martes, 26 de febrero de 2019

Childhood Cancer Genomics (PDQ®) 2/8 —Health Professional Version - National Cancer Institute

Childhood Cancer Genomics (PDQ®)—Health Professional Version - National Cancer Institute

National Cancer Institute

Early T-cell precursor ALL
Detailed molecular characterization of early T-cell precursor ALL showed this entity to be highly heterogeneous at the molecular level, with no single gene affected by mutation or copy number alteration in more than one-third of cases.[138] Compared with other T-cell ALL cases, the early T-cell precursor group had a lower rate of NOTCH1 mutations and significantly higher frequencies of alterations in genes regulating cytokine receptors and RAS signaling, hematopoietic development, and histone modification. The transcriptional profile of early T-cell precursor ALL shows similarities to that of normal hematopoietic stem cells and myeloid leukemia stem cells.[138]
Studies have found that the absence of biallelic deletion of the TCRgamma locus (ABGD), as detected by comparative genomic hybridization and/or quantitative DNA-PCR, was associated with early treatment failure in patients with T-cell ALL.[139,140] ABGD is characteristic of early thymic precursor cells, and many of the T-cell ALL patients with ABGD have an immunophenotype consistent with the diagnosis of early T-cell precursor phenotype.

Gene polymorphisms in drug metabolic pathways

A number of polymorphisms of genes involved in the metabolism of chemotherapeutic agents have been reported to have prognostic significance in childhood ALL.[141-143] For example, patients with mutant phenotypes of thiopurine methyltransferase (TPMT, a gene involved in the metabolism of thiopurines, such as mercaptopurine [6-MP]), appear to have more favorable outcomes,[144] although such patients may also be at higher risk of developing significant treatment-related toxicities, including myelosuppression and infection.[145,146] Patients with homozygosity for TPMT variants associated with low enzymatic activity tolerate only very low doses of mercaptopurine (approximately 10% of the standard dose) and are treated with reduced doses of mercaptopurine to avoid excessive toxicity. Patients who are heterozygous for this mutant enzyme gene generally tolerate mercaptopurine without serious toxicity, but they do require more frequent dose reductions for hematologic toxicity than do patients who are homozygous for the normal allele.[147,148]
Germline variants in nucleoside diphosphate–linked moiety X-type motif 15 (NUDT15) that reduce or abolish activity of this enzyme also lead to diminished tolerance to thiopurines.[147,149] The variants are most common in East Asians and Hispanics, and they are rare in Europeans and Africans. Patients homozygous for the risk variants tolerate only very low doses of mercaptopurine, while patients heterozygous for the risk alleles tolerate lower doses than do patients homozygous for the wild-type allele (approximately 25% dose reduction on average), but there is broad overlap in tolerated doses between the two groups.[147,150]
Gene polymorphisms may also affect the expression of proteins that play central roles in the cellular effects of anticancer drugs. As an example, patients who are homozygous for a polymorphism in the promoter region of CEP72 (a centrosomal protein involved in microtubule formation) are at increased risk of vincristine neurotoxicity.[151]
Genome-wide polymorphism analysis has identified specific single nucleotide polymorphisms associated with high end-induction MRD and risk of relapse. Polymorphisms of IL-15, as well as genes associated with the metabolism of etoposide and methotrexate, were significantly associated with treatment response in two large cohorts of ALL patients treated on SJCRH and COG protocols.[152] Polymorphic variants involving the reduced folate carrier and methotrexate metabolism have been linked to toxicity and outcome.[153,154] While these associations suggest that individual variations in drug metabolism can affect outcome, few studies have attempted to adjust for these variations; it is unknown whether individualized dose modification on the basis of these findings will improve outcome.
(Refer to the PDQ summary on Childhood Acute Lymphoblastic Leukemia Treatment for information about the treatment of childhood ALL.)

Acute Myeloid Leukemia (AML)

