Tyrosine kinase inhibitors (TKIs) are the standard-of-care for patients with Philadelphia chromosome-positive (Ph+) leukaemias.

However, some patients do not respond (primary resistance) or lose response (secondary resistance) to the TKI they receive. Regular monitoring of BCR-ABL1 transcript levels in response to TKIs is crucial to detect the emergence of resistance.[1–5]

A common mechanism of resistance is the presence of mutations in the BCR-ABL1 kinase domain. These mutations can impair or prevent the binding of certain TKIs, reducing their efficacy and ultimately leading to resistance.

Therefore, timely detection of mutations in the BCR-ABL1 kinase domain that confer TKI resistance can help facilitate appropriate treatment decisions.[1]

Although it is widely accepted that BCR-ABL1 mutations that cause TKI resistance are clinically relevant, open questions remain.

  1. When should we perform mutation testing in patients with Ph+ leukaemias? (E.g. at specific time points and/or in response to certain triggers?)
  2. What is the clinical relevance of low-level BCR-ABL1 mutations (i.e. mutations not detected by Sanger sequencing) detected at baseline or during treatment in CML and Ph+ ALL?
  3. What are the pros and cons of using sensitive mutation testing methods (e.g. next generation sequencing and digital PCR) versus Sanger sequencing in CML and Ph+ ALL?
  4. How are heat maps that show TKI-responses to individual BCR-ABL1 mutations best interpreted and translated into clinical decisions?
  5. What barriers can affect adherence to the clinical recommendations with respect to BCR-ABL1 molecular monitoring and mutation testing?
Educational Resources

Incyte recognises the importance of optimising molecular monitoring and mutation testing for patients with Ph+ leukaemias, and has made significant investments in this area.

Download Incyte Mission Statement

Incyte initiated the Think Test Treat programme to raise awareness and improve understanding of regular BCR-ABL1 transcript level monitoring and detection of mutations driving resistance to TKIs in CML and Ph+ ALL.

About when BCR-ABL1 transcript monitoring and mutation testing is appropriate
For BCR-ABL1 mutations as a possible driver of TKI resistance to identify patients at risk of treatment failure 
in a timely manner
Accordingly, taking into consideration the indications and resistance profiles of the different TKIs, and know when/how to act upon low-level mutations

A Steering Committee of European BCR-ABL1 laboratory experts was assembled to guide the programme and address relevant technical and clinical challenges.

Steering Committee
Magnifying Glass

Incyte also supports a number of investigator-initiated research studies that investigate different aspects of mutation testing in CML and Ph+ ALL, including when to perform testing, the clinical relevance of low-level mutations, and optimisation of sensitive mutation testing methods.

For further information, please contact Incyte Medical Information: