martes, 16 de abril de 2019

Childhood Acute Myeloid Leukemia Treatment (PDQ®) 1/3 —Health Professional Version - National Cancer Institute

Childhood Acute Myeloid Leukemia Treatment (PDQ®)—Health Professional Version - National Cancer Institute

National Cancer Institute



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

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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] The majority of myeloid leukemias are acute, and the remainder include chronic and/or subacute myeloproliferative disorders such as chronic myelogenous leukemia and juvenile myelomonocytic leukemia. Myelodysplastic syndromes occur much less frequently in children than in adults and almost invariably represent clonal, preleukemic conditions that may evolve from congenital marrow failure syndromes such as Fanconi anemia and Shwachman-Diamond syndrome.
The general characteristics of myeloid leukemias and other myeloid malignancies are described below:
  • Acute myeloid leukemia (AML). AML is defined as a clonal disorder caused by malignant transformation of a bone marrow–derived, self-renewing stem cell or progenitors, leading to accumulation of immature, nonfunctional myeloid cells. These events lead to increased accumulation in the bone marrow and other organs by these malignant myeloid cells. To be called acute, the bone marrow usually must include greater than 20% immature leukemic blasts, with some exceptions as noted in subsequent sections. (Refer to the Treatment Option Overview for Childhood AML and Treatment of Childhood AML sections of this summary for more information.)
  • Transient abnormal myelopoiesis (TAM). TAM is also termed transient myeloproliferative disorder or transient leukemia. The TAM observed in infants with Down syndrome represents a clonal expansion of myeloblasts that can be difficult to distinguish from AML. Most importantly, TAM spontaneously regresses in most cases within the first 3 months of life. TAM occurs in 4% to 10% of infants with Down syndrome.[3-5]
    TAM blasts most commonly have megakaryoblastic differentiation characteristics and distinctive mutations involving the GATA1 gene.[6,7] TAM may occur in phenotypically normal infants with genetic mosaicism in the bone marrow for trisomy 21. While TAM is generally not characterized by cytogenetic abnormalities other than trisomy 21, the presence of additional cytogenetic findings may predict an increased risk of developing subsequent AML.[8] Approximately 20% of infants with TAM of Down syndrome eventually develop AML, with most cases diagnosed within the first 3 years of life.[7,8]
    Early death from TAM-related complications occurs in 10% to 20% of affected infants.[8-10] Infants with progressive organomegaly, visceral effusions, high blast count (>100,000 cells/μL) and laboratory evidence of progressive liver dysfunction are at a particularly high risk of early mortality.[8,10] (Refer to the Children With Down Syndrome and AML or Transient Abnormal Myelopoiesis [TAM] section of this summary for more information.)
  • Myelodysplastic syndrome (MDS). MDS in children represents a heterogeneous group of disorders characterized by ineffective hematopoiesis, impaired maturation of myeloid progenitors with dysplastic morphologic features, and cytopenias. Although the underlying cause of MDS in children is unclear, there is often an association with marrow failure syndromes. Most patients with MDS may have hypercellular bone marrows without increased numbers of leukemic blasts, but some patients may present with a very hypocellular bone marrow, making the distinction between severe aplastic anemia and MDS difficult.[11]
    The presence of a karyotype abnormality in a hypocellular marrow is consistent with MDS and transformation to AML should be expected. Given the high association of MDS evolving into AML, patients with MDS are typically referred for stem cell transplantation before transformation to AML. (Refer to the Myelodysplastic Syndromes [MDS] section of this summary for more information.)
  • Juvenile myelomonocytic leukemia (JMML). JMML represents the most common myeloproliferative syndrome observed in young children. JMML occurs at a median age of 1.8 years.
    JMML characteristically presents with hepatosplenomegaly, lymphadenopathy, fever, and skin rash along with an elevated white blood cell (WBC) count and increased circulating monocytes.[12] In addition, patients often have an elevated hemoglobin F, hypersensitivity of the leukemic cells to granulocyte-macrophage colony-stimulating factor (GM-CSF), monosomy 7, and leukemia cell mutations in a gene involved in RAS pathway signaling (e.g., NF1, KRAS/NRAS, PTPN11, or CBL).[12-14] (Refer to the Juvenile Myelomonocytic Leukemia [JMML] section of this summary for more information.)
  • Chronic myelogenous leukemia (CML). CML is primarily an adult disease but represents the most common of the chronic myeloproliferative disorders in childhood, accounting for approximately 10% of childhood myeloid leukemia.[2] Although CML has been reported in very young children, most patients are aged 6 years and older.
    CML is a clonal panmyelopathy that involves all hematopoietic cell lineages. While the WBC count can be extremely elevated, the bone marrow does not show increased numbers of leukemic blasts during the chronic phase of this disease. CML is caused by the presence of the Philadelphia chromosome, a translocation between chromosomes 9 and 22 (i.e., t(9;22)) resulting in fusion of the BCR and ABL1 genes. (Refer to the Chronic Myelogenous Leukemia [CML] section of this summary for more information.)
    Other chronic myeloproliferative syndromes, such as polycythemia vera and essential thrombocytosis, are extremely rare in children.

