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)
Current Status of CML
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.
Drugs for CML
Drugs Approved for CML
In recent decades, remarkable progress has been achieved in the therapy of CML, leading to significant improvements in outcomes. These advancements can be attributed to the approval and utilization of tyrosine kinase inhibitors (TKIs). Currently, there are multiple TKIs available for clinical use in CML treatment. The molecular structures of the four TKIs used for CML treatment are depicted in the figure below.
Fig. 2. 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 | 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 inhibito, 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. |
New Targeted Therapeutic Approaches for CML
Despite the significant achievements made in the development of targeted inhibitors, there are still several challenges that exist, such as drug resistance, intolerance, and medication side effects. Researchers are actively exploring the development of novel drugs or alternative therapies to provide innovative approaches for CML treatment. Targeted BCR-ABL or non-BCR-ABL drugs can be considered effective alternatives for CML who are resistant or intolerant to conventional treatments. The following are some of the medications being tested in clinical research.
| Drug | Target | Study Phase | Title | Trial |
|---|---|---|---|---|
| Asciminib (ABL001) |
BCR-ABL1 | I | A Phase I Study of Asciminib (ABL001) in Combination with Dasatinib and Prednisone for BCR-ABL1-Positive ALL in Adults. | NCT03595917 |
| Tipifarnib, Lonafarnib | Farnesyl transferase | I | Zarnestra and Gleevec in Chronic Phase Chronic Myelogenous Leukemia. | NCT00040105 |
| Rapamycin | mTOR | I/II | Rapamycin in With High-Dose Etoposide and Cytarabine in Relapsed/Refractory Aggressive Lymphoid Malignancies (UPCC 25406). | NCT00776373 |
| Ruxolitinib | JAK2/STAT5 | I | Ruxolitinib in Combination With Nilotinib in Chronic Myeloid Leukemia (CML) Patients | NCT01702064 |
| Panobinostat | Histone deacetylase | II | Efficacy and Safety of LBH589B in Adult Patients With Refractory Chronic Myeloid Leukemia in Accelerated or Blast Phase | NCT00449761 |
| Pioglityazone | PPARgamma | II | Pioglityazone and Imatinib for CML Patients (ACTIM). | NCT02888964 |
| Decitabine | DNA | I/II | An Open-Label, Phase I/II Study of Two Different Schedules of Dasatinib (Sprycel) and Decitabine (Dacogen) Used in Combination for Patients With Accelerated or Blastic Phase Chronic Myelogenous Leukemia (Protocol CA180357) | NCT01498445 |
Drug Resistance in CML
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, 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. 3. Resistance mechanisms in CML. (Sundaram, D.N.M. et al., 2019)
If you have an interest in preclinical research concerning CML or are currently engaged in a CML-related project, Alfa Cytology offers an unmatched portfolio of services to expedite the translation of your research findings into clinical applications. Please contact us if you would like more information about our services.
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.