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Can asciminib be used for chronic myeloid leukemia treatment?


Myeloid leukemia

Chronic myeloid leukemia (CML) results in an increase of all the blood cells (myeloid cells, erythroid cells, and platelets) in peripheral blood. It occurs due to the malignancy of hematopoietic stem cells due to the presence of the Philadelphia chromosome in patients' blood, which is inherited genetically. All age groups, including children, are affected by this condition, with the median age of presentation being 53 years. In the majority of cases, thrombocytosis is also present, which is caused by malfunction in a pluripotent hematopoietic stem cell. Although 40% of patients are asymptomatic, fatigue, anorexia, and weight loss are the typical symptoms that are seen in these individuals. The diagnosis is made purely on the basis of an abnormal blood count. Several types of drugs are used in the treatment of CML.


What is asciminib and its mechanism of action?


  • Asciminib is a member of the larger class of drugs referred to as antineoplastics or cancer drugs.

  • It is also known as ABL001, and it is a first-in-class myristoyl allosteric inhibitor of BCR-ABL1 kinase activity (tyrosine kinase inhibitor). Asciminib particularly targets ABL1 in the protein complex of BCR-ABL1.

  • It functions by attaching to the myristoyl pocket of the BCR-ABL1 protein, a protein that plays an important role in the pathogenesis of CML.

  • Administration of asciminib will lead to the conformational changes in the protein, and the myeloid leukemic cells are reduced in their proliferation before being subsequently eliminated by the body [1].


What is the difference between asciminiband other ABL inhibitors?


  • Because of their role in the initiation and growth of tumors, tyrosine kinases have emerged as crucial targets for the development of new drugs.

  • Tyrosine kinase inhibitors have significantly altered the therapy paradigm for CML and enhanced patient survival and quality of life.

  • There were other ABL1 tyro kinase inhibitors available even before asciminib was made available. These medications have had remarkable clinical success and are viewed as a model for how small molecule inhibitors can revolutionize cancer therapy.

  • The existing ABL inhibitors can be divided into those that target the active conformation of the kinase domain (dasatinib, bosutinib) and those that target the inactive kinase domain (imatinib, nilotinib, ponatinib) and compete at the ATP binding sites of these proteins [2].

  • Asciminib is distinctive in that it functions as an allosteric inhibitor, attaching to the BCR-ABL1 protein's myristoyl pocket and converting it into an inactive configuration that no longer participates in the pathogenesis of CML [3].


What is the clinical significance of asciminib?


  • The majority of CML patients in the chronic phase now have prolonged life expectancies because of the ABL inhibitors that target the kinase domains (dasatinib, bosutinib, imatinib, nilotinib, and ponatinib).

  • However, better treatment options are required for the 20% to 30% of patients who experience therapeutic failure with these drugs.

  • For those patients, the Food and Drug Administration (FDA) approved asciminib on October 29, 2021. It is available under the trade name Scemblix® and is used in the treatment of chronic-phase chronic myeloid leukemia patients who have previously had two lines of therapy unsuccessfully or in those with the T315I mutation (a type of mutation in the BCR-ABL1 protein).

  • High specificity and potency against BCR-ABL1, action against the majority of kinase domain mutations, and the possibility of combination therapy with ATP-competitive tyrosine kinase inhibitors are all promising characteristics of this drug.

  • It is indicated in patients with severe vascular risk factors, a history of cardiovascular illness, or those who have previously reported toxic effects with the use of ATP-competitive TKIs[4].


The whole sebang of asciminib!


Asciminib appears to have a pretty good safety profile according to the available data, but this opinion may change when more long-term data becomes available. This is because the true prevalence of toxicities, including arterial occlusive disease, and pleural effusion might not become apparent until after prolonged treatment. Algorithms for toxicity control will be improved further using newly discovered information from ongoing clinical trials, as well as data from the previous trials.


References


1. E.-J. Choi, “Asciminib: the first-in-class allosteric inhibitor of BCR::ABL1 kinase,”Blood Res, vol. 58, no. Suppl 1, pp. S29–S36, Apr. 2023, doi: 10.5045/br.2023.2023017.

2. D. T. Yeung, N. Shanmuganathan, and T. P. Hughes, Asciminib: a new therapeutic option in chronic-phase CML with treatment failure,”Blood, vol. 139, no. 24, pp. 3474–3479, Jun. 2022, doi: 10.1182/blood.2021014689.

3. “Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibitor Failure | NEJM.” https://www.nejm.org/doi/full/10.1056/NEJMoa1902328 (accessed Jun. 30, 2023).

4. M. J. Mauro et al., “Asciminib monotherapy in patients with CML-CP without BCR::ABL1 T315I mutations treated with at least two prior TKIs: 4-year phase 1 safety and efficacy results,”Leukemia, vol. 37, no. 5, pp. 1048–1059, May 2023, doi: 10.1038/s41375-023-01860-w.

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Collaborators

IIT Guwahati
University of Manchester
Rhenix Lifesciences
American university of Sharjah
IIT Delhi
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