Conditions Associated With Myeloid Malignancies

Genetic abnormalities (cancer predisposition syndromes) are associated with the development of AML. There is a high concordance rate of AML in identical twins; however, this is not believed to be related to genetic risk, but rather to shared circulation and the inability of one twin to reject leukemic cells from the other twin during fetal development.[15-17] There is an estimated twofold to fourfold increased risk of developing leukemia for the fraternal twin of a pediatric leukemia patient up to about age 6 years, after which the risk is not significantly greater than that of the general population.[18,19]
The development of AML has also been associated with a variety of inherited, acquired, and familial syndromes that result from chromosomal imbalances or instabilities, defects in DNA repair, altered cytokine receptor or signal transduction pathway activation, and altered protein synthesis.[20,21]
Inherited syndromes
  • Chromosomal imbalances:
    • Down syndrome.
    • Familial monosomy 7.
  • Chromosomal instability syndromes:
    • Fanconi anemia.
    • Dyskeratosis congenita.
    • Bloom syndrome.
  • Syndromes of growth and cell survival signaling pathway defects:
    • Neurofibromatosis type 1 (particularly JMML development).
    • Noonan syndrome (particularly JMML development).
    • Severe congenital neutropenia (Kostmann syndrome).
    • Shwachman-Diamond syndrome.
    • Diamond-Blackfan anemia.
    • Congenital amegakaryocytic thrombocytopenia.
    • CBL germline syndrome (particularly in JMML).
    • Li-Fraumeni syndrome (TP53 mutations).
Acquired syndromes
  • Severe aplastic anemia.
  • Paroxysmal nocturnal hemoglobinuria.
  • Amegakaryocytic thrombocytopenia.
  • Acquired monosomy 7.
Familial MDS and AML syndromes
  • Familial platelet disorder with a propensity to develop AML (associated with germline RUNX1 mutations).
  • Familial MDS and AML syndromes with germline GATA2 mutations.
  • Familial MDS and AML syndromes with germline CEBPA mutations.[22]
  • Telomere biology disorders resulting from a mutation in TERC or TERT (i.e., occult dyskeratosis congenita).
Nonsyndromic genetic susceptibility to AML is also being studied. For example, homozygosity for a specific IKZF1 polymorphism has been associated with an increased risk of infant AML.[23]
References
  1. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PUBMED Abstract]
  2. Smith MA, Ries LA, Gurney JG, et al.: Leukemia. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649, pp 17-34. Also available online. Last accessed January 31, 2019.
  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. [PUBMED Abstract]
  4. Zipursky A: Transient leukaemia--a benign form of leukaemia in newborn infants with trisomy 21. Br J Haematol 120 (6): 930-8, 2003. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  9. Homans AC, Verissimo AM, Vlacha V: Transient abnormal myelopoiesis of infancy associated with trisomy 21. Am J Pediatr Hematol Oncol 15 (4): 392-9, 1993. [PUBMED Abstract]
  10. 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. [PUBMED Abstract]
  11. Hasle H, Niemeyer CM: Advances in the prognostication and management of advanced MDS in children. Br J Haematol 154 (2): 185-95, 2011. [PUBMED Abstract]
  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. [PUBMED Abstract]
  13. Loh ML: Recent advances in the pathogenesis and treatment of juvenile myelomonocytic leukaemia. Br J Haematol 152 (6): 677-87, 2011. [PUBMED Abstract]
  14. Stieglitz E, Taylor-Weiner AN, Chang TY, et al.: The genomic landscape of juvenile myelomonocytic leukemia. Nat Genet 47 (11): 1326-33, 2015. [PUBMED Abstract]
  15. Zuelzer WW, Cox DE: Genetic aspects of leukemia. Semin Hematol 6 (3): 228-49, 1969. [PUBMED Abstract]
  16. Miller RW: Persons with exceptionally high risk of leukemia. Cancer Res 27 (12): 2420-3, 1967. [PUBMED Abstract]
  17. Inskip PD, Harvey EB, Boice JD Jr, et al.: Incidence of childhood cancer in twins. Cancer Causes Control 2 (5): 315-24, 1991. [PUBMED Abstract]
  18. Kurita S, Kamei Y, Ota K: Genetic studies on familial leukemia. Cancer 34 (4): 1098-101, 1974. [PUBMED Abstract]
  19. Greaves M: Pre-natal origins of childhood leukemia. Rev Clin Exp Hematol 7 (3): 233-45, 2003. [PUBMED Abstract]
  20. Puumala SE, Ross JA, Aplenc R, et al.: Epidemiology of childhood acute myeloid leukemia. Pediatr Blood Cancer 60 (5): 728-33, 2013. [PUBMED Abstract]
  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. [PUBMED Abstract]
  22. Tawana K, Wang J, Renneville A, et al.: Disease evolution and outcomes in familial AML with germline CEBPA mutations. Blood 126 (10): 1214-23, 2015. [PUBMED Abstract]
  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. [PUBMED Abstract]

