Acute Myeloid Leukemia (AML)
Alfa Cytology offers comprehensive preclinical services for drug development related to leukemia. Our solutions help clients save time and resources, making the drug development process more efficient.
Introduction to AML
Acute Myeloid Leukemia (AML) is a type of cancer that affects blood and bone marrow. It is characterized by the rapid increase of immature “blast” cells, which leads to ineffective red blood cell production and bone marrow failure. Despite advances in therapy, the outlook for certain patients remains poor.
Epidemiology of AML
In the United States, AML occurs at a rate of about 3 to 5 cases per 100,000 people. The incidence increases with age, from about 1.3 cases per 100,000 people under 65 to 12.2 cases per 100,000 people 65 and older. Without proper treatment, AML can quickly lead to serious complications like infections, bleeding, and organ failure.
Fig. 1. Incidence of patients with acute myeloid leukemia in the United States by age at diagnosis. (Shallis, R.M. et al., 2019)
Therapy Development for AML
Many medications and treatment options exist for AML. Chemotherapy drugs like cytarabine are commonly used, often in combination with anthracyclines. These drugs work by inhibiting DNA replication, thereby damaging leukemia cells.
Therapy Development for Acute Myeloid Leukemia
As shown in Figure 2, there are multiple medications as well as therapy options for AML. Cytarabine is a chemotherapy drug that is often used as a backbone of AML therapy. Anthracyclines are potent chemotherapy drugs that are commonly used in combination with cytarabine. They work by inhibiting the enzymes responsible for DNA replication and causing damage to leukemia cells.
Fig. 2. Drugs used in the treatment of acute myeloid leukemia. (DiNardo, C.D.; Wei, A.H., 2020)
Drugs in the Pipeline
Drug resistance reduces monotherapy effectiveness. Developing innovative therapies targeting AML’s complexity is urgent. New drugs are in development to address different aspects of leukemia.
| Drugs | Target | Phase | Trial |
|---|---|---|---|
| Gilteritinib | FLT3-ITD, FLT3-TKD | NCT03836209 | |
| Ivosidenib, Enasidenib | IDH1/IDH2 | NCT0383977 | |
| APR-246 | TP53 | NCT03745716 | |
| Venetoclax | BCL2 | NCT02993523 | |
| Tagraxofusp | CD123 | NCT02270463 | |
| Venetoclax + Ivosidenib | IDH1, BCL2 | NCT03471260 | |
| NKR-2 | Investigational CAR-T | NCT03018405 |
The acute myeloid leukemia (AML) therapy is focused on advancing innovative therapies for this aggressive hematologic cancer. Using cutting-edge technologies such as targeted therapy, immunotherapy and gene analysis to simplify the development process and improve prognosis.
Case Study
In Vitro Efficacy Evaluation
The compound's anti-proliferative activity was assessed in multiple human AML cell lines, including MV4-11 and MOLM-13, through cell viability assays, with GI50 values determined for each (Fig. 3).
Fig. 3 In Vitro Efficacy Evaluation of Drug A on MV4-11 and MOLM-13 Cell Lines
Through western blot analysis, it was confirmed that this compound effectively inhibits FLT3 phosphorylation and its downstream signaling pathways mediated by key effector molecules, including STAT5, ERK, and AKT, thereby elucidating its mechanism of action in suppressing cell proliferation and inducing apoptosis.
Fig. 4 Detection of Phosphorylation Levels Downstream of Signaling Pathways
In Vivo Efficacy Evaluation
The HL-60-luc Orthotopic Model of Acute Myeloid Leukemia (AML)
- Model Information
Cell Line: HL-60-luc
Age: 7-8 Weeks
Species: NSG Mice
Weight: 20-22 g
- Model Construction
Following randomization, mice received cyclophosphamide pretreatment (100 mg/kg, i.p.) once daily for 2 days. On day 3, all animals were inoculated intravenously with 1×10^7 HL-60 AML cells per mouse. Tumor engraftment was confirmed at week 3 by assessing leukemic infiltration in liver and spleen tissues, along with elevated peripheral leukocyte counts. The blank control group remained untreated throughout the study.
Fig. 5 HL-60-luc Orthotopic Model Construction Flowchart.
- Results
Treatment with Drug A resulted in significant antitumor efficacy, reduced leukemic infiltration, and prolonged survival compared to control animals.
Fig. 6 Image of Individual Mouse Radiance of HL-60-luc Orthotopic Models
Fig. 7 Effect of Drug A on Survival Rate in HL-60-luc Orthotopic Models
In addition to the HL-60-luc model featured in the case study, we also customize other cell line-transplanted AML models (KG-1a), patient-derived xenograft AML models, and genetically engineered AML models according to client requirements. Alfa Cytology offers a full range of supportive research services to support your preclinical research. Contact us to learn more about our services.
References
- DiNardo, C.D.; Wei, A.H. How I treat acute myeloid leukemia in the era of new drugs. Blood, The Journal of the American Society of Hematology. 2020, 135(2): 85-96.
- Stanchina, M.; et al. Advances in acute myeloid leukemia: recently approved therapies and drugs in development. Cancers. 2020, 12(11): 3225.
- Shallis, R.M.; et al. Epidemiology of acute myeloid leukemia: Recent progress and enduring challenges. Blood Reviews. 2019, 36: 70-87.