase II study of amifostine in children with myelodysplastic syndrome: a report from the Children's Oncology Group study (AAML0121). Pediatr Blood Cancer 57 (7): 1230-2, 2011.
61. Schanz J, Jung H, Wörmann B, et al.: Amifostine has the potential to induce haematologic responses and decelerate disease progression in individual patients with low- and intermediate-1-risk myelodysplastic syndromes. Leuk Res 33 (9): 1183-8, 2009.
62. Sadek I, Zayed E, Hayne O, et al.: Prolonged complete remission of myelodysplastic syndrome treated with danazol, retinoic acid and low-dose prednisone. Am J Hematol 64 (4): 306-10, 2000.
63. Silverman LR, Demakos EP, Peterson BL, et al.: Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 20 (10): 2429-40, 2002.
64. Yazji S, Giles FJ, Tsimberidou AM, et al.: Antithymocyte globulin (ATG)-based therapy in patients with myelodysplastic syndromes. Leukemia 17 (11): 2101-6, 2003.
65. Yoshimi A, Baumann I, Führer M, et al.: Immunosuppressive therapy with anti-thymocyte globulin and cyclosporine A in selected children with hypoplastic refractory cytopenia. Haematologica 92 (3): 397-400, 2007.

Therapy-Related AML and Therapy-Related Myelodysplastic Syndromes

Pathogenesis

The development of acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) after treatment with ionizing radiation or chemotherapy, particularly alkylating agents and topoisomerase inhibitors, is termed 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.[1,2,3,4]

The risk of t-AML or t-MDS is regimen-dependent and 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 epipodophyllotoxins and other topoisomerase II inhibitors (e.g., anthracyclines) usually occur within 2 years of exposure and are commonly associated with chromosome 11q23 abnormalities,[7] although other subtypes of AML (e.g., acute promyelocytic leukemia) have 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 transplantation (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 for the previous malignancy.

Accordingly, CR rates and overall survival (OS) rates are usually lower for patients with t-AML compared with patients with de novo AML.[10,11,12] Also, survival for pediatric patients with t-MDS is worse than survival for 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 transplantation between 1975 and 2007.[11]
   • Survival 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 low-risk cytogenetics rarely occurred.[15]
   • Although rates of achieving CR and OS at 3 years were worse in the t-AML/t-MDS group (CR, 50% vs. 72%; P = .016; OS rate, 26% vs. 47%; P = .007), survival was similar (OS rate, 45% vs. 53%; P = .87) if patients achieved a CR.
4. The importance of remission to survival in these patients is 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.
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.
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.
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.
5. Leone G, Mele L, Pulsoni A, et al.: The incidence of secondary leukemias. Haematologica 84 (10): 937-45, 1999.
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.
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.
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.
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.
10. Larson RA: Etiology and management of therapy-related myeloid leukemia. Hematology Am Soc Hematol Educ Program : 453-9, 2007.
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.
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.
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.
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.
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.
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.

Juvenile Myelomonocytic Leukemia (JMML)

Incidence

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

Clinical Presentation and Diagnostic Criteria

Common clinical features at diagnosis include the following:[2]

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

In children presenting with clinical features suggestive of JMML, current criteria used for a definitive diagnosis are described in Table 8.[3]

Table 8. Diagnostic Criteria for Juvenile Myelomonocytic Leukemia (JMML) Per the 2016 Revision to World Health Organization Classification

Category 1 (All are Required)	Category 2 (One is Sufficient)a	Category 3 (Patients Without Genetic Features Must Have the Following in Addition to Category 1b)
Clinical and Hematologic Features	Genetic Studies	Other Features
GM-CSF = granulocyte-macrophage colony-stimulating factor; NF1 = neurofibromatosis type 1.
a Patients who are found to have a category 2 lesion need to meet the criteria in category 1 but do not need to meet the category 3 criteria. Patients who are not found to have a category 2 lesion must meet the category 1 and 3 criteria.
b Note that only 7% of patients with JMML will NOT present with splenomegaly, but virtually all patients develop splenomegaly within several weeks to months of initial presentation.
Absence of theBCR-ABL1fusion gene	Somatic mutation inKRAS,NRAS, orPTPN11(germline mutations need to be excluded)	Monosomy 7 or other chromosomal abnormality, or at least 2 of the criteria listed below:
>1 × 109 /L circulating monocytes	Clinical diagnosis of NF1 orNF1gene mutation	— Circulating myeloid or erythroid precursors
<20% blasts in the peripheral blood and bone marrow	GermlineCBLmutation and loss of heterozygosity ofCBL	— Increased hemoglobin F for age
Splenomegaly		— Hyperphosphorylation of STAT5
		— GM-CSF hypersensitivity

Pathogenesis and Related Syndromes

The pathogenesis of JMML has been closely linked to activation of the RAS oncogene pathway, along with related syndromes (refer to Figure 1).[4,5] In addition, distinctive RNA expression and DNA methylation patterns have been reported; they are correlated with clinical factors such as age and appear to be associated with prognosis.[6,7]

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

Children with neurofibromatosis type 1 (NF1) and Noonan syndrome are at increased risk of developing JMML:[8,9]

