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.