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

Table 1 Classification of BCR::ABL1 inhibitors

Classification	Example and Ref.	Mechanism of action	Resistance mutations	Toxicities
First generation TKI	Imatinib1: Corbin et al[35], 2002; Druker et al[36], 2001; O'Brien et al[38], 2003 - IRIS	Competitive ATP inhibition	E255V, Y253F, G250E, T315I	Fluid retention, hepatotoxicity, muscle cramps
Second generation TKI	Nilotinib1: Kantarjian et al[39], 2006	High affinity ATP inhibition	E255K/V, Y253H, T315I	QTc prolongation, arterial occlusion
	Dasatinib1: Osman and Deininger[34], 2021	Dual SRC/ABL inhibition	V299L, T315I	Pleural effusion, pulmonary hypertension
	Bosutinib1: Osman and Deininger[34], 2021	Dual SRC/ABL1 inhibition	V299L, T315I	Diarrhoea, hepatotoxicity
Third generation TKI	Ponatinib1: Schenk et al[40], 2026 PONDEROSA real-world observational cohort study; Huang et al[48], 2010	ATP binding inhibition with ethynyl linkage	T315I+Y253H, T315I+E255V/K, T315I+F359V/C	Cardiovascular toxicity, pancreatitis
	Olverembatinib2: Haque et al[43], 2024; Wen et al[44], 2025	Competitive ATP inhibition. Multi-kinase activity including FLT3, KIT, FGFR1	Possibly parallel pathways e.g., RUNX1, STAT5. BCR::ABL1 independent e.g., Hedgehog, JAK/STAT	Cytopenias, proteinuria
STAMP inhibitor	Asciminib1: Cortes et al[41], 2026 (ASC4FIRST trial); Hughes et al[42], 2019; Wylie et al[68], 2017	Allosteric inhibition, binds to the myristoyl pocket	P465S, A337V	Asymptomatic hyperlipidaemia, cytopenias

¹Approved.

²Investigational.

ATP: Adenosine triphosphate; FGFR1: Fibroblast growth factor receptor 1; FLT3: FMS-like tyrosine kinase 3; JAK: Janus kinase; RUNX1: Runt-related transcription factor 1; STAMP: Specifically targeting the ABL myristoyl pocket; STAT5: Signal transducer and activator of transcription 5; TKI: Tyrosine kinase inhibitor.

Table 2 Comparison of resistance mechanisms in chronic myeloid leukaemia

Mechanism	BCR::ABL1 kinase-dependent resistance[47]2,[49]1	BCR::ABL1 kinase independent resistance[47]2
Pathophysiology	Intrinsic changes to BCR::ABL1 gene or protein e.g., point mutations in the tyrosine kinase domain e.g., T315I[68]1. BCR::ABL1 gene amplification or over expression. Compound mutations on the same allele causing resistance to multiple TKIs	Alternative pathways or protective niches e.g., activation of parallel oncogenic pathways e.g., STAT3, PI3/AKT, Wnt/β-catenin[47]. Quiescence of leukaemia stem cell. Altered pharmacokinetics e.g., through the overexpression of efflux transporters (ABCB1) or downregulation of influx transporters (OCT1)
Effect of dose escalating or TKI switch	Very effective	Limited efficacy because BCR::ABL1 is already suppressed
Clinical presentation	Loss of major molecular remission	Primary TKI resistance. Persistence of minimal residual disease. Failure of treatment-free remission
Diagnosis	RT-qPCR for BCR::ABL1. Sanger sequencing	Cytogenetics. Transcriptomic profiling
Management	Mutation-guided TKI switching. Allosteric binding combinations e.g., competitive TKI + asciminib. Allogeneic Haematopoietic stem cell transplantation	Combination targeted therapies e.g., TKI + BCL-2 inhibitor like venetoclax. Leukaemia stem cell eradication strategies. Allogeneic haematopoietic stem cell transplantation

¹Preclinical study.

²Review.