• NF1. Up to 14% of cases of JMML occur in children with NF1.[2]
• Noonan syndrome. Noonan syndrome is usually inherited as an autosomal dominant condition, but can also arise spontaneously. It is characterized by facial dysmorphism, short stature, webbed neck, neurocognitive abnormalities, and cardiac abnormalities. Germline mutations in PTPN11 are observed in children with Noonan syndrome and in children with JMML.[10,11,12]

  Importantly, some children with Noonan syndrome have a hematologic picture indistinguishable from JMML that self-resolves during infancy, similar to what happens in children with Down syndrome and transient myeloproliferative disorder.[5,12]

  Within a large prospective cohort of 641 patients with Noonan syndrome and a germline PTPN11 mutation, 36 patients (approximately 6%) showed myeloproliferative features, with 20 patients (approximately 3%) meeting the consensus diagnostic criteria for JMML.[12] Of the 20 patients meeting the criteria for JMML, 12 patients had severe neonatal manifestations (e.g., life-threatening complications related to congenital heart defects, pleural effusion, leukemia infiltrates, and/or thrombocytopenia), and 10 of 20 patients died during the first month of life. Among the remaining eight patients, none required intensive therapy at diagnosis or during follow-up. All 16 patients with myeloproliferative features not meeting JMML criteria were alive, with a median follow-up of 3 years, and none of the patients received chemotherapy.

Mutations in the CBL gene, an E3 ubiquitin-protein ligase that is involved in targeting proteins, particularly tyrosine kinases, for proteasomal degradation occur in 10% to 15% of JMML cases,[13,14] with many of these cases occurring in children with germline CBL mutations.[15,16]CBL germline mutations result in an autosomal dominant developmental disorder that is characterized by impaired growth, developmental delay, cryptorchidism, and a predisposition to JMML.[15] Some individuals with CBL germline mutations experience spontaneous regression of their JMML but develop vasculitis later in life.[15]CBL mutations are nearly always mutually exclusive of RAS and PTPN11 mutations.[13]

Genomics of JMML

Molecular features of JMML

The genomic landscape of JMML is characterized by mutations in one of five genes of the RAS pathway: NF1, NRAS, KRAS, PTPN11, and CBL.[17,18,19] In a series of 118 consecutively diagnosed JMML cases with RAS pathway–activating mutations, PTPN11 was the most commonly mutated gene, accounting for 51% of cases (19% germline and 32% somatic) (refer to Figure 2).[17] Patients with mutated NRAS accounted for 19% of cases, and patients with mutated KRAS accounted for 15% of cases. NF1 mutations accounted for 8% of cases, and CBL mutations accounted for 11% of cases. Although mutations among these five genes are generally mutually exclusive, 4% to 17% of cases have mutations in two of these RAS pathway genes,[17,18,19] a finding that is associated with poorer prognosis.[17,19]

The mutation rate in JMML leukemia cells is very low, but additional mutations beyond those of the five RAS pathway genes described above are observed.[17,18,19] Secondary genomic alterations are observed for genes of the transcriptional repressor complex PRC2 (e.g., ASXL1 was mutated in 7%–8% of cases). Some genes associated with myeloproliferative neoplasms in adults are also mutated at low rates in JMML (e.g., SETBP1 was mutated in 6%–9% of cases).[17,18,19,20]JAK3 mutations are also observed in a small percentage (4%–12%) of JMML cases.[17,18,19,20] Cases with germline PTPN11 and germline CBL mutations showed low rates of additional mutations (refer to Figure 2).[17] The presence of mutations beyond disease-defining RAS pathway mutations is associated with an inferior prognosis.[17,18]

A report describing the genomic landscape of JMML found that 16 of 150 patients (11%) lacked canonical RAS pathway mutations. Among these 16 patients, 3 were observed to have in-frame fusions involving receptor tyrosine kinases (DCTN1-ALK, RANBP2-ALK, and TBL1XR1-ROS1). These patients all had monosomy 7 and were aged 56 months or older. One patient with an ALK fusion was treated with crizotinib plus conventional chemotherapy and achieved a complete molecular remission and proceeded to allogeneic bone marrow transplantation.[19]

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

Prognosis (genomic and molecular factors)

Several genomic factors affect the prognosis of patients with JMML, including the following:

1. Number of non–RAS pathway mutations. A predictor of prognosis for children with JMML is the number of mutations beyond the disease-defining RAS pathway mutations.[17,18]
   • One study observed that zero or one somatic alteration (pathogenic mutation or monosomy 7) was identified in 64 patients (65.3%) at diagnosis, whereas two or more alterations were identified in 34 patients (34.7%).[18] In multivariate analysis, mutation number (2 or more vs. 0 or 1) maintained significance as a predictor of inferior event-free survival (EFS) and overall survival (OS). A higher proportion of patients diagnosed with two or more alterations were older and male, and these patients also demonstrated a higher rate of monosomy 7 or somatic NF1 mutations.[18]
   • Another study observed that approximately 60% of patients had one or more additional mutations beyond their disease-defining RAS pathway mutation. These patients had an inferior OS compared with patients who had no additional mutations (3-year OS rate, 61% vs. 85%, respectively).[17]
   • A third study observed a trend for an inferior OS for patients with two or more mutations compared with patients with zero or one mutation.[19]
2. RAS pathway double mutations. Although mutations in the five canonical RAS pathway genes associated with JMML (NF1, NRAS, KRAS, PTPN11, and CBL) are generally mutually exclusive, 4% to 17% of cases have mutations in two of these RAS pathway genes,[17,18] a finding that has been associated with a poorer prognosis.[17,18]
   • Two RAS pathway mutations were identified in 11% of JMML patients in one report, and these patients had a significantly inferior EFS rate (14%) compared with patients who had a single RAS pathway mutation (62%). Patients with Noonan syndrome were excluded from the analyses.[18]
   • Similar findings for RAS pathway mutations were reported in a second study that observed that patients with RAS pathway double mutations (15 of 96 patients) had lower survival rates than did patients with either no additional mutations or with additional mutations beyond the RAS pathway mutation.[17]
3. DNA methylation profile.
   • One study applied DNA methylation profiling to a discovery cohort of 39 patients with JMML and to a validation cohort of 40 patients. Distinctive subsets of JMML with either high, intermediate, or low methylation levels were observed in both cohorts. Patients with the lowest methylation levels had the highest survival rates, and all but 1 of 15 patients experienced spontaneous resolution in the low methylation cohort. High methylation status was associated with lower EFS rates.[21]
   • Another study applied DNA methylation profiling to a cohort of 106 patients with JMML and observed one subgroup of patients with a hypermethylation profile and one subgroup of patients with a hypomethylation profile. Patients in the hypermethylation group had a significantly lower OS rate than did patients in the hypomethylation group (5-year OS rate, 46% vs. 73%, respectively). Patients in the hypermethylation group also had a significantly poorer 5-year transplant-free survival rate than did patients in the hypomethylation group (2.2%; 95% CI, 0.2%–10.1% vs. 41.2%; 95% CI, 27.1%–54.8%). Hypermethylation status was associated with two or more mutations, higher fetal hemoglobin levels, older age, and lower platelet count at diagnosis. All patients with Noonan syndrome were in the hypomethylation group.[19]
4. LIN28B overexpression. LIN28B overexpression is present in approximately one-half of children with JMML and identifies a biologically distinctive subset of JMML. LIN28B is an RNA-binding protein that regulates stem cell renewal.[22]
   • LIN28B overexpression was positively correlated with high blood fetal hemoglobin level and age (both of which are associated with poor prognosis), and it was negatively correlated with presence of monosomy 7 (also associated with inferior prognosis). Although LIN28B overexpression identifies a subset of patients with increased risk of treatment failure, it was not found to be an independent prognostic factor when other factors such as age and monosomy 7 status are considered.[22]
   • Another study also observed a subset of JMML patients with elevated LIN28B expression and identified LIN28B as the gene for which expression was most strongly associated with hypermethylation status.[19]

Prognosis (Clinical Factors)

Age, platelet count, and fetal hemoglobin level after any treatment. Historically, more than 90% of patients with JMML died despite the use of chemotherapy;[23] however, with the application of hematopoietic stem cell transplantation (HSCT), survival rates of approximately 50% are now observed.[24] Patients appeared to follow three distinct clinical courses:

• Rapidly progressive disease and early demise.
• Transiently stable disease followed by progression and death.
• Clinical improvement that lasted up to 9 years before progression or, rarely, long-term survival.

Favorable prognostic factors for survival after any therapy include age younger than 2 years, platelet count greater than 33 × 10⁹ /L, and low age-adjusted fetal hemoglobin levels.[1,2] In contrast, being older than 2 years and having high blood fetal hemoglobin levels at diagnosis are predictors of poor outcome.[1,2]

Treatment of JMML

Treatment options for JMML include the following:

• Hematopoietic stem cell transplant (HSCT).

The role of conventional antileukemia therapy in the treatment of JMML is not defined. Determining the role of specific agents in the treatment of JMML is complicated because of the absence of consensus response criteria.[25] Some agents that have shown antileukemia activity against JMML include etoposide, cytarabine, thiopurines (thioguanine and mercaptopurine), isotretinoin, and farnesyl inhibitors, but none of these have been shown to improve outcome.[25,26,27,28,29]; [30][Level of evidence: 2B]

HSCT currently offers the best chance of cure for JMML.[24,31,32,33,34]

Evidence (HSCT):