Pediatric AML is typically a disease of recurring chromosomal alterations, with conventional cytogenetics detecting structural and numerical cytogenetic abnormalities in 70% to 80% of children with AML, while the recently recognized cryptic translocations (e.g., NUP98/NSD1CBFA2T3/GLIS2, and NUP98/KDM5A) and mutations (e.g., CEBPA and NPM1) account for many of the remaining cases.[155,156]
A unifying concept for the role of specific mutations in AML is that mutations that promote proliferation (Type I) and mutations that block normal myeloid development (Type II) are required for full conversion of hematopoietic stem/precursor cells to malignancy.[157,158] Support for this conceptual construct comes from the observation that there is generally mutual exclusivity within each type of mutation, such that only a single Type I and a single Type II mutation are present within each case. Further support comes from genetically engineered models of AML for which cooperative events rather than single mutations are required for leukemia development. Type I mutations are commonly in genes involved in growth factor signal transduction and include mutations in FLT3KITNRASKRAS, and PTNP11.[159] Alterations in RAS genes, KIT, and FLT3 are the most common gene mutations occurring in children with AML.[160] Examples of Type II genomic alterations include the common translocations and mutations associated with favorable prognosis (t(8;21), inv(16), t(16;16), t(15;17), CEBPA, and NPM1), as well as MLL (KMT2A) rearrangements (translocations and partial tandem duplication) and NUP98-fusion genes.
Comprehensive molecular profiling of AML in pediatric and adult cases has characterized AML as a disease showing both commonalities and distinct differences between the age groups.[156,160] One difference is that pediatric patients with AML have lower rates of mutations than do adult patients with AML; in most cases, children have less than one somatic change in protein-coding regions per megabase.[160] Figure 3 (A) illustrates the frequencies of recurring gene mutations in adult and pediatric AML, showing that some mutations are differentially present between pediatric and adults cases (e.g., IDH1TP53RUNX1, and DNMT3A mutations being much more common in adults than in children).[156,160]Figure 3 (B) shows that common genomic alterations in adult AML (FLT3-ITDNPM1, and CEBPA mutations) are uncommon in children younger than 5 years but increase in frequency during the pediatric age range.[156]
ENLARGECharts showing (A) prevalence of AML-associated mutations in pediatric versus adult AML and (B) age-based prevalence of common AML-associated mutations.
Figure 3. (A) Prevalence of AML-associated mutations in pediatric versus adult AML, demonstrating lower incidence of mutations in pediatric AML. Bordered panel shows 2 newly discovered mutations in adults that are absent in pediatric AML. (B) Age-based prevalence of common AML-associated mutations. Reprinted from Pediatric Clinics of North America, Volume 62, Katherine Tarlock, Soheil Meshinchi, Pediatric Acute Myeloid Leukemia: Biology and Therapeutic Implications of Genomic Variants, Pages 75–93, Copyright (2015), with permission from Elsevier.
Figure 4 (A) shows the marked variation in MLL (KMT2A)-rearranged AML by age, with much higher frequencies for infants compared with older children and adults.[156] Normal karyotype AML and core-binding factor AML show an opposing pattern, with very low rates in infancy and with increasing rates in the first two decades of life. Figure 4 (B) shows specific cryptic translocations that occur primarily in children (NUP98/NSD1CBFA2T3/GLIS2, and NUP98/KDM5A) and vary by age.[156]
ENLARGECharts showing age-based prevalence of specific karyotypic (A) or cryptic (B) translocations in AML.
Figure 4. Age-based prevalence of specific karyotypic (A) or cryptic (B) translocations in AML. Reprinted from Pediatric Clinics of North America, Volume 62, Katherine Tarlock, Soheil Meshinchi, Pediatric Acute Myeloid Leukemia: Biology and Therapeutic Implications of Genomic Variants, Pages 75–93, Copyright (2015), with permission from Elsevier.
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.[161] 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.
Genetic analyses of leukemia (using both conventional cytogenetic methods and molecular methods) are performed on children with acute myeloid leukemia (AML) because both chromosomal and molecular abnormalities are important diagnostic and prognostic markers.[155,162-167] Clonal chromosomal abnormalities have been identified in the blasts of about 75% of children with AML and are useful in defining subtypes with particular characteristics (e.g., t(8;21), t(15;17), inv(16), 11q23 abnormalities, t(1;22)). Leukemias with the chromosomal abnormalities t(8;21) and inv(16) are called core-binding factor leukemias; core-binding factor (a transcription factor involved in hematopoietic stem cell differentiation) is disrupted by each of these abnormalities.
Molecular abnormalities can aid in risk stratification and treatment allocation. For example, mutations of NPM and CEBPA are associated with favorable outcome while certain mutations of FLT3 portend a high risk of relapse, and identifying these mutations may allow for targeted therapy.[168-171]
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.[20] 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 1.[20] Table 1 also shows, in the bottom three rows, additional relatively common recurrent translocations observed in children with AML.[165,166,172]
Table 1. 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
CBFB-MYH11inv(16)(p13.1;q22) or t(16;16)(p13.1;q22)4–9
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.[173,174] Adults with t(8;21) have a more favorable prognosis than do adults with other types of AML.[162,175] Children with t(8;21) have a more favorable outcome than do children with AML characterized by normal or complex karyotypes,[162,176-178] with 5-year overall survival (OS) of 74% to 90%.[165,166,179] The t(8;21) translocation occurs in approximately 12% of children with AML.[165,166,179]
    • AML with inv(16)(p13.1;q22) or t(16;16)(p13.1;q22); CBFB-MYH11: In leukemias with inv(16), the CBF beta gene (CBFB) 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.[180] Inv(16) confers a favorable prognosis for both adults and children with AML,[162,176-178] with a 5-year OS of about 85%.[165,166] Inv(16) occurs in 7% to 9% of children with AML.[165,166,179] 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 (NRASFLT3, and KIT).[181,182]
    • 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.[183] 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%.[183]
    Both RUNX1-RUNX1T1 and CBFB-MYH11 subtypes commonly show mutations in genes that activate receptor tyrosine kinase signaling (e.g., NRASFLT3, 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).[181,182] 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.[179]
    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.[181,182]
    • 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.[181,182]
    • 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.[184] Similar results, albeit with smaller numbers, were reported for children with RUNX1-RUNX1T1 AML and ASXL1 and ASXL2mutations.[185]
  • Acute promyelocytic leukemia (APL) with PML-RARA: APL represents about 7% of children with AML.[166,186] 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-transretinoic 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.[187] 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.[20]
    Utilization of quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) for PML-RARA transcripts has become standard practice.[188] 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.[189] 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).[190-192] Identification of cases with the t(11;17)(q23;q21) is important because of their decreased sensitivity to all-transretinoic acid.[187,190]
  • AML with mutated NPM1NPM1 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.[193] 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,[194] and an improved prognosis in the absence of FLT3–internal tandem duplication (ITD) mutations in adults and younger adults.[194-199]
    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.[158,168,169,200NPM1 mutations are associated with a favorable prognosis in patients with AML characterized by a normal karyotype.[158,168,169] 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,[168,201] but other studies showed no impact of a FLT3-ITD mutation on the favorable prognosis associated with an NPM1 mutation.[158,160,169]
  • AML with biallelic mutations of CEBPA: Mutations in the CCAAT/Enhancer Binding Protein Alpha (CEBPA) gene occur in a subset of children and adults with cytogenetically normal AML.[202] In adults younger than 60 years, approximately 15% of cytogenetically normal AML cases have mutations in CEBPA.[198] Outcomes for adults with AML with CEBPA mutations appear to be relatively favorable and similar to that of patients with core-binding factor leukemias.[198,203] Studies in adults with AML have demonstrated that CEBPA double-mutant, but not single-mutant, AML is independently associated with a favorable prognosis,[204-207] leading to the WHO 2016 revision that requires biallelic mutations for the disease definition.[20]
    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.[170,208] Although both double-mutant and single-mutant alleles of CEBPA were associated with a favorable prognosis in children with AML in one large study,[170] a second study observed inferior outcome for patients with single CEBPA mutations.[208] 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.[170] 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.[202]
  • 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).[209-212]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).[213GATA1 is a transcription factor that is required for normal development of erythroid cells, megakaryocytes, eosinophils, and mast cells.[214]
    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.[215]

