Acute Myeloid Leukemia: From Biology to Clinical Practices Through Development and Pre-Clinical Therapeutics

Abstract

Recent studies have provided several insights into acute myeloid leukemia. Studies based on molecular biology have identified eight functional mutations involved in leukemogenesis, including driver and passenger mutations. Insight into Leukemia stem cells (LSCs) and assessment of cell surface markers have enabled characterization of LSCs from hematopoietic stem and progenitor cells. Clonal evolution has been described as having an effect similar to that of microenvironment alterations. Such biological findings have enabled the development of new targeted drugs, including drug inhibitors and monoclonal antibodies with blockage functions. Some recently approved targeted drugs have resulted in new therapeutic strategies that enhance standard intensive chemotherapy regimens as well as supportive care regimens. Besides the progress made in adoptive immunotherapy, since allogenic hematopoietic stem cell transplantation enabled the development of new T-cell transfer therapies, such as chimeric antigen receptor T-cell and transgenic TCR T-cell engineering, new promising strategies that are investigated.

Keywords: CAR T cells; acute myeloid leukemia; clinical trials; immunotherapies; management.

Figure 1

Targeted therapies available and in development in Acute Myeloid Leukemia (AML). Many tyrosine kinases inhibitors are either currently available or in development. These include: Fms-Like Tyrosine Kinase 3 (FLT3) inhibitors (such as sorafenib, quizartinib, gilteritinib, crenolanib), pan-kinase inhibitors (including midostaurin), FLT3 and KIT inhibitors (including pacritinib), Janus Kinase-2 (JAK2) and interleukine-1 Receptor (IL-1R) Associated Kinases 1/4 (IRAK1/4) inhibitors, the IRAK4 inhibitor Ca-4948, the JAK2 inhibitor ruxolitinib, NRAS, KRAS and MAP Kinases (MAPK) inhibitors (such as vemurafenib, pazopanib, tivozanib), mTOR inhibitors (everolimus and dactolisib), TEC kinases inhibitors (including ibrutinib), and vascular and endothelial growth factor receptor (VEGFR) inhibitor cediranib. Several targeted-drugs are available, or in development, for transcription factors: ivosidenib, an Isocitrate Deshydrogenase-1 (IDH1) inhibitor, enasidenib, an IDH2 inhibitor, azacytidine, decitabine, guadecitabine as hypomethylated agents, the histone deacetylase vorinostat and panobinostat, DS-3201b, a zeste 2 polycomb repressive complex 2 subunit (EZH2) inhibitor, pinometostat, a DOT1-like histone lysine methyltransferase (DOT1L) inhibitor, crizotinib, the Bcl6 Corepressor (BCOR) inhibitor, OTX015, a cyclin-dependent kinase 9/bromodomain and extraterminal (CDK9/BET) inhibitor, and elesclomol, a TP53 inhibitor. Selinexor inhibits the XPO1 exporter, which inhibits leukemic activity of mutated NPM1 proteins. Glasdegib inhibits smoothened multi-transmembrane (SMO), a member of the Hedgehog pathway. Tagraxofusp inhibits CD123, whereas IMGN632 transports chemotherapy through CD123 internalization, as does gemtuzumab ozogamicin and SGN-CD33A through CD33. Venetoclax inhibits the BCL2 anti-apoptotic protein. Several microenvironment targeted drug are in development: etomoxir inhibits fatty acid oxidation metabolism, tigecycline inhibits mitochondrial heterocellular transfer, thus inhibiting drug resistance exchange, ulocuplumab inhibits CXCR4/CXCL12 interaction from inducing leukemia myeloid cell migration, mirabegron, an agonist for sympathetic neuropathy β3-adrenergic receptor (β3-AR), and cavtratin, the NO synthase inhibitor.