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.[1-5] 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 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.[8-10]
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]
Table 1. Acute Leukemias of Ambiguous Lineage According to the World Health Organization Classification of Tumors of Hematopoietic and Lymphoid Tissuesa
ConditionDefinition
NOS = not otherwise specified.
aBéné MC: Biphenotypic, bilineal, ambiguous or mixed lineage: strange leukemias! Haematologica 94 (7): 891-3, 2009.[13] Obtained from Haematologica/the Hematology Journal website http://www.haematologica.org.
Acute undifferentiated leukemiaAcute 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-ABL1Acute leukemia meeting the diagnostic criteria for mixed phenotype acute leukemia in which the blasts also have the (9;22) translocation or the BCR-ABL1 rearrangement
Mixed phenotype acute leukemia with t(v;11q23); KMT2A (MLL) rearrangedAcute leukemia meeting the diagnostic criteria for mixed phenotype acute leukemia in which the blasts also have a translocation involving the KMT2A gene
Mixed phenotype acute leukemia, B/myeloid, NOSAcute leukemia meeting the diagnostic criteria for assignment to both B and myeloid lineage, in which the blasts lack genetic abnormalities involving BCR-ABL1 or KMT2A
Mixed phenotype acute leukemia, T/myeloid, NOSAcute leukemia meeting the diagnostic criteria for assignment to both T and myeloid lineage, in which the blasts lack genetic abnormalities involving BCR-ABL1 or KMT2A
Mixed phenotype acute leukemia, B/myeloid, NOS—rare typesAcute leukemia meeting the diagnostic criteria for assignment to both B- and T-lineage
Other ambiguous lineage leukemiasNatural 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 Leukemiaa
LineageCriteria
aAdapted from Arber et al.[12]
bStrong defined as equal to or brighter than the normal B or T cells in the sample.
Myeloid LineageMyeloperoxidase (flow cytometry, immunohistochemistry, or cytochemistry); ormonocytic differentiation (at least two of the following: nonspecific esterase cytochemistry, CD11c, CD14, CD64, lysozyme)
T LineageStrongb cytoplasmic CD3 (with antibodies to CD3 epsilon chain); or surface CD3
B LineageStrongb 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.[15] 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.[15] Some studies suggest that patients with biphenotypic leukemia may fare better with a lymphoid, as opposed to a myeloid, treatment regimen.[16-19] 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.[19]

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.[20,21] Traditionally, MDS classification systems have been divided into several distinct categories based on the presence of the following:[21-24]
  • 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.[25] 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).[26] 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.[12,25] 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 WHO 2016 guidelines caution that reactive etiologies, rather than clonal, may have more than 10% dysplasia and should be excluded especially when dysplasia is subtle and/or restricted to a single lineage.[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.[27] 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:[26]
  • 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 [28] or SAMD9/SAMD9L [29-31] 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.[30,32]
Table 3. World Health Organization (WHO) Classification of Bone Marrow and Peripheral Blood Findings for Myelodysplastic Syndromes (MDS)a
Type of MDSBone MarrowPeripheral Blood
aAdapted from Arber et al.[12]
bNote that cases with pancytopenia would be classified as MDS-U.
cWhen the marrow has <5% myeloblasts, but the peripheral blood has 2%–4% myeloblasts, the diagnosis is MDS-EB-1.
dThe 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.
eRecurring 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.
fThe diagnostic criteria for childhood MDS (refractory cytopenia of childhood [RCC]-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 dysplasiaUnilineage dysplasia: ≥10% in one myeloid lineage1–2 cytopeniasb
<5% blastsBlasts <1%c
<15% ring sideroblasts 
 
MDS with ring sideroblasts (MDS-RS)Erythroid dysplasia only
<5% blastsNo blasts
≥15% ring sideroblasts 
 
MDS with multilineage dysplasiaDysplasia in ≥10% of cells in ≥2 myeloid lineages1–3 cytopenias
<5% blastsBlasts (none or <1%)c
±15% ring sideroblasts 
No Auer rodsNo Auer rods
 <1×109 monocytes/L
 
