Novel tyrosine-kinase inhibitors for the treatment of chronic myeloid leukemia: safety and efficacy

ABSTRACT

Introduction: 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.

KEYWORDS:

• Chronic myeloid leukemia
• tyrosine kinase inhibitors
• deep molecular response
• treatment-free remission
• bosutinib
• radotinib
• asciminib

Declaration of interest

M Breccia has received honoraria from Novartis, Bristol-Myer Squibb, Pfizer, and Incyte. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. One peer review declares consultant work and research funding from Novartis, Bristol-Myer Squibb, Pfizer, and Ariad. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.