Acute Promyelocytic Leukemia (APL)
In modern drug discovery, we encounter challenges such as enhancing throughput, reducing the time from laboratory to clinical application, and providing clients with personalized solutions. Alfa Cytology provides drug development services for APL, with the aim of developing effective therapeutic drugs for APL tailored to the needs of our clients.
Background of Acute Promyelocytic Leukemia (APL)
AML encompasses a distinct subtype known as APL. APL is characterized by impaired cell differentiation and the arrest of leukemic cells at the promyelocytic stage. The chromosomal translocation t(15;17) (q22; q12-21) leads to the fusion of the promyelocytic leukemia (PML) gene and the retinoic acid receptor alpha (RARα) gene, resulting in APL. The disease was first described in 1957 and accounts for 10-15% of newly diagnosed cases of AML.
Fig. 1. Acute promyelocytic leukemia milestones. (Yilmaz, M. et al., 2021)
Current Status of APL
APL comprises 10-15% of AML cases. In the US, about 800 patients are diagnosed annually. It presents with abnormal WBC counts, low platelets, coagulation issues, and bleeding, requiring prompt diagnosis and treatment. ATRA monotherapy showed high response rates but short duration in the mid-80s. ATRA revolutionized APL treatment, along with chemotherapy, rendering it highly curable.
Drug Development for APL
Approved Drugs
The most crucial drug in the initial treatment of APL is all-trans retinoic acid. This is typically approached through the following strategies.
| Therapeutic Strategies | Description |
|---|---|
| ATRA Plus Chemotherapy | The combination of ATRA with anthracycline-based regimens aims to enhance survival rates and achieve higher cure rates. While the sequencing of ATRA with chemotherapy has shown improved outcomes, around one-third of patients experienced relapse. The ongoing trials are investigating the effectiveness of concurrent use versus sequential administration of ATRA and chemotherapy. |
| ATRA Plus Arsenic Trioxide | Although its exact mechanism of action remains incompletely understood, ATO exerts a dual dose-dependent effect on APL cells by preferentially inducing apoptosis and differentiation. Preclinical studies have demonstrated significant synergistic effects of ATRA and ATO in inducing cellular differentiation and apoptosis in APL. |
| ATRA - ATO Plus Gemtuzumab Ozogamicin | Gemtuzumab ozogamicin is a monoclonal antibody conjugated with calicheamicin, which has been investigated as an adjunctive therapy in high-risk APL. For patients with severe comorbidities, elderly individuals, those intolerant to anthracycline-based drugs, or those with impaired cardiac function, ATRA - ATO plus gemtuzumab ozogamicin is the preferred choice. |
Clinical Trials for APL
Recent evidence from in vitro models suggests that mutations in the PML protein B2 domain can mediate arsenic resistance. Alternative drugs and approaches considering these clinical findings are needed to address ATO resistance and the relapse rate in high-risk APL. The following table presents some therapies currently under development.
| Drug | Phase | Title | CR Rate |
|---|---|---|---|
| ATRA + oral ATO | II | Oral arsenic trioxide incorporation into frontline treatment with all-trans retinoic acid and chemotherapy in newly diagnosed acute promyelocytic leukemia: A 5-year prospective study | 100% |
| ATRA + RIF | II | Oral arsenic and all-trans retinoic acid for high-risk acute promyelocytic leukemia | 100% |
| ATRA + IV ATO | III | Oral arsenic plus retinoic acid versus intravenous arsenic plus retinoic acid for non-high-risk acute promyelocytic leukaemia: a non-inferiority, randomised phase 3 trial | 94% |
| ATRA + RIF + MT | III | Multicenter randomized trial of arsenic trioxide and Realgar-Indigo naturalis formula in pediatric patients with acute promyelocytic leukemia: Interim results of the SCCLG-APL clinical study. | 100% |
Resistance to Therapy in APL
Although the introduction of ATO has changed the treatment landscape for APL, the issue of drug resistance persists. Understanding the mechanisms of treatment resistance in APL is crucial for the development of novel therapies. Resistance to ATRA and ATO may arise from various factors, as depicted in the diagram below.
Fig. 2. Mechanism of resistance to arsenic trioxide- all-trans retinoic acid (ATO-ATRA) therapy in APL. (Noguera, N.I. et al., 2019)
Alfa Cytology offers specialized technical support for your APL research. Whether you are investigating the disease's mechanisms or are involved in drug development, we are your ideal partner. Contact us to learn more about our services.
References
- Yilmaz, M.; et al. Acute promyelocytic leukemia current treatment algorithms. Blood Cancer Journal. 2021, 11(6): 123.
- Jimenez, J.J.; et al. Acute promyelocytic leukemia (APL): a review of the literature. Oncotarget. 2020, 11(11): 992.
- Noguera, N.I.; et al. Acute promyelocytic leukemia: update on the mechanisms of leukemogenesis, resistance and on innovative treatment strategies. Cancers. 2019, 11(10): 1591.