Abstract
Currently, there is a crucial need for new treatment approaches to overcome the resistance and intolerance of several tyrosine kinase inhibitor (TKI) therapy lines in chronic myeloid leukemia (CML) patients. Asciminib, the first in its class BCR::ABL1-tyrosine kinase inhibitor specifically targeting ABL myristoyl pocket (STAMP), demonstrated efficacy and safety in CML patients with prior TKI therapy failure, including the cases with pan-resistant T315I mutation in the chimeric BCR::ABL1 gene. The present review focuses on the asciminib mechanism of action, the results of both preclinical and clinical phase I and III studies. Due to the favorable cardiovascular toxicity profile of asciminib, the scope of its application can be extended to patients with cardiovascular co-morbidities. Asciminib is registered in the Russian Federation in January 2023, so treatment algorithms for CML patients with ineffectiveness or intolerance of prior therapy should be updated in line with this new option.
References
- Bower H, Bjorkholm M, Dickman PW, et al. Life expectancy of patients with chronic myeloid leukemia approaches the life expectancy of the general population. J Clin Oncol. 2016;34(24):2851–7. doi: 10.1200/JCO.2015.66.2866.
- Лямкина А.С., Поспелова Т.И., Маслова Л.М. и др. Сегодняшний день в терапии хронического миелолейкоза: результаты и сложности. Сибирский журнал клинической и экспериментальной медицины. 2017;32(2):31–5. doi: 10.29001/2073-8552-2017-32-2-31-35.
- [Lyamkina AS, Pospelova TI, Maslova LM, et al. Today in the treatment of chronic myeloid leukemia: results and difficulty. The Siberian Journal of Clinical and Experimental Medicine. 2017;32(2):31–5. doi: 10.29001/2073-8552-2017-32-2-31-35. (In Russ)]
- Лазарева О.В., Туркина А.Г., Гусарова Г.А. и др. Итоги 12-летней терапии ингибиторами тирозинкиназ больных в поздней хронической фазе хронического миелолейкоза после неудач лечения ИФН-α. Сибирский научный медицинский журнал. 2015;35(1):90–7.
- [Lazareva OV, Turkina AG, Gusarova GA, et al. The results of 12 year therapy with tyrosine kinase inhibitors in patients in the late chronic phase of chronic myeloid leukemia after IFN-α treatment failures. Sibirskii nauchnyi meditsinskii zhurnal. 2015;35(1):90–7. (In Russ)]
- Hochhaus A, Larson RA, Guilhot F, et al. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med. 2017;376(10):917–27. doi: 10.1056/NEJMoa1609324.
- Куликов С.М., Виноградова О.Ю., Челышева Е.Ю. и др. Заболеваемость хроническим миелолейкозом в 6 регионах России по данным популяционного исследования 2009–2012 гг. Терапевтический архив. 2014;86(7):24–30.
- [Kulikov SM, Vinogradova OYu, Chelysheva EYu, et al. The incidence of chronic myeloid leukemia in 6 regions of Russia according to the data of the 2009–2012 population-based study. Terapevticheskii arkhiv. 2014;86(7):24–30. (In Russ)]
- Brunner AM, Campigotto F, Sadrzadeh H, et al. Trends in all-cause mortality among patients with chronic myeloid leukemia: a surveillance, epidemiology, and end results database analysis. Cancer. 2013;119(14):2620–9. doi: 10.1002/cncr.28106.
- Sasaki K, Strom SS, O’Brien S, et al. Relative survival in patients with chronic-phase chronic myeloid leukaemia in the tyrosine-kinase inhibitor era: analysis of patient data from six prospective clinical trials. Lancet Haematol. 2015;2(5):186–93. doi: 10.1016/S2352-3026(15)00048-4.
- Туркина А.Г., Новицкая Н.В., Голенков А.К. и др. Регистр больных хроническим миелолейкозом в Российской Федерации: от наблюдательного исследования к оценке эффективности терапии в клинической практике. Клиническая онкогематология. 2017;10(3):390–401. doi: 10.21320/2500-2139-2017-10-3-390-401.
