How to ensure you have an optimal response to TKI therapy

Adherence: the importance of taking your drugs daily

TKI therapies keep the levels of BCR-ABL1 transcripts very low, so it is vitally important to adhere to therapy by taking the tablets at a regular time every day.

Regularly missing more than three daily doses in one month is likely to affect optimal responses to therapy. In patients whose adherence to therapy was monitored, those whose adherence rate was greater than 90%, meaning that they took more than 90% of their prescribed doses in a month, were more likely to achieve the lower molecular levels of remission required for optimal response, such as MR3; MR4.5 or lower.

In practice, studies show that no deep molecular responses were observed when adherence was less than 90%.  In patients with CML treated with imatinib for some years, poor adherence may be the predominant reason for inability to obtain adequate molecular responses

Drug Resistant Mutations

Mutations can sometimes develop in part of the BCR-ABL1 gene, which can affect how well a particular tyrosine kinase inhibitor can block the protein that signals for Ph+cell division.

The prevalence of ABL1 mutations increases with ‘disease time’: that is, rare in newly diagnosed chronic phase and increasing with late chronic-phase and advanced-phase disease (i.e. with increasing Sokal score). Thus, ABL1 mutations occur as part of the natural history of CML, rather than as merely a manifestation of selective pressure from TKI therapy. J P Radich

Mutation testing is an important tool to asses why a patient fails to meet a particular treatment milestone, or loses an established response in spite of continuous treatment without adherence issues. Identification of specific mutations can help indicate a particular TKI that would be a more effective treatment option.