Chronic myeloid leukemia (CML) is characterized by a pathognomonic chromosomal 
translocation, which leads to the fusion of breakpoint cluster region (BCR) and 
Abelson leukemia virus 1 (ABL1) genes, generating an oncoprotein with 
deregulated tyrosine kinase activity. Areas covered: In the last two decades, 
BCR/ABL1 kinase has become the molecular target for tyrosine kinase inhibitors 
(TKIs), a class of drugs that impressively improved overall survival. Despite 
these results, a proportion of patients experiences resistance to TKIs and need 
to change treatment. Furthermore, TKIs are unable to eradicate leukemic stem 
cells, allowing the persistence of neoplastic clones. Therefore, there is still 
clinical need for new agents to overcome common resistance mechanisms to 
available drugs. This review explores the horizon of drugs actually under 
investigation for CML patients resistant to conventional treatment. Expert 
commentary: Radotinib is an ATP-competitive TKI that showed significant activity 
also in front-line setting and could find employment indications in CML. 
Asciminib, an allosteric ABL1 inhibitor, could demonstrate a higher capacity in 
overcoming common TKIs resistant mutations, including T315I, but clinical 
findings are needed. CML stem cell target will probably require new therapeutic 
strategies: combinations of several compounds acting with different mechanisms 
of action are actually under investigation.