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Classification of Pediatric Myeloid Malignancies

Table 2. Acute Leukemias of Ambiguous Lineage According to the WHO Classification of Tumors of Hematopoietic and Lymphoid Tissuesa continued...

Other molecular abnormalities observed in pediatric AML include the following:

  • MLL gene rearrangements: Translocations of chromosomal band 11q23 involving the MLL gene, including most AML secondary to epipodophyllotoxin,[86] are associated with monocytic differentiation (FAB M4 and M5). The most common translocation, representing approximately 50% of MLL-rearranged cases in the pediatric AML population, is t(9;11)(p22;q23) in which the MLL gene is fused with the AF9 gene.[87] However, more than 50 different fusion partners have been identified for the MLL gene in patients with AML. The median age for 11q23/MLL-rearranged cases in the pediatric AML setting is approximately 2 years and most translocation subgroups have a median age at presentation of younger than 5 years.[87] However, pediatric cases with t(6;11)(q27;q23) and t(11;17)(q23;q21) have significantly older median ages at presentation (12 years and 9 years, respectively).[87]

    Outcome for patients with de novo AML and MLL gene rearrangement are generally reported as being similar to that for other patients with AML.[26,29,87,88] However, as the MLL 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 MLL-rearranged AML.[87] For example, cases with t(1;11)(q21;q23), representing 3% of all 11q23/MLL-rearranged AML, showed a highly favorable outcome with 5-year EFS of 92%. While reports from single clinical trial groups have variably described more favorable prognosis for cases with t(9;11), in which the MLL gene is fused with the AF9 gene, the international retrospective study did not confirm the favorable prognosis of the t(9;11)(p22;q23) subgroup.[26,29,87,89,90,91]

    Several 11q23/MLL-rearranged AML subgroups appear to be associated with poor outcome. For example, cases with the t(10;11) translocation are a group at high risk of relapse in bone marrow and the central nervous system (CNS).[26,30,92] Some cases with the t(10;11) translocation have fusion of the MLL gene with the AF10/MLLT10 at 10p12, while others have fusion of MLL with ABI1 at 10p11.2.[93,94] The international retrospective study found that these cases, which present at a median age of approximately 1 year, have a 5-year EFS in the 20% to 30% range.[87] Patients with t(6;11)(q27;q23) and with t(4;11)(q21;q23) also show poor outcome, with a 5-year EFS of 11% and 29%, respectively, in the international retrospective study.[87] A follow-up study by the international collaborative group demonstrated that additional cytogenetic abnormalities further influenced outcome of children with MLL translocations, with complex karyotypes and trisomy 19 predicting poor outcome and trisomy 8 predicting a more favorable outcome.[95]

  • t(6;9): t(6;9) leads to the formation of a leukemia-associated fusion protein DEK-NUP214.[96] This subgroup of AML has been associated with a poor prognosis in adults with AML,[96,97,98] and occurs infrequently in children (approximately 2% of AML cases). This subtype appears to be associated with a high risk of treatment failure in children.[29]
  • t(1;22): The t(1;22)(p13;q13) translocation is uncommon (<1% of pediatric AML) and is restricted to acute megakaryocytic leukemia (AMKL).[29,99,100,101] Most AMKL cases with t(1;22) occur in infants, and the translocation is uncommon in children with Down syndrome who develop AMKL.[99,101] In leukemias with t(1;22), the OTT (RBM15) gene on chromosome 1 is fused to the MAL (MLK1) gene on chromosome 22.[102,103] Cases with detectable OTT/MAL fusion transcripts in the absence of t(1;22) have been reported, as well.[101] In the small number of children reported, the presence of the t(1;22) appears to be associated with poor prognosis, though long-term survivors have been noted following intensive therapy.[101,104]
  • 12p: Cytogenetically detectable aberrations on the short arm of chromosome 12 are uncommon in unselected pediatric AML patients (2%–4%) and appear to predict poor outcome.[29,30]

    A subset of patients with 12p abnormalities have the t(7;12)(q36;p13) translocation involving ETV6 on chromosome 12p13 and HLXB9 on chromosome 7q36.[105] This alteration occurs virtually exclusively in children younger than 2 years, is mutually exclusive with MLL rearrangement, and is associated with a high risk of treatment failure.[29,30,34,106,107]