1. A report from the European Working Group on Childhood Myelodysplastic Syndromes included 100 transplant recipients at multiple centers treated with a common preparative regimen of busulfan, cyclophosphamide, and melphalan, with or without antithymocyte globulin. Recipients had been treated with varying degrees of pretransplant chemotherapy or differentiating agents, and some patients had splenectomy performed.[24]
   • The 5-year event-free survival rate was 55% for children with JMML who underwent HSCT using HLA-identical matched family donor cells and 49% for children with JMML who underwent HSCT using unrelated donor cells.
   • The multivariate analysis showed no effect on survival of previous AML-like chemotherapy versus low-dose chemotherapy or no chemotherapy.
   • No effect on survival was observed for splenectomy pretransplant or difference in spleen size.
   • Comparison of outcomes on the basis of related versus unrelated donors also found no difference.
   • Only age older than 4 years and sex were shown to be poor prognostic factors for outcome and increased risk of relapse (relative risk [RR], 2.24 [1.07–4.69]; P = .032 for older age; RR, 2.22 [1.09–4.50]; P = .028 for females).[24]
2. Cord blood transplantation results in a 5-year disease-free survival rate of 44%, with improved outcome in children younger than 1.4 years at diagnosis, those with nonmonosomy 7 karyotype, and those receiving 5/6 to 6/6 HLA-matched cord units.[35][Level of evidence: 3iiDii] This suggests that cord blood can provide an additional donor pool for this group of children.
3. The use of reduced-intensity preparative regimens to decrease the adverse side effects of transplantation have also been reported in small numbers of patients, generally for patients ineligible for myeloablative HSCT.[36,37]
   1. The COG conducted a randomized trial in children with JMML that compared a standard-intensity preparative regimen (busulfan/cyclophosphamide/melphalan) with a reduced-intensity regimen (busulfan/fludarabine).[38]
      • The trial closed to enrollment early when an interim analysis revealed a higher frequency of relapse/disease persistence (7 of 9 patients) in children who received the reduced-intensity regimen than in children who received the standard-intensity regimen (1 of 6 patients).

Disease recurrence is the primary cause of treatment failure for children with JMML after HSCT and occurs in 30% to 40% of cases.[24,31,32] While the role of donor lymphocyte infusions is uncertain,[39] reports indicate that approximately 50% of patients with relapsed JMML can be successfully treated with a second HSCT.[40]

Treatment Options Under Clinical Evaluation

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

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

• COG-ADVL1521 (NCT03190915) (Trametinib in Treating Patients With Relapsed or Refractory JMML): This trial is evaluating the activity of trametinib (inhibitor of MEK1/2, which is downstream of RAS/MAPK signaling) in pediatric patients with relapsed or refractory JMML. The rationale for studying this agent is based on the finding that nearly all genetic mutations found in JMML lead to aberrant RAS pathway signaling. Eligible patients are those who have relapsed or have persistent disease after intravenous chemotherapy (such as fludarabine or cytarabine) and/or HSCT, but not after low-dose oral chemotherapy (such as mercaptopurine). The primary objective is to determine the response rate of trametinib administered orally once daily in 28-day cycles.

References:

1. Passmore SJ, Chessells JM, Kempski H, et al.: Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia in the UK: a population-based study of incidence and survival. Br J Haematol 121 (5): 758-67, 2003.
2. 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.
3. Arber DA, Orazi A, Hasserjian R, et al.: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127 (20): 2391-405, 2016.
4. Chan RJ, Cooper T, Kratz CP, et al.: Juvenile myelomonocytic leukemia: a report from the 2nd International JMML Symposium. Leuk Res 33 (3): 355-62, 2009.
5. Loh ML: Recent advances in the pathogenesis and treatment of juvenile myelomonocytic leukaemia. Br J Haematol 152 (6): 677-87, 2011.
6. Bresolin S, Zecca M, Flotho C, et al.: Gene expression-based classification as an independent predictor of clinical outcome in juvenile myelomonocytic leukemia. J Clin Oncol 28 (11): 1919-27, 2010.
7. Olk-Batz C, Poetsch AR, Nöllke P, et al.: Aberrant DNA methylation characterizes juvenile myelomonocytic leukemia with poor outcome. Blood 117 (18): 4871-80, 2011.
8. Stiller CA, Chessells JM, Fitchett M: Neurofibromatosis and childhood leukaemia/lymphoma: a population-based UKCCSG study. Br J Cancer 70 (5): 969-72, 1994.
9. Choong K, Freedman MH, Chitayat D, et al.: Juvenile myelomonocytic leukemia and Noonan syndrome. J Pediatr Hematol Oncol 21 (6): 523-7, 1999 Nov-Dec.
10. Tartaglia M, Niemeyer CM, Fragale A, et al.: Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet 34 (2): 148-50, 2003.
11. Kratz CP, Niemeyer CM, Castleberry RP, et al.: The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease. Blood 106 (6): 2183-5, 2005.
12. Strullu M, Caye A, Lachenaud J, et al.: Juvenile myelomonocytic leukaemia and Noonan syndrome. J Med Genet 51 (10): 689-97, 2014.
13. Loh ML, Sakai DS, Flotho C, et al.: Mutations in CBL occur frequently in juvenile myelomonocytic leukemia. Blood 114 (9): 1859-63, 2009.
14. Muramatsu H, Makishima H, Jankowska AM, et al.: Mutations of an E3 ubiquitin ligase c-Cbl but not TET2 mutations are pathogenic in juvenile myelomonocytic leukemia. Blood 115 (10): 1969-75, 2010.
15. Niemeyer CM, Kang MW, Shin DH, et al.: Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nat Genet 42 (9): 794-800, 2010.
16. Pérez B, Mechinaud F, Galambrun C, et al.: Germline mutations of the CBL gene define a new genetic syndrome with predisposition to juvenile myelomonocytic leukaemia. J Med Genet 47 (10): 686-91, 2010.
17. Caye A, Strullu M, Guidez F, et al.: Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network. Nat Genet 47 (11): 1334-40, 2015.
18. Stieglitz E, Taylor-Weiner AN, Chang TY, et al.: The genomic landscape of juvenile myelomonocytic leukemia. Nat Genet 47 (11): 1326-33, 2015.
19. Murakami N, Okuno Y, Yoshida K, et al.: Integrated molecular profiling of juvenile myelomonocytic leukemia. Blood 131 (14): 1576-1586, 2018.
20. Sakaguchi H, Okuno Y, Muramatsu H, et al.: Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia. Nat Genet 45 (8): 937-41, 2013.
21. Stieglitz E, Mazor T, Olshen AB, et al.: Genome-wide DNA methylation is predictive of outcome in juvenile myelomonocytic leukemia. Nat Commun 8 (1): 2127, 2017.
22. Helsmoortel HH, Bresolin S, Lammens T, et al.: LIN28B overexpression defines a novel fetal-like subgroup of juvenile myelomonocytic leukemia. Blood 127 (9): 1163-72, 2016.
23. Freedman MH, Estrov Z, Chan HS: Juvenile chronic myelogenous leukemia. Am J Pediatr Hematol Oncol 10 (3): 261-7, 1988 Fall.
24. Locatelli F, Nöllke P, Zecca M, et al.: Hematopoietic stem cell transplantation (HSCT) in children with juvenile myelomonocytic leukemia (JMML): results of the EWOG-MDS/EBMT trial. Blood 105 (1): 410-9, 2005.
25. Bergstraesser E, Hasle H, Rogge T, et al.: Non-hematopoietic stem cell transplantation treatment of juvenile myelomonocytic leukemia: a retrospective analysis and definition of response criteria. Pediatr Blood Cancer 49 (5): 629-33, 2007.
26. Castleberry RP, Emanuel PD, Zuckerman KS, et al.: A pilot study of isotretinoin in the treatment of juvenile chronic myelogenous leukemia. N Engl J Med 331 (25): 1680-4, 1994.
27. Woods WG, Barnard DR, Alonzo TA, et al.: Prospective study of 90 children requiring treatment for juvenile myelomonocytic leukemia or myelodysplastic syndrome: a report from the Children's Cancer Group. J Clin Oncol 20 (2): 434-40, 2002.
28. Loh ML: Childhood myelodysplastic syndrome: focus on the approach to diagnosis and treatment of juvenile myelomonocytic leukemia. Hematology Am Soc Hematol Educ Program 2010: 357-62, 2010.
29. Hasle H: Myelodysplastic and myeloproliferative disorders in children. Curr Opin Pediatr 19 (1): 1-8, 2007.
30. Stieglitz E, Ward AF, Gerbing RB, et al.: Phase II/III trial of a pre-transplant farnesyl transferase inhibitor in juvenile myelomonocytic leukemia: a report from the Children's Oncology Group. Pediatr Blood Cancer 62 (4): 629-36, 2015.
31. Smith FO, King R, Nelson G, et al.: Unrelated donor bone marrow transplantation for children with juvenile myelomonocytic leukaemia. Br J Haematol 116 (3): 716-24, 2002.
32. Yusuf U, Frangoul HA, Gooley TA, et al.: Allogeneic bone marrow transplantation in children with myelodysplastic syndrome or juvenile myelomonocytic leukemia: the Seattle experience. Bone Marrow Transplant 33 (8): 805-14, 2004.
33. Baker D, Cole C, Price J, et al.: Allogeneic bone marrow transplantation in juvenile myelomonocytic leukemia without total body irradiation. J Pediatr Hematol Oncol 26 (3): 200-3, 2004.
34. Locatelli F, Niemeyer CM: How I treat juvenile myelomonocytic leukemia. Blood 125 (7): 1083-90, 2015.
35. Locatelli F, Crotta A, Ruggeri A, et al.: Analysis of risk factors influencing outcomes after cord blood transplantation in children with juvenile myelomonocytic leukemia: a EUROCORD, EBMT, EWOG-MDS, CIBMTR study. Blood 122 (12): 2135-41, 2013.
36. Yabe M, Sako M, Yabe H, et al.: A conditioning regimen of busulfan, fludarabine, and melphalan for allogeneic stem cell transplantation in children with juvenile myelomonocytic leukemia. Pediatr Transplant 12 (8): 862-7, 2008.
37. Koyama M, Nakano T, Takeshita Y, et al.: Successful treatment of JMML with related bone marrow transplantation after reduced-intensity conditioning. Bone Marrow Transplant 36 (5): 453-4; author reply 454, 2005.
38. Dvorak CC, Satwani P, Stieglitz E, et al.: Disease burden and conditioning regimens in ASCT1221, a randomized phase II trial in children with juvenile myelomonocytic leukemia: A Children's Oncology Group study. Pediatr Blood Cancer 65 (7): e27034, 2018.
39. Yoshimi A, Bader P, Matthes-Martin S, et al.: Donor leukocyte infusion after hematopoietic stem cell transplantation in patients with juvenile myelomonocytic leukemia. Leukemia 19 (6): 971-7, 2005.
40. Yoshimi A, Mohamed M, Bierings M, et al.: Second allogeneic hematopoietic stem cell transplantation (HSCT) results in outcome similar to that of first HSCT for patients with juvenile myelomonocytic leukemia. Leukemia 21 (3): 556-60, 2007.

