Immunotherapy as a turning point in the Treatment of Acute Myeloid Leukemia NGUYEN UYEN THU - NGUYEN PHUONG ANH - NGUYEN TRAN YEN NGOC - DUONG HA TRUC TAM Introduction Acute myeloid leukemia (AML) is a heterogeneous clonal disorder characterized by immature myeloid cell proliferation and bone marrow failure. This type of cancer usually gets worse quickly ifit is not treated. AML is also called acute myelogenous leukemia and acute nonlymphocytic leukemia, Cytogenetics and mutation testing remain a critical prognostic tool for post induction treatment. Despite rapid advances in the field including new drug targets and increased understanding of the biology, AML treatment remains unchanged for the past three decades with the majority of patients eventually relapsing and dying of the disease. Allogeneic transplant remains the best chance for cure for patients with intermediate or high risk disease. In this review, we discuss the landmark genetic studies that have improved outcome prediction and novel therapies. Pathophysiology e Howcan leukemia cells form in the body? Red blood cells (RBCs), white bfood cells (WBCs), and platelets are among the three cell types found in blood fluid. The spongy inside of the bone called the bone marrow is where these cells are created. Stem cells are the biological parents of all blood cells. RBCs provide oxygen to the tissues of the body. The body Uses platelets and WBCs to help the blood clot and to fight off infections and other dangerous pathogens, A certain. WBC during their formation is where leukemia develops. in leukemia, the bone marrow's stem cells produce an excessive number of aberrant WBCs that are dysfunctional. This weakens the immune system. Leukernia may also lower the number of RBCs ‘and platelets. WBCs termed myeloid cells are affected by myeloid leukemia; when there are too many of these ceils, they divide abnormally. Many more myeloid cells become aberrant ‘and divide into abnormal myeloblasts or granulocytes, which are various forms of WBCs, in myeloid leukemia, which affects WBCs known as myeloid cells. These blasts in AML evolve into immature or aberrant cells rather than mature, healthy cells, According to how developed the WBCs are at the time of diagnosis and how distinct they are from healthy blood cells, there are several subtypes of AML. The cancer cells have the ability to spread, or metastasis, to other bodily organs where they can start new tumors. Leukemic blasts: do not function correctly, stop the growth of healthy cells, and develop and survive more successfully than healthy cells e __ Risk factors Besides the most common risk factor, myelodysplastic syndrome, there are some other risk factors that increase the chance to get AML ‘© Old age: More than half of patients are recorded to get AML although this disease can occur at any age. ‘Smoking: Even in the case of passive smoking, the lungs can take up cancer-causing substances from tobacco smoke, which then spread through the bloodstream throughout the body. ‘* Hematological disorders: including aplastic anemia, and chronic myeloproliferative disorders (e.g. polycythemia vera, essential thrombocy themia, and idiopathic myelofibrosis) Normal Blood Leukemia © Symtomps Patients who are at the early stages of acute myelogenous Jeukernia may face general signs and symptoms which do not differ from those of the flu or other common diseases as following: Fever, Bone pain, lethargy and fatigue, shortness of breath, pale skin, frequent infections, unusual bieeding, such as frequent nosebleeds and bleeding from the gums Fr ‘What are the symptoms of AML? ¢ Treatment 4 Induction Therapy The most typical strategy is “3 and 7," which consists of three days of a 15- to 30-minute infusion of an anthracycline (idarubicin or daunorubicin) or anthracenedione (mitoxantrone) paired with araC, 100 mg/m2 as a 24-hour infusion daily for seven days. Idarubicin is administered at a dose of 12 mg/m2/d for three days, daunorubicin at a dose of mg/m2/d for three days, or mitoxantrone at a dose of 12 mg/m 2/d for three days. These: protocols necessitate sufficient cardiac, hepatic, and renal function. With these regimens, roughly half of the patients achieve remission after just one treatment. Another 10-15% achieve remission after a second session of therapy. 