  • NUP98/NSD1 translocation: The NUP98/NSD1 translocation, which is often cytogenetically cryptic, results in the fusion of NUP98 (chromosome 11p15) with NSD1 (chromosome 5q35).[108,109,110,111,112] This alteration occurs in approximately 4% of pediatric AML cases.[110,112] NUP98/NSD1 cases have not been observed in children younger than 2 years,[108,109,110,111,112] and they present with high WBC (median 147 × 109 /L in one study).[112] Most NUP98/NSD1 AML cases do not show cytogenetic aberrations,[108,112] although del(5q) is noted in some.[110,111] A high percentage of NUP98/NSD1 cases (91% in one study) have FLT3-ITD.[112] Presence of NUP98/NSD1 independently predicted for poor prognosis, and children with NUP98/NSD1 AML had a high risk of relapse with a resulting 4-year EFS of approximately 10%.[112]
  • 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.[34,113,114,115] Mutations in NRAS are observed more commonly than KRAS mutations in pediatric AML cases.[34,35]RAS mutations occur with similar frequency for all Type II alteration subtypes with the exception of APL, for which RAS mutations are seldom observed.[34]
  • KIT mutations: Mutations in KIT occur in approximately 5% of AML, but in 10% to 40% of AML with core-binding factor abnormalities.[34,35,116,117] 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 KIT mutation.[117,118,119] The prognostic significance of KIT mutations occurring in pediatric core-binding factor AML remains unclear,[116,120,121,122] although the largest pediatric study reported to date observed no prognostic significance for KIT mutations.[123]
  • GATA1 mutations: GATA1 mutations are present in most, if not all, Down syndrome children with either transient myeloproliferative disease or AMKL.[124,125,126,127]GATA1 mutations are not observed in non-Down syndrome children with AMKL or in Down syndrome children with other types of leukemia.[126,127]GATA1 is a transcription factor that is required for normal development of erythroid cells, megakaryocytes, eosinophils, and mast cells.[128]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.[129]
  • EVI1: High expression of EVI1 on chromosome 3q26 has been observed in approximately 10% of adults with AML and, like inv(3)/t(3;3), is associated with poor prognosis.[130] Some adult AML cases with high EVI1 expression have inv(3)/t(3;3), but most cases with high EVI1 expression do not.[130,131] High expression is virtually absent in cases with favorable cytogenetics, but is common in cases with monosomy 7 and in cases with MLL gene rearrangement.[130,131]EVI1 overexpression has been identified in approximately 10% of children with AML, predominantly cases with MLL gene rearrangement, monosomy 7, or FAB M6/M7.[68] Similar to adults, EVI1 overexpression was mutually exclusive with core-binding factor AML and was associated with poor prognosis.[68]
  • WT1 mutations: WT1, a zinc-finger protein regulating gene transcription, is mutated in approximately 10% of cytogenetically normal cases of AML in adults.[132,133,134,135] The WT1 mutation has been shown in some,[132,133,135] but not all,[134] studies to be an independent predictor of worse disease-free, event-free, and overall survival of adults. In children with AML, WT1 mutations are observed in approximately 10% of cases.[136,137] Cases with WT1 mutations are enriched among children with normal cytogenetics and FLT3-ITD, but are less common among children younger than 3 years.[136,137] 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.[136,137] 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%.[136]
  • DNMT3A mutations: Mutations of the DNA cytosine methyltransferase gene (DNMT3A) have been identified in approximately 20% of adult AML patients, being virtually absent in patients with favorable cytogenetics but occurring in one-third of adult patients with intermediate-risk cytogenetics.[138] Mutations in this gene are independently associated with poor outcome.[138,139,140]DNMT3A mutations appear to be very uncommon in children.[141]
  • IDH1 and IDH2 mutations: Mutations in IDH1 and IDH2, which code for isocitrate dehydrogenase, occur in approximately 20% of adults with AML,[142,143,144,145,146] and they are enriched in patients with NPM1 mutations.[143,144,147] The specific mutations that occur in IDH1 and IDH2 create a novel enzymatic activity that promotes conversion of alpha-ketoglutarate to 2-hydroxyglutarate.[148,149] This novel activity appears to induce a DNA hypermethylation phenotype similar to that observed in AML cases with loss of function mutations in TET2.[147] Mutations in IDH1 and IDH2 are uncommon in pediatric AML, occurring in 0% to 4% of cases.[141,150,151,152,153,154] There is no indication of a negative prognostic effect for IDH1 and IDH2 mutations in children with AML.[150]
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