Novel investigational approaches for high-risk genetic subsets of AML: TP53, KMT2A, FLT3

Abstract

The treatment landscape in acute myeloid leukemia (AML) is rapidly evolving, with multiple new therapies approved in recent years. However, the prognosis for patients with high-risk genetic subsets of AML remains poor, and the development of more effective treatment options for these patients is ongoing. Three of these high-risk AML patient subsets include TP53-mutated AML, FLT3-internal tandem duplication (ITD)-mutated AML, and AML harboring rearrangements affecting the KMT2A locus (KMT2A-r AML). The prognosis for TP53-mutated AML remains poor with both intensive and targeted regimens, including those incorporating the BCL-2 inhibitor, venetoclax. Allogeneic hematopoietic stem cell transplantation is the only potentially curative therapy for these patients, but posttransplant relapse rates remain high. Patients with FLT3-ITD-mutated AML continue to have suboptimal outcomes with standard therapies and experience high rates of relapse following transplant. KMT2A-r AML is also associated with poor outcomes with current treatment approaches, and effective standards of care are lacking for patients with relapsed/refractory disease. This article discusses current treatment approaches, along with the investigational agents being explored for the treatment of these 3 AML subsets, focusing primarily on agents that are further along in development.

Transforming growth factor-β1 and vascular endothelial growth factor levels in senile acute myeloid leukemia and correlation with prognosis

“…TGFβ1 is a multifunctional cytokine capable of modulating cell growth, differentiation, migration, and apoptosis[ 22 ]. Abnormal expression of VEGF and TGFβ1 enable AML cells to escape immune attack by suppressing the immune response[ 23 ].…”

A 2024 Update on Menin Inhibitors. A New Class of Target Agents against KMT2A-Rearranged and NPM1-Mutated Acute Myeloid Leukemia

“…A dependence on menin is known in KMT2Ar leukemias, in NPM1mut AML and in other types of neoplasms. In this context, the interactions of menin with the KTM2A protein are considered critical for the leukemic transcriptional program in AML through the upregulation of HOX/MEIS1 gene expression (see Figure 1 ) [ 8 , 9 , 10 , 11 ].…”

“…Nuclear localization leads to the stimulation of aberrant transcription of HOXA and other genes, which is critical for KMT2Ar AML pathogenesis [ 8 ]. The fundamental role of the interaction between menin and the N-terminal region of KMT2A in leukemogenesis has been demonstrated in many in vivo and in vitro studies, where loss of menin binding eliminates the oncogenic properties of KMT2A fusion proteins (see Figure 1 ) [ 9 , 10 ].…”

Menin Inhibitors: New Players in KMT2A-Rearranged and NPM1-Mutated Acute Myeloid Leukemia

“…A dependence on menin is known in KMT2Ar leukemias, in NPM1mut AML and in other types of neoplasms. In this context, the interactions of menin with the KTM2A protein are considered critical for the leukemic transcriptional program in AML through upregulation of HOX/MEIS1 gene expression-FIGURE 1 [8][9][10][11].…”

“…Nuclear localization leads to the stimulation of aberrant transcription of HOXA and other genes, which is critical for the KMT2Ar AML pathogenesis [8]. The fundamental role of the interaction between menin and the N-terminal region of KMT2A in leukemogenesis has been demonstrated in many in vivo and in vitro studies, where loss of menin binding eliminates the oncogenic properties of KMT2A fusion proteins-FIGURE 1 [9,10].…”