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تسجيل

Acute Myeloid Leukemia in Children

المؤلف:  Hoffman, R., Benz, E. J., Silberstein, L. E., Heslop, H., Weitz, J., & Salama, M. E.

المصدر:  Hematology : Basic Principles and Practice

الجزء والصفحة:  8th E , P861-862

2026-09-06

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The Children Oncology Group (COG)–National Cancer Institute (NCI) TARGET AML Initiative has characterized the genomic land scape of almost 1000 pediatric AML patients. This extensive effort revealed similarities and unique differences between adult and pediatric AML. The most important observation was that the overall frequency of myeloid malignancy gene mutations is lower in pediatric AML than that in adult patients. The mutational burden increases with age, with fusions and copy number alterations being more common in younger patients while smaller sequence variants are more frequent in older patients. Mutations in DNMT3A, IDH1/2, NPM1, and TP53 are less common in pediatric patients while co-occurring NUP98 and FLT3 or WT1 mutations were demonstrated to affect pediatric AML outcomes. The TARGET initiative also revealed some “novel” pediatric-specific chromosomal copy number changes including focal deletions of MBNL1 gene (3q25.2) and ELF1 (13q14.11). Although the TARGET pediatric study did not report PML-RARA fusion-positive children, about 5% to 10% of pediatric AML patients harbor PML-RARA fusion. However, in about 10% of these patients who are morphologically diagnosed as APL, RARA rearrangements could not be identified which suggests that these children should be classified as a subclass of AML rather than APL. The impact of cytogenetics on outcome in a pediatric group of patients with AML (excluding APL) demonstrated about 80% OS at 10 years in patients with CBFA2T3 AML. Within these groups, t(16;21)(q24;q22) resulting in CBFA2T3-GLIS2 fusion is an exclusive pediatric cytogenetic abnormality which leads to a strong downregulation of GATA1. It is currently thought that pediatric acute megakaryocytic leukemia associated with DS (+21 constitutional) targets ERG and GATA1 genes but that the CBFA2T3-GLIS2 fusion is able alone to maintain both high ERG and low GATA1.

In contrast to CBFA2T3 AML, pediatric patients with MLL(KMT2A) abnormalities had an intermediate prognosis (61% OS at 10 years) with no evidence of heterogeneity according to the translocation partner of MLL. Additional abnormalities among the 11q23 leukemias have diverse prognoses; trisomy 8 is an independent favorable, whereas trisomy 19 is considered an adverse prognostic factor in the MLL rearranged group of pediatric patients. Approximately 10% to 15% of children and adolescents and 30% to 60% of infants have KMT2A AML. Most of the KMT2A fusion positive AMLs are considered an aggressive form of AML, although the outcome is overall neutral (fusion specific impact on prognosis) and notably t(9;11)(p22;q23)/ and ins(10;11)(p12;q23q13) are more prevalent in children than adults. MLL10 (10p12.31) is the fourth common gene fusion partner and is predominantly observed in pediatric AML, although it has been reported in B- and T-cell ALL. In infant patients with t(9;11) the patients present with ALL rather than AML, and the phenotype usually changes into typical myelomonocytic AML with increasing age of patients. FLT3-ITD alterations are found in about 10% to 20% of newly diagnosed pediatric AML patients and is an independent prognostic factor for poor outcome particularly for patients with high ITD allelic ratios and/ or loss of the wild-type allele leading to copy number-neutral ITD homozygosity.

Recurrent fusions involving NUP98 (11p15) with over 30 different partner chromosomes have been identified in approximately 4% to 9% of pediatric AML patients. NUP98-KMT5A fusions are more prevalent in children below 3 years of age. Clinically NUP98 rearrangements are associated with normal karyotype AML and most frequently occur in the myelomonocytic subtype with the exception of NUP98-KDM5A fusions [t(11;12)(p15.4;p13–33)] which are enriched in acute megakaryocytic leukemia occurring in approximately 10% of such cases. The presence of a NUP98 KDM5A fusions in megakaryocytic leukemia is associated with a poor prognosis with an EFS of 25%. The NUP98 fusions are associated with a poor prognosis in acute erythroleukemia, with 20% of children with this rare form of AML. Isolated NUP98 rearrangements are not independently prognostic but the combi nation of NSD1-NUP98/ [t(5;11)(q35.2;p15.4)] fusion and concomitant FLT3ITD mutation is strongly associated with a poor outcome.