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).[162,175,216] These cytogenetic subgroups represent approximately 2% and 4% of pediatric AML cases, respectively, and are also associated with poor prognosis in children.[165,175,216-220]
    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.[167] However, outcome for children with del(7q), but not monosomy 7, appears comparable to that of other children with AML.[166,219] The presence of del(7q) does not abrogate the prognostic significance of favorable cytogenetic characteristics (e.g., inv(16) and t(8;21)).[162,219,221]
    Chromosome 5 and 7 abnormalities appear to lack prognostic significance in AML patients with Down syndrome who are aged 4 years and younger.[222]
  • AML with inv(3)(q21.3;q26.2) or t(3;3)(q21.3;q26.2); GATA2MECOMMECOM 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.[223,224] These abnormalities are associated with poor prognosis in adults with AML,[162,175,225] but are very uncommon in children (<1% of pediatric AML cases).[165,177,226]
    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,[227] particularly when both alleles are mutated or there is a high ratio of the mutant allele to the normal allele.[228,229FLT3-ITD mutations also convey a poor prognosis in children with AML.[171,201,230-233] 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).[232-234]
    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.[235,236] 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.[236] 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.[160] 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.[160]
    For APL, FLT3-ITD and point mutations occur in 30% to 40% of children and adults.[228,231,232,237-241] Presence of the FLT3-ITD mutation is strongly associated with the microgranular variant (M3v) of APL and with hyperleukocytosis.[231,239,242,243] 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.[237,238,241,242,244-247]
    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.[160]
  • AML with t(16;21)(p11;q22); FUS-ERGIn 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.[183] 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%.[183]

