Asciminib – a novel drug for chronic myeloid leukemia with a distinct mechanism of action
Authors:
J. Mayer
Authors‘ workplace:
Interní hematologická a onkologická klinika LF MU a FN Brno
Published in:
Transfuze Hematol. dnes,32, 2026, No. 3, p. 181-189.
Category:
Review/Educational Papers
doi:
https://doi.org/10.48095/cctahd202620
Overview
Chronic myeloid leukemia (CML) is now a relatively well-controlled disease with excellent overall survival outcomes. Nevertheless, many drugs used in its treatment are associated with long-term and sometimes clinically significant toxicity. Tyrosine kinase inhibitors (TKIs) used in the treatment of CML essentially share a common mechanism of action: they inhibit the ABL1 kinase domain of the BCR:: ABL1 fusion protein by targeting its ATP-binding site. As a result, phosphorylation of downstream substrates is prevented, and BCR:: ABL1 loses most of its oncogenic potential. However, the human genome encodes more than 500 protein kinases, many of which exhibit considerable structural homology. Consequently, the development of a tyrosine kinase inhibitor that is entirely specific for BCR:: ABL1 remains extremely challenging. The ABL1 protein itself can adopt either an active or an inactive conformation. Detailed crystallographic studies have demonstrated that the inactive, autoinhibited conformation results from binding of the myristoylated N-terminus of the ABL1 protein to the so-called myristoyl pocket of ABL1. In the BCR:: ABL1 fusion protein, however, the N-terminus of ABL1 is absent. Consequently, myristoylation and the resulting autoinhibitory mechanism are lost. In 2006, the discovery of a novel class of molecules capable of inhibiting BCR:: ABL1 function was reported. Unlike conventional tyrosine kinase inhibitors, which target the catalytic ATP-binding site, these compounds bind to the myristoyl pocket of the ABL1 protein, thereby mimicking the interaction of the myristoylated N-terminus. This mechanism represents a form of allosteric inhibition. Further optimization of these compounds ultimately led to the development of ABL001, now known as asciminib. Asciminib is also referred to as a STAMP inhibitor (Specifically Targeting the ABL Myristoyl Pocket). Asciminib has demonstrated excellent efficacy and a favorable safety profile in phase I, II, and III clinical trials and is currently approved for use across all lines of therapy in patients with chronic-phase CML. Numerous additional studies are ongoing, including investigations in pediatric populations and combination treatment strategies. In general, several mechanisms may contribute to resistance to TKIs, many of which may also affect asciminib. The best characterized and most extensively documented mechanisms involve mutations in BCR:: ABL1, not only within the myristoyl pocket (e. g. A337T/V and G463D) but also involving specific variant forms of the BCR:: ABL1 protein. Asciminib represents a major addition to the therapeutic armamentarium for chronic myeloid leukemia. It has demonstrated excellent efficacy and tolerability across all treatment lines, and its wider availability as a standard therapeutic option in routine clinical practice would undoubtedly be welcomed by both physicians and patients. Its importance is also clearly reflected in the most recent treatment recommendations for chronic myeloid leukemia published by the European LeukemiaNet (ELN).
Keywords:
chronic myeloid leukaemia – asciminib
Sources
1. Bělohlávková P, Žáčková D, Klamová H, et al. Clinical efficacy and safety of first-line nilotinib or imatinib therapy in patients with chronic myeloid leukemia – nationwide real life data. Cancer Med. 2024; 13 (17): e70158. doi: 10.1002/cam4.70158.
2. Changeux JP. 50th anniversary of the word “allosteric”. Protein Sci. 2011; 20 (7): 1119–1124. doi: 10.1002/pro.658.
3. Nagar B, Hantschel O, Young MA, et al. Structural basis for the autoinhibition of c-Abl tyrosine kinase. Cell. 2003; 112 (6): 859–871. doi: 10.1016/s0092-8674 (03) 00194-6.
4. Adrián FJ, Ding Q, Sim T, et al. Allosteric inhibitors of Bcr-abl-dependent cell proliferation. Nat Chem Biol. 2006; 2 (2): 95–102. doi: 10.1038/nchembio760.
5. Wylie AA, Schoepfer J, Jahnke W, et al. The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1. Nature. 2017; 543 (7647): 733–737. doi: 10.1038/nature21702.
6. 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): 8120–8135. doi: 10.1021/acs.jmedchem.8b01040.
7. 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): 2315–2326. doi: 10.1056/NEJMoa1902328.
8. Cortes JE, Sasaki K, Kim DW, et al. Asciminib monotherapy in patients with chronic-phasechronic myeloid leukemia with the T315I muta-tion after ≥1 prior tyrosine kinase inhibitor: 2-year follow-up results. Leukemia. 2024; 38 (7): 1522–1533. doi: 10.1038/s41375-024-02278-8.