Chronic Myelogenous Leukemia (CML)

Incidence

Chronic myelogenous leukemia (CML) accounts for less than 5% of all childhood leukemia, and in the pediatric age range, occurs most commonly in older adolescents.[1]

Molecular Abnormality

The cytogenetic abnormality most characteristic of CML is the Philadelphia chromosome (Ph), which represents a translocation of chromosomes 9 and 22 (t(9;22)) resulting in a BCR-ABL1 fusion protein.[2]

Clinical Presentation

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

CML has the following three clinical phases:

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

Treatment of CML: Historical Perspective

Before the tyrosine kinase inhibitor (TKI) era, allogeneic hematopoietic stem cell transplantation (HSCT) was the primary treatment for children with CML. Published reports from this period described survival rates of 70% to 80% when an HLA–matched-family donor (MFD) was used in the treatment of children in early chronic phase, with lower survival rates when HLA–matched-unrelated donors were used.[4,5,6]

Relapse rates were low (less than 20%) when transplant was performed in chronic phase.[4,5] The primary cause of death was treatment-related mortality, which was increased with HLA–matched-unrelated donors compared with HLA-MFDs in most reports.[4,5] High-resolution DNA matching for HLA alleles appeared to reduce rates of treatment-related mortality, leading to improved outcome for HSCT using unrelated donors.[7]

Compared with transplantation in chronic phase, transplantation in accelerated phase or blast crisis and in second-chronic phase resulted in significantly reduced survival.[4,5,6] The use of T-lymphocyte depletion to avoid graft-versus-host disease resulted in a higher relapse rate and decreased overall survival (OS),[8] supporting the contribution of a graft-versus-leukemia effect to favorable outcome after allogeneic HSCT.

The introduction of the TKI imatinib as a therapeutic drug targeted at inhibiting the BCR-ABL1 fusion kinase revolutionized the treatment of patients with CML, for both children and adults.[9] As most data on the use of TKIs for CML is from adult clinical trials, the adult experience is initially described, followed by a description of the more limited experience in children.

Treatment of Adult CML With TKIs

Imatinib is a potent inhibitor of the ABL1 tyrosine kinase, platelet-derived growth factor (PDGF) receptors (alpha and beta), and KIT. Imatinib treatment achieves clinical, cytogenetic, and molecular remissions (as defined by the absence of BCR-ABL1 fusion transcripts) in a high proportion of CML patients treated in chronic phase.[10]

Evidence (imatinib for adults):

1. Imatinib replaced the use of recombinant interferon alfa in the initial treatment of CML on the basis of the results of a large phase III trial that compared imatinib with interferon plus cytarabine (IRIS).[11,12]
   • Patients who received imatinib had higher complete cytogenetic response rates (76% vs. 14% at 18 months).[11] The rate of treatment failure diminished over time, from 3.3% and 7.5% in the first and second years of imatinib treatment, respectively, to less than 1% by the fifth year of treatment.[12]
   • After censoring for patients who died from causes unrelated to CML or transplantation, the overall estimated survival rate for patients randomly assigned to imatinib was 95% at 60 months.[12]

Guidelines for imatinib treatment have been developed for adults with CML on the basis of patient response to treatment, including the timing of achieving complete hematologic response, complete cytogenetic response, and major molecular response (defined as attainment of a 3-log reduction in BCR-ABL1/control gene ratio).[13,14,15,16]

Poor adherence is a major reason for loss of complete cytogenetic response and imatinib failure for adult patients with CML on long-term therapy.[17] The identification of BCR-ABL1 kinase domain mutations at the time of failure or of suboptimal response to imatinib treatment also has clinical implications,[18] because there are alternative BCR-ABL1 kinase inhibitors (e.g., dasatinib and nilotinib) that maintain their activity against some (but not all) mutations that confer resistance to imatinib.[13,19,20]

Two TKIs, dasatinib and nilotinib, have been shown to be effective in patients who have an inadequate response to imatinib, although not in patients with the T315I mutation. Both dasatinib and nilotinib have also received regulatory approval for the treatment of newly diagnosed chronic-phase CML in adults, on the basis of the following studies:

• Dasatinib. Dasatinib was approved on the basis of a phase III trial that compared dasatinib (100 mg daily) with imatinib (400 mg daily).[21] There was no significant difference in progression-free survival (PFS) or OS. However, after 12 months of treatment, dasatinib was associated with a higher rate of complete cytogenetic response (83% vs. 72%, P = .001) and major molecular response (46% vs. 28%, P < .0001). Responses were achieved in a shorter time with dasatinib (P < .0001).
• Nilotinib. Nilotinib (at a dose of either 300 mg or 400 mg twice daily) was compared with imatinib (400 mg daily) in a phase III trial.[22] At 12 months, the rates of complete cytogenetic response were significantly higher for nilotinib (80% for the 300-mg dose and 78% for the 400-mg dose) than were the rates for imatinib (65%) (P < .001 for both comparisons). Also, nilotinib was associated with higher rates of major molecular response (44% for the 300-mg dose and 43% for the 400-mg dose compared with 22% for imatinib, P < .001 for both comparisons). The 300-mg twice-daily dose of nilotinib was associated with a more favorable safety profile compared with the 400-mg dose.

