Acute Myeloid Leukemia in Children: Emerging Paradigms in Genetics and New Approaches to Therapy

Abstract

Purpose of Review Acute myeloid leukemia (AML) in children remains a challenging disease to cure with suboptimal outcomes particularly when compared to the more common lymphoid leukemias. Recent advances in the genetic characterization of AML have enhanced understanding of individualized patient risk, which has also led to the development of new therapeutic strategies. Here, we review key cytogenetic and molecular features of pediatric AML and how new therapies are being used to improve outcomes. Recent Findings Recent studies have revealed an increasing number of mutations, including WT1, CBFA2T3-GLIS2, and KAT6A fusions, DEK-NUP214 and NUP98 fusions, and specific KMT2A rearrangements, which are associated with poor outcomes. However, outcomes are starting to improve with the addition of therapies such as gemtuzumab ozogamicin and FLT3 inhibitors, initially developed in adult AML. Summary The combination of advanced risk stratification and ongoing improvements and innovations in treatment strategy will undoubtedly lead to better outcomes for children with AML.

Cytogenetics of Pediatric Acute Myeloid Leukemia: A Review of the Current Knowledge

“…Normal karyotypes account for around one-quarter (22–26%) of pediatric AML [ 22 , 28 , 36 ]. Their risk assignment is based on the search for cryptic cytogenetic abnormalities (for example, NUP98 r) and for somatic mutations with well-established prognosis relevance, such as NPM1 , FLT3-ITD and CEBPAdm , in the current adult and pediatric therapeutic trials [ 7 , 8 , 132 ]. Indeed, even though these mutations are found at a much lower level in children than in adults, increasing with age, they share the same prognostic significance [ 132 , 133 ].…”

“…Complete remission (CR) is now achieved in 90% of cases, whereas event-free (EFS) and overall survival (OS) rates are commonly around 50% and 70%, respectively, due to the high rate of relapse. Moreover, short and long term therapy-related toxicities have to be taken into consideration, with a persistent high risk of death due to intensive therapy (4–10%) and significant long term side-effects of certain chemotherapies (anthracycline) [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 ].…”

“…In terms of clinical impact, adult classification systems, such as those defined by ELN, cannot be completely transferred to the classification of childhood AML, because the cytogenetic (and genomic) landscapes of pediatric and adult AML and the cytogenetic risk associations are different according to age [ 1 , 8 , 21 , 22 , 23 ].…”

Inhibitors of Chemoresistance Pathways in Combination with Ara-C to Overcome Multidrug Resistance in AML. A Mini Review

“…In general, patients with a recent diagnosis of AML in the absence of treatment have a survival of days or weeks. With standard therapy, between 60% and 75% of children achieve an overall survival of 5 years, largely due to fewer genetic mutations and their greater ability to tolerate both high-intensity chemotherapy and HCT [ 1 , 20 , 21 ]. In contrast, only 24% of adult patients who are selected for intensive therapy and 10%–15% of older patients not eligible for intensive therapy survive to five years, [ 1 , 6 , 22 , 23 ] and almost 80% of patients diagnosed at an age ≥65 years die within one year [ 19 ].…”

“…R/R may exist prior to exposure to chemotherapeutic agents (intrinsic or primary resistance), or it can develop or increase during drug treatment (acquired or secondary resistance), leading to chemoresistance and relapse [ 29 ]. Sixty percent of patients in the favorable risk category and 85% in the adverse risk category develop R/R, and only 10–20% survive to five years [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ].…”