9. Hochhaus A, Kim DW, Cortes JE, et al. Asciminib monotherapy in patients with chronic myeloid leukemia in chronic phase without BCR:: ABL1 T315I treated with at least 2 prior TKIs: Phase 1 final results. Leukemia. 2025; 39 (5): 1114–1123. doi: 10.1038/s41375-025-02578-7.
10. Réa D, Mauro MJ, Boquimpani C, et al. A phase 3, open-label, randomized study ofasciminib, a STAMP inhibitor, vs bosutinib inCML after 2 or more prior TKIs. Blood. 2021; 138 (21): 2031–2041. doi: 10.1182/blood.2020009984.
11. Hochhaus A, Réa 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): 617–626. doi: 10.1038/s41375-023-01829-9.
12. Mauro MJ, Minami Y, Hochhaus A, et al. Asciminib remained superior vs bosutinib in late-line CML-CP after nearly 4 years of follow-up in ASCEMBL. Blood Adv. 2025; 9 (16): 4248–4259. doi: 10.1182/bloodadvances.2025016042.
13. Yeung DT, Shanmuganathan N, Reynolds J, et al. Asciminib monotherapy as frontline treatment of chronic-phase chronic myeloid leukemia: results from the ASCEND study. Blood. 2024; 144 (19): 1993–2001. doi: 10.1182/blood.2024024657.
14. Hochhaus A, Wang J, Kim DW, et al. Asciminib in newly diagnosed chronic myeloid leukemia. N Engl J Med. 2024; 391 (10): 885–898. doi: 10.1056/NEJMoa2400858.
15. Cortes JE, Hughes TP, Wang J, et al. Asciminib demonstrates superior efficacy and safety in newly diagnosed chronic myeloid leukemia in the ASC4FIRST trial. Blood. 2026; 147 (13): 1433–1446. blood.2025029210. doi: 10.1182/blood.2025029210.
16. Cortes JE, Lang F, Rea D, et al. Asciminib in combination with imatinib, nilotinib, or dasatinib in patients with chronic myeloid leukemia in chronic or accelerated phase: phase 1 study final results. Leukemia. 2025; 39 (5): 1124–1134. doi: 10.1038/s41375-025-02592-9.
17. Hughes TP, Saglio G, Geissler J, et al. Asciminib add-on to imatinib demonstrates sustained high rates of ongoing therapy and deep molecular responses with prolonged follow-up in the ASC4MORE study. J Hematol Oncol. 2024; 17 (1): 125. doi: 10.1186/s13045-024-01642-6.
18. Sembill S, Marx M, Eikelberg I, et al. Catch-up growth after switch to asciminib in a twin with chronic myeloid leukaemia. Lancet. 2025; 406 (10519): 2533–2535. doi: 10.1016/S0140-6736 (25) 01732-5.
19. Innes AJ, Hayden C, Orovboni V, et al. Impact of BCR:: ABL1 single nucleotide variants on asciminib efficacy. Leukemia. 2024; 38 (11): 2443–2455. doi: 10.1038/s41375-024-02411-7.
20. Hughes TP, White DL, Yeung DT. Asciminib for Philadelphia chromosome-positive leukemias. Haematologica. 2025; 110 (10): 2273–2280. doi: 10.3324/haematol.2024.286798.
21. Lee BJ, Shah NP. Identification and characterization of activating ABL1 1b kinase mutations: impact on sensitivity to ATP-competitive and allosteric ABL1 inhibitors. Leukemia. 2017; 31 (5): 1096–1107. doi: 10.1038/leu.2016.353.
22. 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.
23. Leyte-Vidal A, Garrido Ruiz D, DeFilippis R, et al. BCR:: ABL1 kinase N-lobe mutants confer moderate to high degrees of resistance to asciminib. Blood. 2024; 144 (6): 639–645. doi: 10.1182/blood.2023022538.
24. Apperley JF, Milojkovic D, Cross NCP, et el. 2025 European LeukemiaNet recommendations for the management of chronic myeloid leukemia. Leukemia. 2025; 39 (8): 1797–1813. doi: 10.1038/s41375-025-02664-w.
25. Leyte-Vidal A, DeFilippis R, Outhwaite IR, et al. Absence of ABL1 exon 2-encoded SH3 residues in BCR:: ABL1 destabilizes the autoinhibited kinase conformation and confers resistance to asciminib. Leukemia. 2024; 38 (9): 2046–2050. doi: 10.1038/s41375-024-02353-0.
26. Leske IB, Hantschel O. The e13a3 (b2a3) and e14a3 (b3a3) BCR:: ABL1 isoforms are resistant to asciminib. Leukemia. 2024; 38 (9): 2041–2045. doi: 10.1038/s41375-024-02314-7.
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