2. Consolidation Therapy, Consolidation therapy is started with high dose cytarabine, «also known as HIDAC, and hematopoietic cell transplantation following the achievement of CR with induction therapy (HCT). When the prognosis is intermediate or poor, HCT is preferred in patients under the age of 60. Allogeneic HCT is Preferred over autologous HCT if donor is availabe, They need to be watched out for any early or late signs or symptoms of acute or chronic graft versus host disease (GvHo).3. Novel Targets (Ongoing research involving immune therapies, IDH inhibitors, and Fms-like tyrosine kinase 3 (FLT3) inhibitor ‘To avoid the usually fatal graft versus host disease caused by transfusions, all blood products must be radioactively treated. Patients who are febrile are given IV antibiotics, and prophylactic antifungal therapy is advised. Immune system response to cancer cells In the early stages of cancer, our immune cells perform an ‘excellent job of eliminating individual cancer ceils when they ‘appear. This is termed as the ‘eliminating phase, in which immune cells take control of the tumor and operate peacefully. Even though their burden is rising, the immune cells are doing a decent enough job of staying on top of cancer cells as they grow ‘and divide. Yet, cancer cells can gain genetic modifications that allow them to evade the immune system over time. This is referred to as the “escape phase." Immune cells are unable to keep up with the developing tumor at this phase. Certain cancer cells in the tumor become overly intelligent, and immune cells ‘are unable to adapt quickly enough to keep them at bay. Immune cells detect danger via a set of chemicals located on the surface of all cells in the body. This allows them to thoroughly analyze possible problems before deciding whether toattack. But, when a cancer enters the ‘escape phase; it might transform. The chemicals that would ordinarily disclose the malignancy to the immune system are lost, and killer T cells ass by, uninformed of the risk the cancer cell potentially pose. The hypothesis is that if these tactics can be reversed or stopped, immune cells' ability to combat cancer can be restored. This has formed the basis of a growing range of cancer treatments called immunotherapies, Immunotherapies for AML © CDI23 Interleukin 3 (IL-3) receptor -chain (IL3RA), also known as D123, is a viable therapeutic target for the treatment of hematological malignancies. While only a tiny percentage of CD56+ monocytes express it, it is highly expressed on myeloid blasts and LSCs. The Seattle Genetics-created CD123-directed immunoconjugate SGN-CD123A is a humanized anti-CD123 antibody coupled to a potent DNA-binding pyrrolobenzodiazepine (PBD) dimer medication via a protease- cleavable dipeptide linker. It exhibits strong anticancer effect in preclinical models of MDR-positive AML, which is typically resistant to chemotherapy, and against a wide range of primary AML samples. The anti~CD123 single chain (scFv) is joined toa shortened Pseudomonas exotoxin that lacks its native domain of targeting, making up the SL-101 molecule in addition to SGN-CD123A. A phase | research is now being conducted on this chemical, which has demonstrated cytotoxic action on primary and lab AML cells. Nevertheless, a novel fusion protein made of IL-3 and a shortened diphtheria toxin has recently been used. SL-401, also known as tagraxofusp, was created from this combination and showed considerable effectiveness, particularly in patients with blastic plasmacytoid dendritic cel neoplasm (BPDCN), an aggressive hematologic malignancy whose blasts overexpress IL-3R and which develops quickly into a leukemia phase. Research results from SL-401 treatment in AML patients were optimistic and hopeful since MRD was completely eradicated and distinct myeloid malignancies achieved clear response rates. Its use in conjunction with azacytidine. is also being researched right now (NCT03113643). Significant findings were obtained in the NCTO2113982 research including untreated