Treatment of chronic myeloid leukemia chronic phase patients in third-line setting and beyond: recommendations from a...

Tyrosine kinase inhibitors (TKIs) have revolutionized the therapy of chronic myeloid leukemia (CML) in chronic phase, opening up the perspective of a normal life expectancy for most patients and of treatment-free remission for some of them. However, intolerance or resistance may necessitate treatment modifications.

A panel of five Belgian experts reviewed the treatment options in Belgium in 2025 for patients with chronic phase CML with resistance or intolerance to at least two lines of therapy.

In contrast to the early years of TKI therapy, several options are available as third-line therapy or beyond for CML patients resistant or intolerant to at least two prior TKIs. These include the third generation TKI ponatinib, the allosteric BCR::ABL1 inhibitor asciminib, allogeneic hematopoietic stem cell transplantation, continuation of ongoing second-line TKI therapy with or without dose modification, or switching to alternative second generation TKIs. Careful consideration of the potency and safety profiles of these options, the clinical context, and treatment goal is needed. Ponatinib is currently reimbursed in Belgium for patients with CML showing resistance or intolerance to at least two prior TKIs, or with the BCR::ABL1 T315I mutation, regardless of the number of previous TKIs. Asciminib is currently reimbursed for patients with resistance or intolerance to at least two prior TKIs, excluding those with the BCR::ABL1 T315I mutation. This review provides guidance to weigh available safety and efficacy data in a setting of resistance or intolerance to second-line therapy with the goal of selecting the best available personalized treatment.