- [Turkina AG, Novitskaya NV, Golenkov AK, et al. Chronic Myeloid Leukemia Patient Registry in the Russian Federation: From Observational Studies to the Efficacy Evaluation in Clinical Practice. Clinical oncohematology. 2017;10(3):390–401. doi: 10.21320/2500-2139-2017-10-3-390-401. (In Russ)]
- Hochhaus A, Baccarani M, Silver RT, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34(4):966–84. doi: 10.1038/s41375-020-0776-2.
- Gorre ME, Mohammed M, Ellwood K, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001;293(5531):876–80. doi: 10.1126/science.1062538.
- Apperley JF. Part I: mechanisms of resistance to imatinib in chronic myeloid leukemia. Lancet Oncol. 2007;8(11):1018–29. doi: 10.1016/S1470-2045(07)70342-X.
- Khorashad JS, de Lavallade H, Apperley JF, et al. Finding of kinase domain mutations in patients with chronic phase chronic myeloid leukemia responding to imatinib may identify those at risk of disease progression. J Clin Oncol. 2008;26(29):4806–13. doi: 10.1200/JCO.2008.16.9953.
- Soverini S, Branford S, Nicolini FE, et al. Implications of BCR-ABL1 kinase domain-mediated resistance in chronic myeloid leukemia. Leuk Res. 2014;38(1):10–20. doi: 10.1016/j.leukres.2013.09.011.
- Челышева Е.Ю., Шухов О.А., Лазарева О.В., Туркина А.Г. Мутации киназного домена гена BCR-ABL при хроническом миелолейкозе. Клиническая онкогематология. 2012;5(1):13–21.
- [Chelysheva EYu, Shukhov OA, Lazareva OV, Turkina AG. BCR-ABL kinase domain mutations in chronic myeloid leukemia. Klinicheskaya onkogematologiya. 2012;5(1):13–21. (In Russ)]
- Куцев С.И., Вельченко М.В., Зельцер А.Н. Молекулярно-генетический мониторинг хронического миелолейкоза при терапии ингибиторами тирозинкиназ. Онкогематология. 2008;4:17–25. doi: 10.17650/1818-8346-2008-0-4-17-25.
- [Kutsev SI, Velchenko MV, Zelzer AN. Molecular genetics monitoring of tyrosine kinase inhibitor therapy for chronic myeloid leukemia. Oncohematology. 2008;4:17–25. doi: 10.17650/1818-8346-2008-0-4-17-25. (In Russ)]
- Мисюрина Е.Н., Мисюрин А.В., Крутов А.А. и др. Частота встречаемости мутаций киназного домена BCR-ABL у больных ХМЛ, резистентных к терапии иматинибом. Вестник гематологии. 2013;9(2):35–6.
- [Misyurina EN, Misyurin AV, Krutov AA, et al. Frequency of BCR-ABL kinase domain mutations in CML patients resistant to imatinib therapy. Vestnik gematologii. 2013;9(2):35–6. (In Russ)]
- Manley PW, Barys L, Cowan-Jacob SW. The specificity of asciminib, a potential treatment for chronic myeloid leukemia, as a myristate-pocket binding ABL inhibitor and analysis of its interactions with mutant forms of BCR-ABL1 kinase. Leuk Res. 2020;98:106458. doi: 10.1016/j.leukres.2020.106458.
- Nicolini F, Basak GW, Soverini S, et al. Allogeneic stem cell transplantation for patients harboring T315I BCR-ABL mutated leukemias. Blood. 2011;118(20):5697–700. doi: 10.1182/blood-2011-07-367326.
- O’Hare T, Shakespeare WC, Zhu X, et al. AP24534, a Pan-BCR-ABL Inhibitor for Chronic Myeloid Leukemia, Potently Inhibits the T315I Mutant and Overcomes Mutation-Based Resistance. Cancer Cell. 2009;16(5):401–12. doi: 10.1016/j.ccr.2009.09.028.