or relapsed BPDCN and _R/R AML patients, who received intravenous tagraxofusp (7 jug or 12 ug/Kg) on days 1-5 every 3 weeks until progression or severe toxicity. According to the research, 57% of individuals who had not previously had a therapy had full or mild skin reactions. Figure 1: Immunotargeting of v». __ Validated targets in AML using investigational seem molecules, with CD33 and intermediate AML, SGN-CD33A and AMG: 330 under investigation, and CD123_ targeting tagraxofusp approved. Jone * Vaccine-based therapy The potent graft-versus-leukemia (GVL) impact, mediated by allogeneic donor lymphocytes, has emerged as the most compelling proof of the immune system's ability to inhibit the development of AML after HSCT. Nevertheless, the Tecipient may experience graft-versus-host _ disease (GVHD), which has been related to higher morbidity and death, due to the donor lymphocytes’ limited range of specificity. Producing certain T cells is an appealing method for eliciting a particular immunological response. ‘Although several candidate antigens have been reported, the AMLassociated antigen has not yet been found Leukemia-specific antigens (LSAs), such as_myeloid primary granule proteins, leukemia-associated antigens (LAAs), cancer/testis antigens (CTAs), and ubiquitous antigens are some of them. Using peptides delivered by expert antigen-presenting cells (APCs), such as dendritic cells, vaccines can be created (DCs). By targeting cells like stem cells that are resistant to chemotherapy, the intention is to avoid recurrence. However, only a small percentage of AML patients have LSA expression, even though LSAs like the promyelocytic leukemia-retinoic acid receptor (PMLRAR) are an attractive target. While LAAs can be overexpressed in leukemia cells, they are also expressed in normal cells. As a result, they qualify for immunotherapy. The three proteinases (PR)-1 and -3, Wilms’ tumor 1 (WT1) antigen, and receptor for hyaluronic acid-mediated motility {RHAMM) are most often utilized as peptide vaccines. In micellar delivery systems, these peptides are selectively infected to achieve a delayed release to APC.Peptides are then more successfully delivered to T cells via APCs. The benefits of this treatment have been proven in several research. cs 8 - he, Figure 2: T cell responses to AML tumor-associated antigen (TAA) are generated by DCs, which activate and expand AML- specific T cells, allowing CTL to recognize and kill AML cells.Ss § “gy. Conclusion be SS] AML is « complex disease with a diverse genetic landscape. The field is rapidly expaneling with SS | increased understanding of the biology as well as potential new drug targets. Despite our best i, | MW | | efforts at targeted therapy, it has become apparent that single drug options may be less likely to succeed over multiple drug targets. Relapse disease remains the highest cause of mortality after HCT. Immunotherapy is also an exciting new therapeutic approach which may offer long term ures for relapsed patients. We remain hopeful that the therapeutic options will continue to improve, with less toxicity and improved efficacy. References 1. Vakiti, A., & Mewawalla, P. (2022, August 15), Acute Myeloid Leukemia - StatPearts - NCBI Bookshelf. Acute Myeloid Leukemia StatPearls - NCBI Bookshelf, https://www.ncbi.nlm.nih.gov/books/NBK507875/ 2. Acute Leukemia | What To Know About This Blood Cancer | LLS. (n.d). Acute Leukemia | What to Know About This Blood Cancer | LLS. https:/wwuls.org/leukemia/acute-myeloid-leukemi foclid= IwAROC 22xDW 9mLkJAeO4Ke4VINrOkgMT430-d247tTI3GriZnvUSFHUFSUByS: 3. Acute myeloid leukaemia - Causes. (r.d.). nhs.uk. https://wwnw.nhs.uk/conditions/acute-myeloid-leukaemnia/causes/ fi erin 20. abet) 28) Wy dome ne ries si tach caret cals aes ee ce eat UK- Cancer News, https://news.cancerresearchuk.org/2019/02/28/science-surgery-why-doesnt-the-immune- system-attack-cancer-cells/ 5, Aurel, A. Marziani, B., Sconocchia, T., Del Principe, M. |., Buzzatti, E., Pasqualone, G., Venditti, A., & Sconocchia, G. (2021, December 13). immunotherapy as a Turning Point in the Treatment of Acute Myeloid Leukemia. MDPI. https://doi.org/10.3390/cancers13246246