Chronic Myeloid Leukemia (CML)
CML is cytogenetically characterized by reciprocal translocations between chromosomes 9 and 22. This translocation, t (9;22) (q34; q11), results in the formation of a truncated chromosome 22, referred to as the Philadelphia (Ph) chromosome. It is observed in 95% of CML. The fusion gene BCR-ABL is produced as a consequence, encoding the fusion protein BCR-ABL. Alfa Cytology offers development services for BCR-ABL inhibitors, aiming to revolutionize the treatment approach for CML.
Fig. 1. Translocation (9;22) and BCR/ABL transcripts associated to CML. (Avelino, K.Y.P.S. et al., 2017)
Overview of Chronic Myeloid Leukemia
In 2024, around 9,280 new CML cases are estimated in the US, with approximately 1,280 deaths projected. The US accounted for over 60% of the $8.58 billion market for CML treatment in 2023. Market growth will be driven by new therapies, increased prevalence, and wider adoption of branded TKIs. The CML treatment market is expected to reach $12.06 billion by 2028, showing robust growth.
Drug Resistance in Chronic Myeloid Leukemia
In frontline treatment, the resistance rate to Imatinib is approximately 10-15%, while the resistance rate to 2GTKIs is less than 10%. In some people, a lack of response may be attributed to poor treatment compliance or intermittent dosing. As shown in figure 3, resistance can be caused by BCR-ABL1 kinase domain mutations that encode a BCR-ABL1 protein with reduced sensitivity to TKIs. Alternative mechanisms of resistance involve clonal evolution and activation of BCR-ABL1-independent pathways.
Fig. 2. Resistance mechanisms in CML. (Sundaram, D.N.M. et al., 2019)
Approved Drugs for Chronic Myeloid Leukemia
In recent decades, considerable advances have been made in the field of treatment of CML, which has consequently greatly improved the outcome. These advances are attributed to the approval and use of tyrosine kinase inhibitors (TKIs). There are quite a few TKIs that are currently approved for clinical use in the treatment of CML. The figure below shows the molecular structures of the TKIs which are used for the treatment of CML. The ultimate goal of treatment for CML is to improve survival so that it equals the general population life expectancy. Imatinib was the first TKI approved for the treatment of CML. Furthermore, other TKIs have been developed for CML therapy. Four TKIs were approved for frontline therapy in CML.
Fig. 3. Molecular formulas for BCR-ABL1 TKI. (Bosch, F.; Dalla-Favera, R., 2019)
The primary objective of CML treatment is to enhance survival rates, aligning them with those of the general population. Imatinib was the first TKI approved for the treatment of CML. Additionally, other TKIs have been developed for CML therapy. Four TKIs have been approved for frontline therapy in CML.
| Drugs | Description |
|---|---|
| Imatinib | Imatinib The combination of imatinib with IFNα or low-dose cytarabine, as well as higher doses, rapidly demonstrated and prolonged the achievement of complete molecular response, establishing a benchmark for deep molecular response and demonstrating the expected lifespan. |
| Dasatinib | Dasatinib, a second-generation tyrosine kinase inhibitor, exhibits greater efficacy than Imatinib and demonstrates activity against several Imatinib-resistant BCR-ABL1 mutations. |
| Bosutinib | Bosutinib, a third-generation 2GTKI, demonstrates superior efficacy compared to Imatinib. Additionally, it inhibits several BCR-ABL1 mutations. |
| Nilotinib | Nilotinib, another 2GTKI, demonstrates greater efficacy than Imatinib and inhibits several Imatinib-resistant BCR-ABL1 mutations. |
Development for Therapy
In spite of the vast advances, therapy with targeted inhibitors still faces several challenges like resistance to the drugs, intolerance, and side effects of medications. Researchers are exploring drug candidates or alternative options for CML treatment. Targeted BCR-ABL or non-BCR-ABL drugs can be viable alternatives for CML patients who show drug resistance or suffer intolerable side effects from standard treatment. Some drugs currently in clinical trials are as follows:
| Drug | Target | Phase | Trial |
|---|---|---|---|
| Asciminib (ABL001) | BCR-ABL1 | NCT03595917 | |
| Tipifarnib, Lonafarnib | Farnesyl transferase | NCT00040105 | |
| Rapamycin | mTOR | NCT00776373 | |
| Ruxolitinib | JAK2/STAT5 | NCT01702064 | |
| Panobinostat | Histone deacetylase | NCT00449761 | |
| Pioglityazone | PPARgamma | NCT02888964 | |
| Decitabine | DNA | NCT01498445 |
From therapies targeting oncogenic substances to immunotherapies to modulation of the tumor microenvironment, Alfa Cytology provides in-depth support for multiple anticancer strategies in CML.
Case Study
Transgenic Mouse Models of BCR/ABL-Positive Chronic Myelogenous Leukemia (CML)
- Model Information
Model Type: Transgenic Mice
Age: 6-8 Weeks
Species: BALB/c Mice
Weight: 20-22 g
Fig. 4 Establishment of a transgenic mouse model of BCR/ABL-positive CML.
Hematopoietic stem cells (HSCs) were isolated from donor mice and transduced with a tetracycline-inducible BCR-ABL lentiviral vector under culture conditions optimized for transformation. Lethally irradiated syngeneic recipients then received these transduced HSCs via tail vein injection. Doxycycline administration in drinking water or feed at designated time points induced BCR-ABL expression and initiated CML progression (Fig. 4).
- Results
Treatment with Drug A resulted in significant antitumor efficacy, reduced leukemic infiltration (Fig. 5), and prolonged survival compared to CML model animals (Fig. 6).
Fig. 5 H&E staining of blood smear
Fig. 6 Survival analysis of the CML model.
Western blot analysis confirmed that the compound effectively suppresses BCR-ABL autophosphorylation and downstream signaling through key effectors including CRKL and STAT5, elucidating its mechanism of action (Fig. 7).
Fig. 7 Effect of Drug A on the phosphorylation levels of key effectors in the BCR-ABL downstream signaling pathway.
In addition to the BCR-ABL transgenic CML models mentioned in the case study, Alfa Cytology offers a range of animal model of CML, including retroviral transduction models, xenograft models, and humanized mouse models. For detailed information or to discuss your specific CML research needs, please contact us.
References
- Avelino, K.Y.P.S.; et al. Smart applications of bionanosensors for BCR/ABL fusion gene detection in leukemia. Journal of King Saud University-Science. 2017, 29(4): 413-423.
- Osman, A.E.G.; Deininger, M.W. Chronic myeloid leukemia: Modern therapies, current challenges and future directions. Blood Reviews. 2021, 49: 100825.
- Hochhaus, A.; et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020, 34(4): 966-984.
- Yurttaş, N.Ö.; Eşkazan, A.E. Novel therapeutic approaches in chronic myeloid leukemia. Leukemia Research. 2020, 91: 106337.
- Westerweel, P.E.; et al. New approaches and treatment combinations for the management of chronic myeloid leukemia. Frontiers in Oncology. 2019, 9: 665.
- Sundaram, D.N.M.; et al. Current outlook on drug resistance in chronic myeloid leukemia (CML) and potential therapeutic options. Drug Discovery Today. 2019, 24(7): 1355-1369.