- Cortes JE, Kim D-W, Pinella-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013;369(19):1783–96. doi: 10.1056/NEJMoa1306494.
- Cortes JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012;367(22):2075–88. doi: 10.1056/NEJMoa1205127.
- Giles FJ, Mauro MJ, Hong F, et al. Rates of peripheral arterial occlusive disease in patients with chronic myeloid leukemia in the chronic phase treated with imatinib, nilotinib, or non-tyrosine kinase therapy: a retrospective cohort analysis. Leukemia. 2013;27(6):1310–5. doi: 10.1038/leu.2013.69.
- Lipton JH, Chuah C, Guerci-Bresler A, et al. Ponatinib versus imatinib for newly diagnosed chronic myeloid leukaemia: an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17(5):612–21. doi: 10.1016/S1470-2045(16)00080-2.
- Schoepfer J, Jahnke W, Berellini G, et al. Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1. J Med Chem. 2018;61(18):8120–35. doi: 10.1021/acs.jmedchem.8b01040.
- Wylie AA, Schoepfer J, Jahnke W, et al. The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1. Nature. 2017;543(7647):733–7. doi: 10.1038/nature21702.
- Eide CA, Zabriskie MS, Savage Stevens SL, et al. Combining the Allosteric Inhibitor Asciminib with Ponatinib Suppresses Emergence of and Restores Efficacy against Highly Resistant BCR-ABL1 Mutants. Cancer Cell. 2019;36(4):431–43.e5. doi: 10.1016/j.ccell.2019.08.004.
- Ben-Neriah Y, Daley GQ, Mes-Masson AM, et al. The chronic myelogenous leukemia-specific P210 protein is the product of the bcr/abl hybrid gene. Science. 1986;233(4760):212–4. doi: 10.1126/science.3460176.
- Hughes TP, Mauro MJ, Cortes JE, et al. Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibitor Failure. N Engl J Med. 2019;381(24):2315–26. doi: 10.1056/NEJMoa1902328.
- La Sala G, Decherchi S, De Vivo M, Rocchia W. Allosteric Communication Networks in Proteins Revealed through Pocket Crosstalk Analysis. ACS Cent Sci. 2017;3(9):949–60. doi: 10.1021/acscentsci.7b00211.
- Hoch M, Sengupta T, Hourcade-Potelleret F. Pharmacokinetic drug interactions of asciminib with the sensitive cytochrome P450 probe substrates midazolam, warfarin, and repaglinide in healthy participants. Clin Transl Sci. 2022;15(6):1406–16. doi: 10.1111/cts.13252.
- Инструкция по применению асциминиба [электронный документ]. Доступно по: https://www.novartis.com/ru-ru/sites/novartis_ru/files/2023-01-24-scemblix-sm-pc.pdf. Ссылка активна на 20.03.2023.
- [Instruction for asciminib use (Internet). Available from: https://www.novartis.com/ru-ru/sites/novartis_ru/files/2023-01-24-scemblix-sm-pc.pdf. Accessed 20.03.2023. (In Russ)]
- Kumar R, Pereira RS, Zanetti C, et al. Specific, targetable interactions with the microenvironment influence imatinib-resistant chronic myeloid leukemia. Leukemia. 2020;34(8):2087–101. doi: 10.1038/s41375-020-0866-1.
- Bavaro L, Martelli M, Cavo M, Soverini S. Mechanisms of Disease Progression and Resistance to Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia: An Update. Int J Mol Sci. 2019;20(24):6141. doi: 10.3390/ijms20246141.
- Combes FP, Li YF, Hoch M, et al. Exposure-Efficacy Analysis of Asciminib in Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase. Clin Pharmacol Ther. 2022;112(5):1040–50. doi: 10.1002/cpt.2699.
- Hughes T, Cortes JE, Rea D, et al. Asciminib provides durable molecular responses in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) with the T315I mutation: updated efficacy and safety data from a phase I trial. Clin Lymphoma Myel Leuk. 2022;22:S300. doi: 10.1016/S2152-2650(22)01388-X.