ABCB1: ATP-binding cassette sub-family B member 1; AKT: Serine/threonine kinase; OCT1: Organic cation transporter 1; PI3: Phosphoinositide 3; STAT3: Signal transducer and activator of transcription 3; TKI: Tyrosine kinase inhibitor.

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.

Table 4 Some preclinical studies and clinical trials on double-hit combination therapies in chronic myeloid leukaemia

S/N	Trial/study	Trial type, phase and strategy	Combination drugs	Mechanism	Experimental or clinical model	Findings
1	NCT02081378 Wylie et al[68], 2017 (Nature)	Preclinical and early phase 1: BCR::ABL1 (TKI) + STAMP	Imatinib or nilotinib or ponatinib + asciminib	Dual targeting competitive ATP binding and allosteric inhibitor	Mouse xenograft models of human leukaemia (Ba/F3 cell lines with single or compound mutations and patient-derived cells)	Complete and sustained regression in mouse xenografts
2	Ko et al[76], 2014 (Oncotarget)	Preclinical: TKI + BCL-2	Imatinib + venetoclax	BCL-2 inhibitor induces apoptosis of LSCs	CML cell lines. Primary human CML progenitor cells and healthy normal cord blood progenitor cells	Selective elimination of stem cells. Venetoclax enhances imatinib activity against CML progenitors
3	Bellodi et al[73], 2009 (J Clin Invest)	Preclinical: TKI + autophagy inhibitor	Imatinib + chloroquine or bafilomycinA1	Autophagy inhibitors block LSC self-renewal	CML cell lines, primary human CML stem/progenitor cells xenograft mice carrying Ph+ leukaemic cells	Imatinib induces autophagy. Autophagy inhibitors selectively eradicate LSCs and improve sensitivity of mutant cells to imatinib-induced apoptosis
4	NCT02081378 Cortes et al[92], 2025 (Leukaemia)	Phase 1 trial: TKI + STAMP	TKI + asciminib	Dual targeting competitive ATP binding and allosteric inhibitor	Chronic phase or accelerated phase CML without T315I mutation	High rates of durable MMR, high rates of adverse events
5	NCT02689440 Jabbour et al[75], 2024 (Cancer)	Phase 2 trial: TKI + BCL-2 inhibitor	dasatinib + venetoclax	Dual targeting competitive ATP binding and anti-apoptotic	Newly diagnosed chronic phase chronic myeloid leukaemia (CML-CP) or accelerated phase with clonal evolution	80% major molecular remission rate, 96% 4-year event-free survival, 100% overall survival
6	NCT04188405 Short et al[93], 2024 (Lancet Haematol)	Phase 2: Target leukemic stem cell survival	Ponatinib + decitabine + venetoclax	Triple combination: TKI + hypomethylating agent + BCL-2 inhibitor	Advanced phase CML and Ph+ AML	50% complete remission, poor overall survival (11.1 months), poor survival rates: 41% at 1 year and 34% at 2 years
7	NCT02201459 PETALs trial, Nicolini et al[81], 2026	Phase 3 randomised clinical trial	Nilotinib vs Nilotinib + Peg-IFN-alpha-2a	Comparative	Newly-diagnosed CML-CP patients	Higher treatment discontinuation rate due to haematological and psychiatric adverse events
8	NCT03117816 trial Burchert et al[82], 2026	Phase 3 randomised clinical trial	Ropeginterferon alfa-2b vs Observation after TKI discontinuation	Comparative	CML patients in DMR preparing for TFR	No significant improvement in 3-year relapse-free survival vs observation

AML: Acute myeloblastic leukaemia; ATP: Adenosine triphosphate; BCL-2: B-cell lymphoma 2; CML: Chronic myeloid leukaemia; CML-CP: Chronic myeloid leukaemia-chronic phase; DMR: Deep molecular remission; LSC: Leukaemia stem cell; MMR: Major molecular remission; STAMP: Specifically targeting the ABL myristoyl pocket; TFR: Treatment-free remission; TKI: Tyrosine kinase inhibitor; IFN: Interferon.