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Acute myeloid leukaemia (AML) is characterized by impaired myeloid differentiation resulting in an accumulation of immature blasts in the bone marrow and peripheral blood. Although AML can occur at any age, the incidence peaks at age 65. The pathobiology of AML also varies with age with associated differences in incidence, as well as the frequency of cytogenetic change and somatic mutations. In addition, 5-year survival rates in paediatrics are 60–75% but fall to 5–15% in older AML patients. This systematic review aimed to determine whether the altered genes in AML affect the same molecular pathways, indifferent of patient age, and, therefore, whether patients could benefit from the repurposing drugs or the use of the same immunotherapeutic strategies across age boundaries to prevent relapse. Using a PICO framework and PRISMA-P checklist, relevant publications were identified using five literature databases and assessed against an inclusion criteria, leaving 36 articles, and 71 targets for therapy, for further analysis. QUADAS-2 was used to determine the risk of bias and perform a quality control step. We then priority-ranked the list of cancer antigens based on predefined and pre-weighted objective criteria as part of an analytical hierarchy process used for dealing with complex decisions. This organized the antigens according to their potential to act as targets for the immunotherapy of AML, a treatment that offers an opportunity to remove residual leukaemia cells at first remission and improve survival rates. It was found that 80% of the top 20 antigens identified in paediatric AML were also within the 20 highest scoring immunotherapy targets in adult AML. To analyse the relationships between the targets and their link to different molecular pathways, PANTHER and STRING analyses were performed on the 20 highest scoring immunotherapy targets for both adult and paediatric AML. There were many similarities in the PANTHER and STRING results, including the most prominent pathways being angiogenesis and inflammation mediated by chemokine and cytokine signalling pathways. The coincidence of targets suggests that the repurposing of immunotherapy drugs across age boundaries could benefit AML patients, especially when used in combination with conventional therapies. However, due to cost implications, we would recommend that efforts are focused on ways to target the highest scoring antigens, such as WT1, NRAS, IDH1 and TP53, although in the future other candidates may prove successful. [ABSTRACT FROM AUTHOR]

Mutations in NPM1, also known as nucleophosmin-1, B23, NO38, or numatrin, are seen in approximately one-third of patients with acute myeloid leukaemia (AML). A plethora of treatment strategies have been studied to determine the best possible approach to curing NPM1-mutated AML. Here, we introduce the structure and function of NPM1 and describe the application of minimal residual disease (MRD) monitoring using molecular methods by means of quantitative polymerase chain reaction (qPCR), droplet digital PCR (ddPCR), next-generation sequencing (NGS), and cytometry by time of flight (CyTOF) to target NPM1-mutated AML. Current drugs, now regarded as the standard of care for AML, as well as potential drugs still under development, will also be explored. This review will focus on the role of targeting aberrant NPM1 pathways such as BCL-2 and SYK; as well as epigenetic regulators (RNA polymerase), DNA intercalators (topoisomerase II), menin inhibitors, and hypomethylating agents. Aside from medication, the effects of stress on AML presentation have been reported, and some possible mechanisms outlined. Moreover, targeted strategies will be briefly discussed, not only for the prevention of abnormal trafficking and localisation of cytoplasmic NPM1 but also for the elimination of mutant NPM1 proteins. Lastly, the advancement of immunotherapy such as targeting CD33, CD123, and PD-1 will be mentioned. [ABSTRACT FROM AUTHOR]