MDS with excess blasts-1 (MDS-EB-1)Single lineage or multilineage dysplasiaCytopenia(s)
5%–9% blastsc<5% blastsc
No Auer rodsNo Auer rods
 <1×109 monocytes/L
 
MDS with excess blasts-2 (MDS-EB-2)Single lineage or multilineage dysplasiaCytopenia(s)
10%–19% blastsd5%–19% blastsd
Auer rods ±dAuer rods ±d
 <1×109 monocytes/L
 
MDS with isolated del(5q)Normal to increased megakaryocytes (hypolobulated nuclei)Anemia
<5% blastsBlasts (none or <1%)
No Auer rodsNormal to increased platelet count
Isolated del(5q) 
 
MDS-unclassifiable (MDS-U)Dysplasia in <10% of cells in ≥1 myeloid cell lineageCytopenias
Cytogenetic abnormality associated with diagnosis of MDSe≤1% blastsc
<5% blasts 
 
Provisional entity: Refractory cytopenia of childhood (RCC)fRefer to Table 4 for more information.
Table 4. Definitions for Minimal Diagnostic Criteria for Childhood Myelodysplastic Syndrome (MDS) (Provisional Entity: Refractory Cytopenia of Childhood [RCC])a
 Erythroid LineageMyeloid LineageMegakaryocyte Lineage
aAdapted from Baumann et al.[33]
bBone marrow trephine/biopsy may be required as bone marrow in childhood RCC is often hypocellular.
cCharacteristics include abnormal nuclear lobulation, multinuclear cells, presence of nuclear bridges.
dPresence of pseudo–Pelger-Huet cells, hypo- or agranular cytoplasm, giant band forms.
eMegakaryocytes have variable size and often round or separated nuclei; the absence of megakaryocytes does not exclude the diagnosis of RCC.
Bone Marrow AspiratebDysplasia and/or megablastoid changes in ≥10% of erythroid precursorscDysplasia in ≥10% of granulocytic precursors and neutrophilsMicromegakaryocytes plus other dysplastic featurese
 <5% blastsd 
 
Bone Marrow BiopsyPresence of erythroid precursorsNo additional criteriaMicromegakaryocytes 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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  4. Bennett JM, Catovsky D, Daniel MT, et al.: A variant form of hypergranular promyelocytic leukaemia (M3) Br J Haematol 44 (1): 169-70, 1980. [PUBMED Abstract]
  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. [PUBMED Abstract]
  6. Bennett JM, Catovsky D, Daniel MT, et al.: Proposal for the recognition of minimally differentiated acute myeloid leukaemia (AML-MO) Br J Haematol 78 (3): 325-9, 1991. [PUBMED Abstract]
  7. Kaleem Z, White G: Diagnostic criteria for minimally differentiated acute myeloid leukemia (AML-M0). Evaluation and a proposal. Am J Clin Pathol 115 (6): 876-84, 2001. [PUBMED Abstract]
  8. Vardiman JW, Harris NL, Brunning RD: The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 100 (7): 2292-302, 2002. [PUBMED Abstract]
  9. Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3.
  10. Hasle H, Niemeyer CM, Chessells JM, et al.: A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases. Leukemia 17 (2): 277-82, 2003. [PUBMED Abstract]
  11. Arber DA, Vardiman JW, Brunning RD: Acute myeloid leukaemia with recurrent genetic abnormalities. 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 110-23.
  12. 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. [PUBMED Abstract]
  13. Béné MC: Biphenotypic, bilineal, ambiguous or mixed lineage: strange leukemias! Haematologica 94 (7): 891-3, 2009. [PUBMED Abstract]
  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. 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. [PUBMED Abstract]
  16. Rubnitz JE, Onciu M, Pounds S, et al.: Acute mixed lineage leukemia in children: the experience of St Jude Children's Research Hospital. Blood 113 (21): 5083-9, 2009. [PUBMED Abstract]
  17. Al-Seraihy AS, Owaidah TM, Ayas M, et al.: Clinical characteristics and outcome of children with biphenotypic acute leukemia. Haematologica 94 (12): 1682-90, 2009. [PUBMED Abstract]
  18. Matutes E, Pickl WF, Van't Veer M, et al.: Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification. Blood 117 (11): 3163-71, 2011. [PUBMED Abstract]
  19. Hrusak O, De Haas V, Stancikova J, et al.: International cooperative study identifies treatment strategy in childhood ambiguous lineage leukemia. Blood : , 2018. [PUBMED Abstract]
  20. Bennett JM, Catovsky D, Daniel MT, et al.: Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51 (2): 189-99, 1982. [PUBMED Abstract]
  21. Mandel K, Dror Y, Poon A, et al.: A practical, comprehensive classification for pediatric myelodysplastic syndromes: the CCC system. J Pediatr Hematol Oncol 24 (7): 596-605, 2002. [PUBMED Abstract]
  22. Bennett JM: World Health Organization classification of the acute leukemias and myelodysplastic syndrome. Int J Hematol 72 (2): 131-3, 2000. [PUBMED Abstract]
  23. Head DR: Proposed changes in the definitions of acute myeloid leukemia and myelodysplastic syndrome: are they helpful? Curr Opin Oncol 14 (1): 19-23, 2002. [PUBMED Abstract]
  24. 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. [PUBMED Abstract]
  25. 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.
  26. Wlodarski MW, Sahoo SS, Niemeyer CM: Monosomy 7 in Pediatric Myelodysplastic Syndromes. Hematol Oncol Clin North Am 32 (4): 729-743, 2018. [PUBMED Abstract]
  27. 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. [PUBMED Abstract]
  28. 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. [PUBMED Abstract]
  29. 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. [PUBMED Abstract]
  30. Schwartz JR, Ma J, Lamprecht T, et al.: The genomic landscape of pediatric myelodysplastic syndromes. Nat Commun 8 (1): 1557, 2017. [PUBMED Abstract]
  31. 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. [PUBMED Abstract]
  32. 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. [PUBMED Abstract]
  33. 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 Patternsa
ENLARGE
 M0AML, 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.
aRefer to the French-American-British (FAB) Classification for Childhood Acute Myeloid Leukemia section of this summary for more information about the morphologic-histochemical classification system for AML.
bThese 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.[1-3] 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).[7]
Less than 5% of cases of acute leukemia in children are of ambiguous lineage, expressing features of both myeloid and lymphoid lineage.[8-10] 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.[11-13] 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).[14]

