Translating recent advances in the pathogenesis of acute myeloid leukemia to the clinic

Abstract

Despite FDA approval of nine new drugs for patients with acute myeloid leukemia (AML) in the United States over the last 4 years, AML remains a major area of unmet medical need among hematologic malignancies. In this review, we discuss the development of promising new molecular targeted approaches for AML, including menin inhibition, novel IDH1/2 inhibitors, and preclinical means to target TET2, ASXL1, and RNA splicing factor mutations. In addition, we review progress in immune targeting of AML through anti-CD47, anti-SIRPα, and anti-TIM-3 antibodies; bispecific and trispecific antibodies; and new cellular therapies in development for AML.

Keywords: ASXL1; IDH1; IDH2; RNA splicing; TET2; acute myeloid leukemia; menin; myelodysplastic syndromes.

Figure 1.

Time line of FDA-approved therapies for the treatment of acute myeloid leukemia (AML). (HMA) Hypomethylating agent.

Figure 2.

Known and novel epigenetic targets for the treatment of acute myeloid leukemia (AML). AML-associated genetic alterations in IDH1, IDH2, TET2, and ASXL1, as well as chromosomal rearrangements in MLL1 (KMT2A), alter histone post-translational modifications and/or DNA cytosine modifications and represent exciting therapeutic targets. AML-associated mutations in NPM1 enforce cytoplasmic localization of the mutant NPM1 (NPM1c) and result in up-regulated HOXA gene cluster expression via a mechanism that is not entirely clear. Menin inhibitors have demonstrated promising efficacy and safety in ongoing phase I/II trials for MLL-rearranged and NPM1 mutant AML. In addition, it is known that KMT2A translocations alter the enzymatic activity of KMT2A from a histone H3 lysine 4 (H3K4) methyltransferase to gain the ability to methylate H3K79 via association with the H3K79 methyltransferase DOT1L. As such, DOT1L inhibitors continue to be evaluated for KMT2A-rearranged AML. IDH1/2 mutations alter the enzymatic activity of IDH1/2 to generate the oncometabolite 2-hydroxyglutarate (2-HG) from isocitrate and reduce levels of α-ketoglutarate (α-KG). This alteration in α-KG levels impacts numerous α-KG-dependent enzymes, including TET2 and the Jumonji family of histone lysine demethylases (JHDM). Currently, IDH1 and IDH2 inhibitors are FDA-approved. A number of methods are being tested to boost TET2 enzymatic activity in AML patients with haploinsufficient TET2 mutations (including increasing levels of the TET2 cofactor vitamin C). Finally, recent data identify that certain ASXL1 mutations promote the activity of the H2AK119 deubiquitinase BAP1. As such, the first class of BAP1 catalytic inhibitors has been developed very recently.

Figure 3.

Therapeutic modalities for targeting aberrant RNA splicing in acute myeloid leukemia. Based on data identifying that leukemia cells with change of function mutations in RNA splicing factor genes are preferentially sensitive to chemical modulators of splicing, a number of means to perturb splicing have been developed. These include SF3b binding agents, RBM39-degrading compounds, and inhibitors of a series of enzymes that place critical post-translational modifications on splicing factors, such as inhibitors of protein arginine methyltransferases (PRMTs), CDC2-like (CLK) protein kinases, and SR protein kinases (SRPKs).

Figure 4.

Innate and adaptive immune targets in clinical evaluation for the treatment of acute myeloid leukemia. Currently, clinical trials combining anti-CD47 antibodies (which block CD47 interaction on AML cells with the receptor SIRPa on macrophages) with DNA hypomethylating agents and the triplet of HMAs and venetoclax are ongoing. In addition, blocking SIRPα is being pursued clinically, and inhibiting signaling downstream from the AXL receptor tyrosine kinase on macrophages has been shown in preclinical settings to promote innate immune killing of AML. While treatment with anti-PD-1/PD-L1 or anti-CTLA-4 antibodies has had limited efficacy if used as monotherapy or combined with hypomethylating agents in MDS and AML to date, targeting adaptive immune signaling via blocking the TIM-3 immune checkpoint is currently being evaluated in AML. Preclinical data suggest a tumor cell-autonomous effect of TIM-3 signaling in AML where the TIM-3 ligand Gal-9 is secreted by AML cells and supports AML survival via an autocrine loop. Finally, a number of AML-associated surface antigens are being targeted via T-cell-engaging approaches, including CD33, CD123, and CD371 (CLL1). Currently, the safety and utility of these latter approaches are unclear, as many of these antigens are expressed on normal myeloid cells and/or hematopoietic precursors.