Figure 2

Adoptive immunotherapies available and in development for Acute Myeloid Leukemia (AML). Cytotoxicity functions of T-cells (T) and NK-cells (NK) are investigated in several ways. Allogenic hematopoietic Stem Cell Transplantation (ASCT), Donor Lymphocytes Infusion (DLI), Cytokine-induced Killer cells and donor NK-cells infusion provide allogenic T-cells (allo T) and NK-cells (allo NK) targeting neoantigens including Human Leukocyte Antigen (HLA) Major Histocompatibility Complex (CMH) mismatch, Killer-cell Immunoglobulin-like Receptor (KIR) mismatch, Minor Histocompatibility Antigen (MiHA), Tumor Specific Antigen (TSA) and Tumor Associated Antigen (TAA). Transgenic T-cell receptor (tgTCR) T-cells could target the nucleophosmin-1- (NPM1) mutated antigen (ΔNPM1), Wilms’ Tumor 1 (WT1), Myeloperoxidase (MPO), Hyaluronan-mediated motility receptor- (HMMR/Rhamm), Melanoma Associated Antigen-A3 (MAGE A-3), leukemia-associated minor H antigen 1- (HA-1). Monoclonal antibodies could target CD38 (Daratumumab), CD70 (Cusatuzumab), CD123 (Talacotuzumab) and IL1RAP (mAb 81.2, mAb3F8, MAB-hR3) and induced AML cells lysis. Blockade antibodies could target Program Cell Death 1 (PD-1) and PD-1 ligand (PD-L1). Bispecific T-cells Engagers (BiTE) (AMG-330, XmAb14045, MCLA-117), Dual-Affinity Re-Targeting (DART) (MGD006), Bi- and Tri-specific Killer Engagers (BiKE, TriKE) (1633, SPM-2) and Checkpoint inhibitor T-cell Engager (CiTE) antibodies could engage T-cell targeting toward specific antigens. Debileukin difitoxin could block IL-2 receptor (CD25) and then induce regulatory T-cells (Treg) apoptosis. Chimeric Antigen Receptor (CAR) T-cells could target CD33, CD123, C-type lectin domain family 12 member A (CLEC12A or CCL-1), CD33 and CD123, CD123 and CCL-1 (compound CAR), CD13 and T-cells Immunoglobulin Mucin-3 (TIM-3) (bispecific CAR), CD38, CD44, Lewis Y (LeY), Natural Killer Group 2D Ligand (NKG2DL), B7-H3, Fms-Like Tyrosine Kinase 3 (FLT3), c-KIT (CD117) and interleukine-1 Receptor Accessory Protein (IL1RAP).

Figure 3

Acute Myeloid Leukemia (AML) intensive strategy perspectives in younger patients. Standard treatments are in regular small captions, putative investigated treatments are in italics. Standard chemotherapy could be combined with targeted drug inhibitors (targeted inhibitor), such as FLT3 inhibitors or targeted chemotherapeutic agents such as CD33-conjugated antibodies. In the case of first complete response (CR1), intermediate and high-risk patients with or without maintenance therapy are subjected to consolidation via chemotherapy, with or without targeted drug inhibitors, such FLT3 inhibitors, followed by allogeneic hematopoietic stem cell transplantation (ASCT). In the case of primary refractory AML, salvage therapy may be improved via chemotherapy by the addition of a hypomethylated agent (HMA), targeted inhibitors, targeted-drug immunotherapy (immunotherapy) or chimeric antigen receptor (CAR) T-cells, followed by ASCT. Measurable residual disease or low burden relapse may be treated with HMA or a donor lymphocyte infusion (DLI) in case of ASCT, and improved through the addition or the single use of a target inhibitor, immunotherapy or transgenic T-cell receptor (tgTCR) T-cells. Relapses with greater AML burden may be treated via chemotherapy and improved via the addition or single use of a targeted inhibitor, immunotherapy, or CAR T-cells. Next, ASCT following chemotherapy, single or several targeted therapy regimens depending on the response or CAR T-cells may be performed. Consolidation with or without maintenance may also be performed using HMA, donor lymphocyte infusion (DLI) in case of ASCT, or targeted therapy.