Molecular Evaluation

Comprehensive molecular profiling of pediatric and adult AML has shown that AML is a disease demonstrating both commonalities and differences across the age spectrum.[15,16]
  • 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).[15,17] 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.[16] 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).[16]
  • 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.[15,16]
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.[17-23] 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.[24-27]
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.[14] 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.[14] Table 6 also shows, in the bottom three rows, additional relatively common recurrent translocations observed in children with AML.[21,22,28]
Table 6. Common Pediatric Acute Myeloid Leukemia (AML) Chromosomal Translocations
Gene Fusion ProductChromosomal TranslocationPrevalence in Pediatric AML (%)
aCryptic chromosomal translocation.
KMT2A (MLL) translocated11q23.325.0
NUP98-NSD1 at(5;11)(q35.3;p15.5)7.0
CBFA2T3-GLIS2 ainv(16)(p13.3;q24.3)3.0
NUP98-KDM5A4 at(11;12)(p15.5;p13.5)3.0
DEK-NUP214t(6;9)(p23;q34.1)1.7
RBM15(OTT)-MKL1(MAL)t(1;22)(p13.3;q13.1)0.8
MNX1-ETV6t(7;12)(q36.3;p13.2)0.8
KAT6A-CREBBPt(8;16)(p11.2;p13.3)0.5
RUNX1-RUNX1T1t(8;21)(q22;q22)13–14
CBFB-MYH11inv(16)(p13.1;q22) or t(16;16)(p13.1;q22)4–9
PML-RARAt(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.[29] 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 the FLT3-ITDmutation 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.