Because of the superiority over imatinib in terms of complete cytogenetic response rate and major molecular response rate, both dasatinib and nilotinib are extensively used as first-line therapy in adults with CML. However, despite more rapid responses with dasatinib and nilotinib than with imatinib when used as frontline therapy, PFS and OS appear to be similar for all three agents.[23,24] Additional follow-up will be required to better define the impact of these agents on long-term PFS and OS.

Bosutinib is another TKI that targets the BCR-ABL1 fusion and has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of all phases of CML in adults who show intolerance to or whose disease shows resistance to previous therapy with another TKI. Bosutinib has not been studied in the pediatric population.

Ponatinib is a BCR-ABL1 inhibitor that is effective against the T315I mutation.[25] Ponatinib induced objective responses in approximately 70% of heavily pretreated adults with chronic-phase CML, with responses observed regardless of the baseline BCR-ABL1 kinase domain mutation.[26] Development of ponatinib has been complicated by the high rate of vascular occlusion observed in patients receiving the agent, with arterial and venous thrombosis and occlusions (including myocardial infarction and stroke) occurring in more than 20% of treated patients.[27] Ponatinib has not been prospectively studied in the pediatric population.

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

Evidence (imatinib followed by HSCT in adults):

1. A retrospective study that compared 145 patients who received imatinib before transplant with a historical cohort of 231 patients showed no difference in early hepatic toxic effects or engraftment delay.[28]
   • In addition, OS, disease-free survival, relapse, and nonrelapse mortality were similar between the two cohorts.
   • The only factor associated with poor outcome in the cohort that received imatinib was a poor initial response to imatinib.
2. Further evidence for a lack of effect of pretransplant imatinib on posttransplant outcomes was supplied by a report from the Center for International Blood and Marrow Transplant Research; this report compared outcomes of 181 pediatric and adult subjects with CML in first chronic phase treated with imatinib before HSCT with that of 657 subjects who did not receive imatinib before HSCT.[29]
   • Among the patients in first chronic phase, imatinib therapy before HSCT was associated with better OS.
3. A third report of imatinib followed by allogeneic HSCT supports the efficacy of this transplantation strategy in patients with imatinib failure in first chronic phase.[13]
   • The 3-year OS rate was 94% for this group (n = 37), with approximately 90% of patients achieving a complete molecular remission after HSCT.

For adult patients treated with a TKI alone (without HSCT), the optimal duration of therapy remains unknown and most patients continue TKI treatment indefinitely. Studies are ongoing to determine the safety of discontinuing TKI therapy and the criteria most prognostic of sustained remissions after ending TKI therapy.

Evidence (length of imatinib therapy in adults):

1. In an attempt to determine the length of treatment, a prospective study reported on 69 adults treated with imatinib for more than 2 years who had been in a cytogenetic major response for more than 2 years. The patients were monitored monthly and restarted on imatinib if there was evidence of molecular relapse.[30]
   • Of this group, 61% of patients experienced disease relapse, with about 38% still in cytogenetic major response at 24 months.
   • All of the patients who had disease recurrence responded again to the reinitiation of imatinib.
2. Another study reported on 40 patients with chronic-phase CML who discontinued treatment with imatinib after at least 2 years of sustained undetectable minimal residual disease (MRD) by polymerase chain reaction (PCR).[31]
   • At 24 months, the probability of sustained molecular remission for patients no longer receiving imatinib was 47.1%.
   • Most relapses occurred within 4 months of stopping treatment with imatinib, and no relapses beyond 27 months were observed.
   • All patients with molecular relapse demonstrated a favorable response when imatinib was restarted; with a median follow-up of 42 months, no patients had progressive disease or developed the BCR-ABL1 fusion.

Additional research is required before cessation of imatinib or other BCR-ABL1 targeted therapy for selected patients with CML in molecular remission can be recommended as a standard clinical practice.

Treatment of Childhood CML

Treatment options for children with CML may include the following:

1. TKI therapy, such as imatinib.

Imatinib has shown a high level of activity in children with CML that is comparable with the activity observed in adults.[32,33,34,35,36]

Evidence (imatinib in children):

1. In a prospective trial, 44 pediatric patients with newly diagnosed CML were treated with imatinib (260 mg/day).[36]
   • The PFS rate at 36 months was 98%.
   • A complete hematologic response was achieved in 98% of the patients.
   • The rate of complete cytogenetic response was 61% and the rate of major molecular response was 31% at 12 months, similar to the rates seen in adult chronic-phase CML patients treated with imatinib.

