Molecular mechanisms of BCR::ABL1 in chronic myeloid leukaemia: From treatment-free remission to curative therapy

Table 3 Summary of approved monotherapies and investigational combination therapies in chronic myeloid leukaemia

Strategy	Target	Intervention	Status	Mechanism/use	Ref.
Monotherapy	BCR::ABL1 kinase domain (competitive binding at ATP site)	First and second generation TKIs e.g., Imatinib, Nilotinib, Dasatinib, Bosutinib	Approved standard	First- and second-line therapy. Inhibits proliferation of leukaemic clones	Druker et al[36], 2001
Monotherapy	BCR::ABL1 kinase domain (ATP site)	Ponatinib	Approved. Standard. Real world study	T315I and compound mutations	Schenk et al[40], 2026
Monotherapy	BCR::ABL1 (allosteric binding at the myristoyl pocket i.e. STAMP)	Asciminib1	Approved Standard	Allosteric inhibitor	Hughes et al[42], 2019
Monotherapy	Multi-kinase domain/T315I mutation	Olverembatinib	Investigational real-world clinical study	multi-TKI resistant CML	Wen et al[44], 2025
Combination	Myristoyl pocket + Competitive ATP binding	Asciminib1 + TKI	Investigational	Prevents escape mutation and enhances DMR	Ernst et al[71], 2024
Combination	Inhibition of BCL-2 + BCR::ABL1	Venetoclax + TKI	Investigational	Triggers mitochondrial apoptosis in LSCs	Ko et al[76], 2014
Combination	Autophagy + BCR::ABL1	Hydroxychloroquine + TKI	Investigational, preclinical	Inhibits survival of LSCs	Bellodi et al[73], 2009
Combination	Inhibition of hedgehog pathway + BCR::ABL1	Sonidegib + TKI	Investigational	SMO inhibition blocks LSC self-renewal	Irvine et al[72], 2016
Combination	Niche disruptor (CXXR4 inhibitor) + BCR::ABL1	Plerixafor + TKI	Investigational, preclinical	Forces LSCs into cell cycle	Vianello et al[77], 2010; Weisberg et al[78], 2012
Combination	Immunotherapy + BCR::ABL1	Pegylated interferon + TKI	Investigational. Observational study[80], phase 3 trials[81,82]	Immunological eradication of LSCs	Puzzolo et al, 2022[80]; Nicolini et al[81], 2026; Burchert et al[82], 2026

¹Asciminib monotherapy is approved by the United States Food and Drug Administration for frontline treatment in chronic phase chronic myeloid leukaemia (CML) and in heavily-pretreated CML patients but asciminib combination strategies are still investigational.

ATP: Adenosine triphosphate; BCL-2: B-cell lymphoma 2; DMR: Deep molecular remission; LSC: Leukaemia stem cell; TKI: Tyrosine kinase inhibitor.