Molecular abnormalities associated with a favorable prognosis

Molecular abnormalities associated with a favorable prognosis include the following:
  • Core-binding factor (CBF) AML includes cases with RUNX1-RUNX1T1 and CBFB-MYH11fusion genes that disrupt the activity of core-binding factor, 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.[30,31] Adults with t(8;21) have a more favorable prognosis than do adults with other types of AML.[18,32] Children with t(8;21) have a more favorable outcome than do children with AML characterized by normal or complex karyotypes,[18,33-35] with 5-year overall survival (OS) of 74% to 90%.[21,22,36] The t(8;21) translocation occurs in approximately 12% of children with AML.[21,22,36]
    • 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 MYH11gene at chromosome band 16p13. The inv(16) translocation is associated with the FAB M4Eo subtype.[37] Inv(16) confers a favorable prognosis for both adults and children with AML,[18,33-35] with a 5-year OS of about 85%.[21,22] Inv(16) occurs in 7% to 9% of children with AML.[21,22,36] As noted above, cases with CBFB-MYH11and cases with RUNX1-RUNX1T1 have distinctive secondary mutations; CBFB-MYH11secondary mutations are primarily restricted to genes that activate receptor tyrosine kinase signaling (NRAS, FLT3, and KIT).[38,39]
    • 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.[40] 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 of 77% and a cumulative incidence of relapse of 0%.[40]
    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 KITare the most commonly mutated genes for both subtypes. KIT mutations may indicate increased risk of treatment failure for patients with core-binding factor AML, although the prognostic significance of KIT mutations may be dependent on the mutant-allele ratio (high ratio unfavorable) and/or the specific type of mutation (exon 17 mutations unfavorable).[38,39] A study of children with RUNX1-RUNX1T1 AML observed KITmutations in 24% of cases (79% being exon 17 mutations) and RAS mutations in 15%, but neither were significantly associated with outcome.[36]
    Although both RUNX1-RUNX1T1 and CBFB-MYH11 fusion genes disrupt the activity of core-binding factor, cases with these genomic alterations have distinctive secondary mutations.[38,39]
    • 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.[38,39]
    • 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.[41] Similar results, albeit with smaller numbers, were reported for children with RUNX1-RUNX1T1 AML and ASXL1 and ASXL2mutations.[42]
  • Acute promyelocytic leukemia (APL) with PML-RARA: APL represents about 7% of children with AML.[22,43] AML with t(15;17) is invariably associated with APL, a distinct subtype of AML that is treated differently than other types of AML because of its marked sensitivity to arsenic trioxide and the differentiating effects of all-trans retinoic acid. The t(15;17) translocation or other more complex chromosomal rearrangements may lead to the production of a fusion protein involving the retinoid acid receptor alpha and PML.[44] The WHO 2016 revision 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.[14]
    Utilization of quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) for PML-RARA transcripts has become standard practice.[45] 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.[46] 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).[47-49] Identification of cases with the t(11;17)(q23;q21) is important because of their decreased sensitivity to all-trans retinoic acid.[44,47]
  • 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.[50] 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,[51] and an improved prognosis in the absence of FLT3–internal tandem duplication (ITD) mutations in adults and younger adults.[51-56]
    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.[24,25,57,58] NPM1 mutations are associated with a favorable prognosis in patients with AML characterized by a normal karyotype.[24,25,58] 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,[24,59] but other studies showed no impact of a FLT3-ITD mutation on the favorable prognosis associated with an NPM1 mutation.[16,25,58]
  • AML with biallelic mutations of CEBPA: Mutations in the CEBPA gene occur in a subset of children and adults with cytogenetically normal AML.[60] In adults younger than 60 years, approximately 15% of cytogenetically normal AML cases have mutations in CEBPA.[55] Outcomes for adults with AML with CEBPA mutations appear to be relatively favorable and similar to that of patients with core-binding factor leukemias.[55,61] Studies in adults with AML have demonstrated that CEBPA double-mutant, but not single-mutant, AML is independently associated with a favorable prognosis,[62-65] leading to the WHO 2016 revision that requires biallelic mutations for the disease definition.[14]
    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.[26,66] Although both double-mutant and single-mutant alleles of CEBPA were associated with a favorable prognosis in children with AML in one large study,[26] a second study observed inferior outcome for patients with single CEBPA mutations.[66] 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.[26] 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.[60]
  • Myeloid leukemia associated with Down syndrome (GATA1 mutations): GATA1mutations are present in most, if not all, Down syndrome children with either transient abnormal myelopoiesis (TAM) or acute megakaryoblastic leukemia (AMKL).[67-70]GATA1 mutations were also observed in 9% of non–Down syndrome children and 4% of adults with AMKL (with coexistence of amplification of the Down syndrome Critical Region 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.[72]
    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.[73]

Molecular abnormalities associated with an unfavorable prognosis

Molecular abnormalities associated with an unfavorable prognosis include the following:
  • Chromosomes 5 and 7: Chromosomal abnormalities associated with poor prognosis in adults with AML include those involving chromosome 5 (monosomy 5 and del(5q)) and chromosome 7 (monosomy 7).[18,32,74] These cytogenetic subgroups represent approximately 2% and 4% of pediatric AML cases, respectively, and are also associated with poor prognosis in children.[21,32,74-78]
    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.[23] However, outcome for children with del(7q), but not monosomy 7, appears comparable to that of other children with AML.[22,77] The presence of del(7q) does not abrogate the prognostic significance of favorable cytogenetic characteristics (e.g., inv(16) and t(8;21)).[18,77,79]
    Chromosome 5 and 7 abnormalities appear to lack prognostic significance in AML patients with Down syndrome who are aged 4 years and younger.[80]
  • 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.[81,82] These abnormalities are associated with poor prognosis in adults with AML,[18,32,83] but are very uncommon in children (<1% of pediatric AML cases).[21,34,84]
    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,[85] particularly when both alleles are mutated or there is a high ratio of the mutant allele to the normal allele.[86,87] FLT3-ITD mutations also convey a poor prognosis in children with AML.[27,59,88-91] The frequency of FLT3-ITDmutations 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).[90-92]
    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.[93,94] 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.[94] 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-ITDwithout these alterations.[16] Conversely, when FLT3-ITD is accompanied by NPM1mutations, the outcome is relatively favorable and is similar to that of pediatric AML cases without FLT3-ITD.[16]
    For APL, FLT3-ITD and point mutations occur in 30% to 40% of children and adults.[86,89,90,95-99] Presence of the FLT3-ITD mutation is strongly associated with the microgranular variant (M3v) of APL and with hyperleukocytosis.[89,97,100,101] It remains unclear whether FLT3 mutations are associated with poorer prognosis in patients with APL who are treated with modern therapy that includes all-trans retinoic acid and arsenic trioxide.[95,96,99,100,102-105]
    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.[16]
  • AML with t(16;21)(p11;q22); FUS-ERG: In leukemias with t(16;21)(p11;q22), the FUSgene is joined with the ERG gene, producing a distinctive AML subtype with a gene expression profile that clusters separately from other cytogenetic subgroups.[40] 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 of 7% and a cumulative incidence of relapse of 74%.[40]

