Management of Acute Myeloid Leukemia: Current Treatment Options and Future Perspectives

Abstract

Treatment of acute myeloid leukemia (AML) has improved in recent years and several new therapeutic options have been approved. Most of them include mutation-specific approaches (e.g., gilteritinib for AML patients with activating FLT3 mutations), or are restricted to such defined AML subgroups, such as AML-MRC (AML with myeloid-related changes) or therapy-related AML (CPX-351). With this review, we aim to present a comprehensive overview of current AML therapy according to the evolved spectrum of recently approved treatment strategies. We address several aspects of combined epigenetic therapy with the BCL-2 inhibitor venetoclax and provide insight into mechanisms of resistance towards venetoclax-based regimens, and how primary or secondary resistance might be circumvented. Furthermore, a detailed overview on the current status of AML immunotherapy, describing promising concepts, is provided. This review focuses on clinically important aspects of current and future concepts of AML treatment, but will also present the molecular background of distinct targeted therapies, to understand the development and challenges of clinical trials ongoing in AML patients.

Keywords: AML; clinical trial; resistance; targeted therapy.

Figure 1

Mechanisms of resistance towards venetoclax. Left: uptake, processing, and incorporation of HMAs into the leukemic cell are illustrated. Cellular uptake of HMAs mainly depends on cell surface hENT1 receptor expression. Phosphorylation to active cytosine di- and triphosphatases is mediated by DCK, whereas low expression and diminished activity contributes to decreased HMA effect. Augmented enzymatic degradation of dCTPs also contributes to degraded HMA effect. Right: regulation and interactions of proteins that are responsible for venetoclax resistance are shown. Balance between multiple BCL-2 members within the concert of intrinsic apoptosis pathways is pivotal. Downregulation of BCL-2 reduces venetoclax sensitivity as well as reduced activation of mitochondrial apoptosis effectors BAX and BAK. KRAS mutations mediate such gene expression alterations. Upregulation of important anti-apoptotic genes like MCL-1, BCL2A1, and BCL(x)L causes venetoclax resistance by binding and sequestering the effectors BAX and BAK. Activation and upregulation are driven by activating mutations of FLT3-ITD, SHP2, or KRAS. Especially consecutive STAT5 signaling can directly upregulate MCL-1 by activating an MCL-1 promotor. BH3- only proteins acting as pro-apoptotic sensitizers bind pro-apoptotic members causing configuration changes and release of BAX and BAK. Mutations in TP53 can reduce its function as tumor suppressor and confer alterations of expression of BCL-2 family members. One consequence of TP53 deletion is an increase of cellular stress, which is known to contribute resistance towards different cancer drugs. Created with BioRender.com. Abbreviations: HMA hypomethylating agent; hENT1 human equilibrated nucleoside transporter-1; DCK deoxycytidine kinase; CDA cytidine deaminases; dCTP deoxycytidine triphosphate; FLT3-ITD FMS-like tyrosine kinase receptor III with internal tandem duplication; SHP2 SH2 containing protein tyrosine phosphatase-2; BCL-2 b-cell lymphoma 2; MOMP mitochondrial outer membrane permeabilization; KRAS Kirsten rat sarcoma virus; MCL-1 induced leukemia cell differentiation protein; BCL2A1 BCL-2 related protein A1; BCL(x)L b-cell lymphoma extra-large; STAT5 signal transducer and activator of transcription 5; TP53 tumor protein p53; VEN venetoclax.

Figure 2

Current immunotherapeutic approaches targeting leukemic stem cells in AML patients. TIM-3 is a membrane bound glycoprotein and immunoreceptor expressed on both LSCs and cytotoxic CD4⁺ and CD8⁺ T-cells. It can be addressed by monoclonal antibodies (MB453 or PDR001) and bispecific directed CAR-T cells against CD13 and TIM-3. GPR56, a G-protein coupled transmembrane receptor, can be overexpressed in LSCs causing upregulation of leukemia driving transcription factor HOXA1. CD44 is an adhesion molecule, which physically interacts with the transmembrane protein CXCR4 and activated by CXCL12, which is crucial for anchorage of LSCs in the bone marrow niche. Inhibition of CD44 overcomes resistance to BCL-2 inhibitor venetoclax whereas CXCR4 can directly be inhibited by plerixafor, leading to mobilization of LSCs from the bone marrow niche [197]. CD47 is an integrin associated membrane protein and able to suppress macrophages and thus preventing eliminating of LSCs. The CD47 directed monoclonal antibody magrolimab could disrupt the connection between CD47 on LSC and SIRPalpha on macrophages. CD123 as interleukin 3 receptor can be targeted by bispecific CD3/CD123 antibodies to redirect T-cell to LSCs. CD70 as a ligand of the TNF superfamily receptor CD27 can be hindered from binding by monoclonal antibody cusatuzumab or CD70 directed CAR-T cells. Same approaches are illustrated for CLL-1 receptor. SHH and MAPK signaling is illustrated since they represent highly conserved pathways in LSCs which mainly contribute to maintenance and cell proliferation. MAPK is known to activate integrated stress response signaling which promotes cellular recovery and restore homeostasis. The transcription factor FOXM1 is crucial for maintaining, survival, and renewing of LSCs, which is activated by b-catenin/WNT signaling. Created with BioRender.com. Abbreviations: TIM-3 T cell immunoglobulin and mucin-domain containing-3; AML acute myeloid leukemia; LSC leukemic stem cell; CAR-T chimeric antigen receptor t cell; GPR56 adhesion G protein–coupled receptor 56; HOXA1 Homeobox A1; CXCR4 C-X-C chemokine receptor type 4; CXCL12 C-X-C chemokine ligand type 12; BCL-2 b-cell lymphoma-2; TNF tumor necrosis factor; CLL-1 C-type lectin domain family 12 member A; SHH sonic hedgehog; MAPK Mitogen-activated protein; FOXM1 Forkhead Box Protein M1; VEN Venetoclax.