Understanding and overcoming resistance to tyrosine kinase inhibitors (TKIs) in Chronic myeloid leukemia (CML).

Introduction: Chronic myeloid leukemia (CML) represents one of the first neoplasms whose molecular pathogenesis was successfully unraveled, with tyrosine kinase inhibitors (TKIs) representing one of the first-targeted therapies. TKIs have revolutionized long-term outcomes of CML patients and their life expectancy. Nonetheless, a minority of patients will develop TKI resistance due to a complex and multifactorial process that ultimately leads to the emergence of an unresponsive cancer clone. Overcoming TKI resistance is considered one of the major challenges in CML management.

Areas covered: In this review, the main findings extrapolated from published research, guidelines, and clinical trials regarding TKI resistance (published before October 2024) are discussed. Data have been obtained through broad research on Medline, Embase, Pubmed, and archives from EHA and ASH congresses.

Expert opinion: Nowadays, asciminib and ponatinib have expanded the therapeutic arsenal for resistant-CML management and allogenic transplant still represents an important alternative in the context of multiple TKI failures. Off-label use of TKIs combination therapies, although theoretically appealing, lacks robust clinical evidence and regulatory approval. Looking ahead, the introduction of novel technologies such as digital PCR (dPCR) and next generation sequencing (NGS) holds great potential to revolutionize the management of TKI-resistant CML cases.