As a result of this high level of activity, it is common to initiate imatinib treatment in children with CML rather than proceeding immediately to allogeneic stem cell transplantation.[37] The pharmacokinetics of imatinib in children appears consistent with previous results in adults.[38]

Doses of imatinib used in phase II trials for children with CML have ranged from 260 mg/m² to 340 mg/m², which provide comparable drug exposures as the adult flat-doses of 400 mg to 600 mg.[34,35,36]

Evidence (imatinib dose in children):

1. In an Italian study of 47 pediatric patients with chronic-phase CML who were treated with 340 mg/m² per day of imatinib, complete cytogenetic response was achieved in 91.5% of patients at a median time of 6 months, and the rate of major molecular response at 12 months was 66.6%.[36]

   Thus, it appears that starting with the higher dose of 340 mg/m² has superior efficacy and is typically tolerable, with dose adjustment as needed for toxicity.[35,36]

2. Early molecular responses, such as PCR-based MRD measurement at 3 months of therapy showing up to 10% BCR-ABL1, have been reported to be associated with improved PFS, similar to early molecular response data in adults.[39]

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

Imatinib is generally well tolerated in children, with adverse effects generally being mild to moderate and reversible with treatment discontinuation or dose reduction.[34,35] Growth retardation occurs in most prepubertal children receiving imatinib.[40] Children receiving imatinib and experiencing growth impairment may show some catch-up growth during their pubertal growth spurts, but they are at risk of having lower-than-expected adult height, as most patients do not achieve midparental height.[40,41]

There are fewer published data regarding the efficacy and toxicities of the two other TKIs approved by the FDA for use in children with CML—dasatinib and nilotinib.

Evidence (dasatinib in children):

1. A phase I trial of dasatinib in children showed that drug disposition, tolerability, and efficacy of this agent was similar to that observed in adults.[42,43]
2. A phase II trial of dasatinib, which included 84 children with newly diagnosed CML in chronic phase, utilized a dose of 60 mg/m² (tablets) or 72 mg/m² (oral solution) given to patients once daily.[44]
   • Complete cytogenetic response and major molecular response (≥3-log reduction or ≤0.1% on the International Scale) were achieved in 92% and 52% of patients, respectively, after 12 months of therapy, with a 4-year PFS rate of 93%.
   • Dasatinib was well tolerated, with very few grade 3 or grade 4 adverse events. No pleural or pericardial effusions or pulmonary complications were observed.

Evidence (nilotinib in children):

1. The approval of nilotinib by the FDA in March 2018 for the treatment of children with CML was based on two sponsored trials.[45,46]

   An initial study (NCT01077544 [CAMN107A2120]) of 11 patients evaluated pharmacokinetic, safety, and preliminary efficacy data; a second study (NCT01844765 [CAMN107A2203; AAML1321]) of 58 patients evaluated efficacy and safety. Data from both studies were combined for a pooled-data analysis of 69 patients, which included 25 patients with newly diagnosed CML and 44 patients with resistant or intolerant CML. Both studies utilized a dose of 230 mg/m² given twice daily (rounded to the nearest 50 mg; maximum dose, 400 mg).[46]

   • In the phase II trial, 64% of patients with newly diagnosed CML achieved a major molecular response at 1 year.
   • The tolerability of nilotinib in children was similar to that observed in adults. Primary side effects affecting more than 30% of children included headache, fever, and hyperbilirubinemia.
   • Prolongation of QTc interval (defined in this trial as an increase of >30 msec over baseline) is a recognized side effect of nilotinib, and it was observed in 25% of children in these trials. The investigators recommend obtaining an electrocardiogram at baseline, 1 week, periodically afterward, and after dose adjustments.

A safe pediatric dose has not yet been established for other TKIs (e.g., bosutinib and ponatinib).

Treatment Options under Clinical Evaluation

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

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

• AAML18P1 (NCT03817398) (Stopping TKIs in Affecting Treatment-Free Remission in Patients With Chronic-Phase CML): This COG study is a nonrandomized, prospective, longitudinal study enrolling children who have achieved a deep remission (BCR-ABL1 <0.01% by real-time quantitative-polymerase chain reaction of peripheral blood [>MR4, i.e., >4-log reduction]) for at least 2 years after receiving the same TKI for at least 3 years. This trial is examining the incidence of molecular recurrence after discontinuing TKI therapy and the ability of patients to re-enter remission if recurrence occurs.

Treatment of Recurrent or Refractory Childhood CML

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

1. Alternative kinase inhibitors such as dasatinib or nilotinib.
2. Allogeneic HSCT.

In children who develop a hematologic or cytogenetic relapse during treatment with imatinib or who have an inadequate initial response to imatinib, determination of BCR-ABL1 kinase domain mutation status should be considered to help guide subsequent therapy. Depending on the patient's mutation status, alternative kinase inhibitors such as dasatinib or nilotinib can be considered on the basis of the adult and pediatric experience with these agents.[21,22,44,47,48,49]

Evidence (dasatinib in children with resistant or intolerant CML):

1. In a study of 14 children with resistant or intolerant CML, the following results were observed:[44]
   • 76% of patients were in complete cytogenetic remission, and 41% of patients had a major molecular response after 12 months of dasatinib therapy.
   • The PFS rate was 78% at 48 months.

Evidence (nilotinib in children with resistant or intolerant CML):

1. In a study of 44 children with CML who were resistant or intolerant to imatinib or dasatinib, the following results were observed:[45]
   • 40.7% of patients achieved a major molecular response after 12 months of nilotinib therapy.