The evolution of targeted therapy in pediatric AML: gemtuzumab ozogamicin, FLT3/IDH/BCL2 inhibitors, and other therapies

Abstract

Despite the maximum intensification of chemotherapy and the increased use of hematopoietic stem cell transplantation (HCT) in pediatric patients with acute myeloid leukemia (AML), nearly 40% of patients still experience relapse, and cure in this setting remains a significant challenge. Recent improvements in AML characterization, including advances in flow cytometry and comprehensive genomic sequencing, have led to a better understanding of AML biology and the identification of multiple potential therapeutic targets. Novel agents targeting genomic lesions, cell surface antigens, and other mechanisms that permit oncogenesis or immune escape are being incorporated into current treatment strategies or are under investigation in efforts to improve outcomes and decrease the toxicities and late effects associated with traditional intensive chemotherapeutic and HCT treatment. However, multiple challenges still exist, including the biologic and immunophenotypic heterogeneity of childhood AML, the differences in underlying biology as compared to adult AML, and the significant potential for on-target/off-tumor toxicity associated with therapies directed at targets common to myeloid cells, both leukemic and normal. This article reviews the current landscape of genomic and cell surface targets for children with AML with a focus on the currently available targeted therapeutic agents, those in active clinical investigation, and those still in development.

Graphical abstract

Figure 1.

Targeted agents in AML encompass small-molecular inhibitors directed against specific genomic alterations and leukemogenic pathways as well as cell surface antigens, which can be targeted by a variety of immunotherapeutic modalities. HLA, human leukocyte antigen; NK, natural killer; TCA, tricarboxylic acid; TCR, T-cell receptor.

Figure 2.

Menin inhibitors block the essential menin-MLL1 interaction, which disrupts the chromatin complex, inhibits HOXA9/MEIS1-mediated leukemogenesis, and induces differentiation. This pathway is critical in KMT2Ar AML. NPM1-mutated and NUP98- rearranged leukemias are also dependent on menin binding and aberrant HOXA9/MEIS1 expression and sensitive to this therapeutic strategy as well.