Acute Myeloid Leukemia (AML)
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.
Introduction to Acute Myeloid Leukemia
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.
Epidemiology of AML
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)
AML Therapeutics Market
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.
Therapy Development for AML
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)
Chemotherapeutic Agents
For AML chemotherapeutic agents are usually used with cytarabine and anthracyclines. Mitoxantrone can also be used interchangeably with anthracyclines. Intensive chemotherapy is usually not a viable option for some patients of advanced age or dysfunction.
Protein Kinase Inhibitors Services
| 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. |
Checkpoint Inhibitors
Immunotherapy checkpoint inhibitors have demonstrated favorable outcomes in various solid malignancies, yet their success rate is comparatively lower when applied to AML patients. In mouse models of AML, promising immune-mediated anti-leukemic effects are observed by targeting inhibitory checkpoints, including CTLA4, PD-1, PD-L1, and TIM3.
Antibody-drug Conjugates (ADCs)
Gemtuzumab ozogamicin (GO) is a DNA-damaging toxin that is conjugated to calicheamicin, a potent toxin, and delivered to leukemia cells through receptor-mediated endocytosis upon binding to CD33. GO is an ADC consisting of a recombinant IgG4 humanized monoclonal antibody against CD33.
Cellular Therapies
Due to the lack of truly AML-specific surface antigens, the development of safe and effective AML CAR T-cell therapy faces challenges. However, building upon the success of chimeric antigen receptor (CAR) T-cell therapies in ALL, diffuse large B-cell lymphoma, and multiple myeloma, early-stage trials for AML are currently underway.
Combination Therapy
The current standard of care for individuals with acute myeloid leukemia (AML) who are over 65 years of age involves the combination therapy of the BCL2 inhibitor venetoclax and the hypomethylating agent. Other novel types of combination therapy for acute myeloid leukemia are currently being actively developed.
Drugs in the Pipeline
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 | Title | Trial |
|---|---|---|---|
| Gilteritinib | FLT3-ITD, FLT3-TKD | Open-Label, Randomized Trial of Daunorubicin/Cytarabine and High Dose Cytarabine + Gilteritinib vs. Midostaurin for Induction and Consolidation. FLT3 mutated patients will be stratified based on TKD vs. ITD. Patients who are FLT3 ITD will be further stratified by Signal Ratio (High vs. Low of FLT3 Wild Type) and Nucleophosmin 1-Mutated (NPM1) (Positive vs. Negative). | NCT03836209 |
| Ivosidenib, Enasidenib | IDH1/IDH2 | A Phase III, Multicenter, Double-blind, Randomized, Placebo-controlled Study of Ivosidenib or Enasidenib in Combination with Induction Therapy and Consolidation Therapy Followed by Maintenance Therapy in Patients with Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndrome with Excess Blasts-2, with an IDH1 or IDH2 Mutation, Respectively, Eligible for Intensive Chemotherapy. | NCT0383977 |
| APR-246 | TP53 | A Phase III Multicenter, Randomized, Open Label Study of APR-246 in Combination with Versus Alone for the Treatment of (Tumor Protein) TP53 Mutant Myelodysplastic Syndromes | NCT03745716 |
| Venetoclax | BCL2 | A Randomized, Double-Blind, Placebo Controlled Phase III Study of Venetoclax in Combination with Versus in Treatment Naïve Subjects with Acute Myeloid Leukemia Who Are Ineligible for Standard Induction Therapy | NCT02993523 |
| Tagraxofusp | CD123 | A Phase I/II Study of SL-401 as Consolidation Therapy for Adult Patients with Adverse Risk Acute Myeloid Leukemia in First CR, and/or Evidence of Minimal Residual Disease (MRD) in First CR | NCT02270463 |
| Venetoclax + Ivosidenib | IDH1, BCL2 | Phase Ib/II Investigator Sponsored Study of the IDH1-Mutant Inhibitor Ivosidenib (AG120) with the BCL2 Inhibitor Venetoclax in IDH1-Mutated Hematologic Malignancies | NCT03471260 |
| NKR-2 | Investigational CAR-T | A Multi-national, Open-label, Dose Escalation Phase I Study to Assess the Safety and Clinical Activity of Multiple Administrations of NKR-2 in Patients with Different Metastatic Tumor Types (THINK - THerapeutic Immunotherapy with NKR-2) | NCT03018405 |
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.
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.