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.[165,166] These cases, including most AMLs secondary to epipodophyllotoxin,[248] 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).[213,249]
    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.[250] 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.[250] 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).[250]
    Outcome for patients with de novo AML and KMT2A gene rearrangement is generally reported as being similar to that for other patients with AML.[162,165,250,251] 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.[250] 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.[162,165,250,252-254] 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.[249]
    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.[162,166,255] 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.[256,257] 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%.[250]
    • 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%.[250]
    • 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.[258]
  • 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.[259,260] This subgroup of AML has been associated with a poor prognosis in adults with AML,[259,261,262] 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.[263,264]
    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.[165,260,263,264]
  • 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)).[265-269] 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.[213,267,270,271] It appears to be associated with unfavorable outcome,[213,265,269-271] with EFS at 2 years less than 20% in two reports that included 28 patients.[213,269,271]
    • KMT2A-rearranged: Cases with KMT2A translocations represent 10% to 17% of pediatric AMKL, with MLLT3 (AF9) being the most common KMT2A fusion partner.[213,249,270KMT2A-rearranged cases appear to be associated with inferior outcome among children with AMKL, with OS rates at 4 to 5 years of approximately 30%.[213,249,270] 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%.[249] 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 [213,270] and is observed at much lower rates in non-AMKL cases.[271NUP98-KDM5A4 cases showed a trend towards inferior prognosis, although the small number of cases studied limits confidence in this assessment.[213,270]
    • 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).[165,271-276] 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.[213,249,270] 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.[249,267,277] 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.[274]
      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.[249] 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/GUS2NUP98/KDM5A4KMT2Arearrangements, monosomy 7).[270]
    • HOX-rearranged: Cases with a gene fusion involving a HOX cluster gene represented 15% of pediatric AMKL in one report.[213] 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.[213] 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).[213]
  • 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.[278] 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.[278-284] 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.[278]
  • 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).[285] The translocation may be cryptic by conventional karyotyping and in some cases may be confirmed only by FISH.[286-288] 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.[158,165,166,286,287,289]
  • NUP98 gene fusions: NUP98 has been reported to form leukemogenic gene fusions with more than 20 different partners.[290] 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).[213,235,267] AML cases with either NUP98 fusion gene show high expression of HOXAand HOXB genes, indicative of a stem cell phenotype.[260,267]
    The NUP98-NSD1 fusion gene, which is often cytogenetically cryptic, results from the fusion of NUP98 (chromosome 11p15) with NSD1 (chromosome 5q35).[235,236,260,291-294] This alteration occurs in approximately 4% to 7% of pediatric AML cases.[20,172,235,260,293] 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).[235,236] Most NUP98-NSD1 AML cases do not show cytogenetic aberrations.[235,260,291] A high percentage of NUP98-NSD1 cases (74% to 90%) have FLT3-ITD.[172,235,236]
    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%.[235] 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%).[236]
  • 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.[158,295-297] Mutations in NRAS are observed more commonly than mutations in KRAS in pediatric AML cases.[158,159RAS mutations occur with similar frequency for all Type II alteration subtypes, with the exception of APL, for which RAS mutations are seldom observed.[158]
  • KIT mutations: Mutations in KIT occur in approximately 5% of AML, but in 10% to 40% of AML with core-binding factor abnormalities.[158,159,298,299]
    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.[298,300,301] The prognostic significance of KIT mutations occurring in pediatric core-binding factor AML remains unclear,[302-305] although the largest pediatric study reported to date observed no prognostic significance for KIT mutations.[306]
  • WT1 mutations: WT1, a zinc-finger protein regulating gene transcription, is mutated in approximately 10% of cytogenetically normal cases of AML in adults.[307-310] The WT1mutation has been shown in some,[307,308,310] but not all studies [309] 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.[311,312] Cases with WT1 mutations are enriched among children with normal cytogenetics and FLT3-ITD, but are less common among children younger than 3 years.[311,312] AML cases with NUP98-NSD1 are enriched for both FLT3-ITD and WT1mutations.[235] In univariate analyses, WT1 mutations are predictive of poorer outcome in pediatric patients, but the independent prognostic significance of WT1mutation status is unclear because of its strong association with FLT3-ITD and its association with NUP98-NSD1.[235,311,312] 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%.[311]
  • DNMT3A mutations: Mutations of the DNA cytosine methyltransferase (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.[313] Mutations in this gene are independently associated with poor outcome.[313-315DNMT3A mutations are virtually absent in children.[316]
  • IDH1 and IDH2 mutations: Mutations in IDH1 and IDH2, which code for isocitrate dehydrogenase, occur in approximately 20% of adults with AML,[317-321] and they are enriched in patients with NPM1 mutations.[318,319,322] The specific mutations that occur in IDH1 and IDH2 create a novel enzymatic activity that promotes conversion of alpha-ketoglutarate to 2-hydroxyglutarate.[323,324] This novel activity appears to induce a DNA hypermethylation phenotype similar to that observed in AML cases with loss of function mutations in TET2.[322]
    Mutations in IDH1 and IDH2 are rare in pediatric AML, occurring in 0% to 4% of cases.[316,325-329] There is no indication of a negative prognostic effect for IDH1 and IDH2mutations in children with AML.[325]
  • 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.[330] 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).[330] 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.[331] 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.[331] 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.[332]
(Refer to the PDQ summary on Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment for information about the treatment of childhood AML.)

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