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Alfa Cytology provides comprehensive preclinical services for drug development in leukemia. Our solutions help clients save time and resources, enhancing overall efficiency in the process of leukemia drug development.
AML, also known as acute myeloid leukemia, is a form of blood and bone marrow cancer. A hallmark of AML is the clonal expansion of immature "blast cells" in the peripheral blood and bone marrow, leading to ineffective red blood cell production and bone marrow failure. Despite advancements in therapy approaches, the prognosis for certain patient populations remains poor.
In the United States, the incidence rate of AML is approximately 3 to 5 cases per 100,000 individuals. The incidence of AML increases with age, rising from around 1.3 cases per 100,000 individuals in patients below the age of 65 to 12.2 cases per 100,000 individuals in patients aged 65 and above. Without effective therapeutic interventions, AML can rapidly progress, leading to life-threatening complications such as severe 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)
Currently, Pfizer Inc., Novartis AG, Sanofi-Aventis (Genzyme Corporation), Otsuka Holdings Co., Ltd., and Bristol Myers Squibb are the major companies operating in the AML market. These companies are actively engaged in AML therapy research and clinical trials, aiming to develop new therapeutic approaches and strategies that overcome drug resistance, minimize toxicity, and enhance efficacy. According to statistics, the global market size for AML therapeutics drugs reached nearly $1 billion in 2021, with an estimated compound annual growth rate of 10.15%. It is projected to reach $2.97 billion by 2029.
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)
| FLT3 Inhibitors | FLT3 inhibitors exert their effects by competitively inhibiting the ATP binding site within the FLT3 receptor. First-generation FLT3 inhibitors, such as midostaurin and sorafenib, exhibit a broad kinase profile, while second-generation FLT3 inhibitors, such as quizartinib and crenolanib, typically possess a greater degree of FLT3-specific kinase selectivity. |
| IDH1 and IDH2 Inhibitors | Enasidenib represents the first orally available mutation-selective small molecule inhibitor to receive approval. The inhibition of mutant IDH2 by enasidenib leads to a reduction of over 90% in serum total 2-hydroxyglutarate (2-HG), thereby reducing aberrant histone hypermethylation and promoting cellular differentiation. |
| TP53 | ALRN-6924 is a peptide that adopts a stable α-helical conformation to mimic the inhibitor binding region of TP53. This conformation enables the binding of MDM2 and MDMX, thereby inhibiting TP53 transcription. |
| BCL2 Inhibitors | BCL2, an anti-apoptotic protein, is overexpressed in AML cells, particularly in leukemia stem cells (LSCs) that may rely on BCL2 for survival. Venetoclax, a BCL2 inhibitor, is utilized in combination therapy for AML. |
Drug resistance has compromised the long-term efficacy of monotherapy in AML. The complexity of AML hinders the urgent need for developing such therapies, thereby stimulating the development of innovative therapeutics targeting different leukemia mechanisms. The following are some drugs currently under development.
| 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.
If you are interested in the pathogenesis of AML or therapy development, Alfa Cytology offers a full range of supportive research services to support your preclinical research. Contact us to learn more about our services.
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