Other molecular abnormalities observed in pediatric AML

Other molecular abnormalities observed in pediatric AML include the following:
  • KMT2A (MLL) gene rearrangements: KMT2A gene rearrangement occurs in approximately 20% of children with AML.[21,22] These cases, including most AMLs secondary to epipodophyllotoxin,[106] 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).[71,107]
    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(AF9) gene.[108] The WHO 2016 revision 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.[108] 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).[108]
    Outcome for patients with de novo AML and KMT2A gene rearrangement is generally reported as being similar to that for other patients with AML.[18,21,108,109] 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.[108] 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) 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.[18,21,108,110-112] 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.[107]
    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.[18,22,113] Some cases with the t(10;11) translocation have fusion of the KMT2A gene with the AF10-MLLT10 at 10p12, while others have fusion of KMT2A with ABI1 at 10p11.2.[114,115] An international retrospective study found that these cases, which present at a median age of approximately 1 year, have a 5-year EFS of 20% to 30%.[108]
    • Patients with t(6;11)(q27;q23) have a poor outcome, with a 5-year EFS of 11%.
    • Patients with t(4;11)(q21;q23) also have a poor outcome, with a 5-year EFS of 29%.[108]
    • 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.[116]
  • 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.[117,118] This subgroup of AML has been associated with a poor prognosis in adults with AML,[117,119,120] 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.[121,122]
    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.[21,118,121,122]
  • 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)(p13.3q24.3)).[123-127] It occurs almost exclusively in non–Down syndrome AMKL, representing 16% to 27% of pediatric AMKL and presenting with a median age of 1 year.[71,125,128,129] It appears to be associated with unfavorable outcome,[71,123,127-129] with EFS at 2 years less than 20% in two reports that included 28 patients.[71,127,129]
    • KMT2A-rearranged: Cases with KMT2A translocations represent 10% to 17% of pediatric AMKL, with MLLT3 (AF9) being the most common KMT2A fusion partner.[71,107,128] 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%.[71,107,128] 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, approximately 20%) compared with other AMKL cases and other KMT2A-rearrangements (n = 17), each with a 5-year OS of 50% to 55%.[107] Inferior outcome was not observed for patients (n = 17) with other KMT2A-rearrangements.
    • NUP98-KDM5A4: NUP98-KDM5A4 is observed in approximately 10% of pediatric AMKL cases [71,128] and is observed at much lower rates in non-AMKL cases.[129] NUP98-KDM5A4 cases showed a trend towards inferior prognosis, although the small number of cases studied limits confidence in this assessment.[71,128]
    • 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).[21,129-134] 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.[71,107,128] 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.[107,125,135] 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.[132]
      An international collaborative retrospective study of 51 t(1;22) cases reported that patients with this abnormality had a 5-year EFS of 54.5% and an OS of 58.2%, similar to the rates for other children with AMKL.[107] In another international retrospective analysis of 153 cases with non–Down syndrome AMKL who had samples available for molecular analysis, the 4-year EFS for patients with t(1;22) was 59% and OS was 70%, significantly better than AMKL patients with other specific genetic abnormalities (CBFA2T3/GUS2, NUP98/KDM5A4, KMT2Arearrangements, monosomy 7).[128]
    • 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 Down syndrome critical region 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 (BFM) AML study of 62 children, presence of this translocation was associated with younger age at diagnosis (median, 1.2 years), FAB M4/M5 phenotype, erythrophagocytosis, leukemia cutis, and disseminated intravascular coagulation.[136] 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.[136-142] 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.[136]
  • 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 (HLXB9).[143] The translocation may be cryptic by conventional karyotyping and in some cases may be confirmed only by FISH.[144-146] This alteration occurs virtually exclusively in children younger than 2 years, is mutually exclusive with the KMT2A (MLL) rearrangement, and is associated with a high risk of treatment failure.[21,22,58,144,145,147]
