Overcoming resistance to tyrosine kinase inhibitors

This content has been sponsored by Incyte Biosciences UK Ltd.

Striking the right balance in CML

Chronic myeloid leukemia (CML) remains a challenging disease to manage and treat. The introduction of tyrosine kinase inhibitors (TKIs) has had a tremendous impact on patient outcomes, with a selection of 1st, 2nd and 3rd generation TKIs available for use as 1st, 2nd and 3rd line treatments. The success of TKIs has reduced the need for hematopoietic stem cell transplant (HSCT), now commonly regarded as a salvage therapy for poor responders. However, for some patients, HSCT remains the best option, due to a number of factors that result in patients being less responsive to TKIs. This article aims to provide an understanding of CML disease progression and the current treatment pathway, as well as some of the challenges of sequencing the available agents and HSCT.


Content in this article has been adapted from Innes AJ et al. Nature Reviews Clinical Oncology 2015;13(2):79-91. Prescribing information is available at the end of the article

CML progression and treatment challenges

CML is characterised by the presence of a translocation of chromosomes 9 and 22, resulting in the Philadelphia chromosome and the production of the BCR-ABL1 oncogenic protein. The disease progression of CML is characterised by 3 phases: chronic, accelerated and blast crisis phases. Patients in the blast crisis phase have the poorest outcomes and pose the greatest treatment challenge. TKIs are effective in targeting the BCR-ABL1 protein, and are a successful treatment strategy in most patients with CML. However, there is a significant subgroup of patients who do not respond to TKIs. They remain a large unmet need in the management and treatment of CML.

Overcoming TKI resistance: the recommended treatment pathway

Patients with CML typically commence their treatment with 1st generation TKI, imatinib, before continuing to 2nd generation TKIs as sequential treatments. It is not uncommon for patients to cycle through multiple 2nd generation TKIs before attempting 3rd generation TKI, ponatinib. However, literature suggests that cycling through 2nd generation TKIs may not be the best solution for all patients. Furthermore, identifying poor responders early in the treatment pathway and beginning the process of donor selection could be a more effective approach.

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