- Hochhaus A, Rea D, Boquimpani C, et al. Asciminib vs bosutinib in chronic-phase chronic myeloid leukemia previously treated with at least two tyrosine kinase inhibitors: longer-term follow-up of ASCEMBL. Leukemia. 2023;37(3):617–26. doi: 10.1038/s41375-023-01829-9.
- Rea D, Hughes TP. Development of asciminib, a novel allosteric inhibitor of BCR-ABL1. Crit Rev Oncol Hematol. 2022;171:103580. doi: 10.1016/j.critrevonc.2022.103580.
- Khadadah F, Xenocostas A, Busque L, et al. A Real-World Canadian Experience of Asciminib Use in Chronic Myeloid Leukemia (CML) Patients Who Failed Multiple Lines of Tyrosine Kinase Inhibitor (TKI) Therapy. Blood. 2021;138(S1):3610. doi: 10.1182/blood-2021-149588.
- Garcia-Gutierrez V, Luna A, Alonso-Dominguez JM, et al. Safety and efficacy of asciminib treatment in chronic myeloid leukemia patients in real-life clinical practice. Blood Cancer J. 2021;11(2):16. doi: 10.1038/s41408-021-00420-8.
- Kockerols CC, Janssen JJ, Blijlevens NM, et al. Clinical outcome of asciminib treatment in a real-world multi-resistant CML patient population. HemaSphere. 2022;6:604–5. doi: 10.1097/01.HS9.0000845720.69342.77.
- Khadadah F, Turkina AG, Lomaia E, et al. Canadian and Russian experiences of asciminib in chronic myeloid leukemia (CML) patients who failed multiple lines of tyrosine kinase inhibitor (TKI) therapy. HemaSphere. 2022;6:603–4. doi: 10.1097/01.HS9.0000845716.75856.2d.
- Breccia M, Russo Rossi AV, Martino B, et al. Asciminib Italian managed access program: efficacy profile in heavily pre-treated CML patients. HemaSphere. 2022;6:607–8. doi: 10.1097/01.HS9.0000845732.28959.a9.
- Innes A, Orovboni V, Claudiani S, et al. Asciminib use in CML: The UK experience. HemaSphere. 2022;6:601–2. doi: 10.1097/01.HS9.0000845708.96602.91.
- Chee LCY, Lee N, Grigg A, et al. Clinical Outcomes of Chronic Myeloid Leukaemia (CML) Patients on Asciminib through the Managed Access Program (MAP) in Australia. Blood. 2022;140(Suppl 1):6800–2. doi: 10.1182/blood-2022-163221.
- Туркина А.Г., Кузьмина Е.А., Ломаиа Е.Г. и др. Асциминиб у больных хроническим миелолейкозом, не имеющих альтернативных методов лечения: результаты исследования в рамках программы расширенного доступа МАР (Managed Access Program, NCT04360005) в России. Клиническая онкогематология. 2023;16(1):54–68. doi: 10.21320/2500-2139-2023-16-1-54-68.
- [Turkina AG, Kuzmina EA, Lomaia EG, et al. Asciminib in Chronic Myeloid Leukemia Patients Without Therapeutic Alternatives Alternatives: Results of the MAP (Managed Access Program, NCT04360005) Trial in Russia. Clinical oncohematology. 2023;16(1):54–68. doi: 10.21320/2500-2139-2023-16-1-54-68. (In Russ)]
- Turkina AG, Kuzmina EA, Lomaia EG, et al. Two-Year Updated Results of Asciminib Managed-Access Program (MAP) in Russia. Blood. 2022;140(Suppl 1):9654–5. doi: 10.1182/blood-2022-162268.
- Luna A, Perez-Lamas L, Boque C, et al. Real-life analysis on safety and efficacy of asciminib for ponatinib pretreated patients with chronic myeloid leukemia. Ann Hematol. 2022;101(10):2263–70. doi: 10.1007/s00277-022-04932-6.
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