  • NUP98 gene fusions: NUP98 has been reported to form leukemogenic gene fusions with more than 20 different partners.[148] In the pediatric AML setting, the two most common fusion genes are NUP98-NSD1 and NUP98-KDM5A4 (JARID1A), 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).[71,93,125] AML cases with either NUP98 fusion gene show high expression of HOXA and HOXBgenes, indicative of a stem cell phenotype.[118,125]
    The NUP98-NSD1 fusion gene, which is often cytogenetically cryptic, results from the fusion of NUP98 (chromosome 11p15) with NSD1 (chromosome 5q35).[93,94,118,149-152] This alteration occurs in approximately 4% to 7% of pediatric AML cases.[14,28,93,118,151] The highest frequency in the pediatric population is in the 5- to 9-year age group (approximately 8%), with lower frequency in younger children (approximately 2% in children younger than 2 years). NUP98-NSD1 cases present with high WBC count (median, 147 × 109/L in one study).[93,94] Most NUP98-NSD1 AML cases do not show cytogenetic aberrations.[93,118,149] A high percentage of NUP98-NSD1cases (74% to 90%) have FLT3-ITD.[28,93,94]
    A study that included 12 children with NUP98-NSD1 AML reported that although all patients achieved CR, 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 of approximately 10%.[93] 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%).[94]
  • 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 was 9%, suggesting that the RUNX1 mutation confers a poor prognosis in both children and adults.[153]
  • 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.[58,154-156] Mutations in NRAS are observed more commonly than mutations in KRAS in pediatric AML cases.[58,157] RAS mutations occur with similar frequency for all Type II alteration subtypes, with the exception of APL, for which RAS mutations are seldom observed.[58]
  • KIT mutations: Mutations in KIT occur in approximately 5% of AML, but in 10% to 40% of AML with core-binding factor abnormalities.[58,157-159]
    The presence of activating KIT mutations in adults with this AML subtype appears to be associated with a poorer prognosis compared with core-binding factor AML without KITmutations.[158,160,161] The prognostic significance of KIT mutations occurring in pediatric core-binding factor AML remains unclear,[162-165] although the largest pediatric study reported to date observed no prognostic significance for KIT mutations.[166]
  • WT1 mutations: WT1, a zinc-finger protein regulating gene transcription, is mutated in approximately 10% of cytogenetically normal cases of AML in adults.[167-170] The WT1mutation has been shown in some,[167,168,170] but not all studies [169] 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.[171,172] Cases with WT1 mutations are enriched among children with normal cytogenetics and FLT3-ITD, but are less common among children younger than 3 years.[171,172] AML cases with NUP98-NSD1 are enriched for both FLT3-ITD and WT1mutations.[93] 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.[93,171,172] 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 WT1mutation and FLT3-ITD had survival rates less than 20%.[171]
  • 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.[173] Mutations in this gene are independently associated with poor outcome.[173-175] DNMT3A mutations are virtually absent in children.[176]
  • IDH1 and IDH2 mutations: Mutations in IDH1 and IDH2, which code for isocitrate dehydrogenase, occur in approximately 20% of adults with AML,[177-181] and they are enriched in patients with NPM1 mutations.[178,179,182] The specific mutations that occur in IDH1 and IDH2 create a novel enzymatic activity that promotes conversion of alpha-ketoglutarate to 2-hydroxyglutarate.[183,184] This novel activity appears to induce a DNA hypermethylation phenotype similar to that observed in AML cases with loss of function mutations in TET2.[182]
    Mutations in IDH1 and IDH2 are rare in pediatric AML, occurring in 0% to 4% of cases.[176,185-189] There is no indication of a negative prognostic effect for IDH1 and IDH2mutations in children with AML.[185]
  • 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.[190] These mutations lead to enhanced signaling through the G-CSF receptor, and they are primarily observed in AML with either CEBPA mutations or with core-binding factor abnormalities (RUNX1-RUNX1T1 and CBFB-MYH11).[190] The clinical characteristics of and prognosis for patients with CSF3R mutations do not seem to be significantly different from those of patients without 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.[191] 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.[191] A study of 31 patients with severe congenital neutropenia who developed AML or MDS observed CSF3Rmutations in approximately 80%, and also observed a high frequency of RUNX1mutations (approximately 60%), suggesting cooperation between CSF3R and RUNX1mutations for leukemia development within the context of severe congenital neutropenia.[192]
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