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

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.