Asciminib in CML

 Mechanism: Binds to the non-kinase domain of BCR-ABL where ATP binds.

This is the only CML TKI that works in this way.

Asciminib is preferred to ponatinib in those with intolerance or lack of response to first and second-line TKI.

However, ponatinib may be preferred if BCR ABL> 10% at 6 months.

Both ponatinib and asciminib may be acceptable in T315 mutation or non-T315I kinase domain mutations.

Omacetaxine is another drug approved for T315 I mutations.

2024 update

https://www.nejm.org/doi/full/10.1056/NEJMoa2400858

How to counsel pt: Imatinib was the first generation TKI. It is still the standard of care. The second gen TKI can induce deeper molecular remission and greater chance of going into TFR, but the OS is not different. The MR3 at 48 weeks is 40% imatinib, 45% second gen and 68% asciminib. 

The drug that induced the highest MR3 was ponatinib but the front line trial EPIC was aborted due to concern for vascular events.

Adverse events of grade 3 or higher and events leading to discontinuation of the trial regimen were less frequent with asciminib (38.0% and 4.5%, respectively) than with imatinib (44.4% and 11.1%) and second-generation TKIs (54.9% and 9.8%).

In conclusion, asciminib is much better tolerated and induces deeper responses that imatinib. The MR3 for asciminib was not statistically superior to second gen TKI.

Adverse events ( G3 or higher):

Asciminib 38%, Imatinib 44%, Second gen TKI 55%

Discontinuation:

Asciminb 4.5%, Imatinib 11%, Second Gen TKI 10%