For whatever reason, this young woman is resistant with very little response - this may be a mutation or clonal progression, but that does not matter. The longer that is waited, there is a chance that she will lose the only treatment that will likely benefit her in the long run, ie an allograft. Playing around with TKIs in combination or not runs the risk that she will blast off. Best result with an allograft is NOW, if a donor is available. Debulking with a TKI will not improve things. Hydroxyurea if necessary and transplant. I am concerned that she was on the cusp of what we used to call accelerated disease at diagnosis - basophils worry me here. Waiting here is a ticking clock.

Having the pending result from 7 months, I would give her a little more time with asciminib, once daily. Asciminib decreased the FISH from 4 months to 6 months.
It would be a good idea to at least consult BMT service and look at the mutation analysis. But I would give her a little more time, a couple of months, as long as she is in CP and BCR::ABL1 is decreasing. The best timing of BMT is not very clear. As long as the patient is in CP, I think it is OK. ASXL1 mutation is known to have less favourable outcome in adults. We do not have data in peds yet.

My response wouldn't differ much from the adult experts- I would continue the asciminib for a longer period before making any changes immediately. Of course, BMT should be considered, as this child has a high chance of treatment failure over time.
Also, the importance of the ASXL1 mutation in children with CML is less clear than in adults.
Hope this helps.

I agree overall with Tim’s response - however I do feel and had (phase 1) and have at present some patients who respond to dose increase; the ASC2ESCALATE study looking into this is not conclusive yet, and insurance reimbursement for non-T315I patients to receive higher dose may not be possible…

I agree with Jorge – “ASXL1 increases the risk of failure and of development mutations”.
I would also like to know if there are other variants that have developed since diagnosis. Mutated RUNX1 for example when acquired during therapy is associated with blast phase progression.

Quite likely heading for an allograft but there is still a chance she will respond well to asciminib or ponatinib.
I would switch to ponatinib if there is no evidence of response after 3-4 months of asciminib.
The ASXL1 mutation at diagnosis puts her at higher risk of resistance, but it doesn’t seem to increase the risk of progression to blast crisis. Her risk is high though, simply on the basis of her poor response to 2G TKI therapy.
Critical that she has frequent RQ-PCR (1-2 monthly) at this stage to accurately determine level and trend of BCR::ABL1.
Probably also worthwhile looking for an ABL mutation (again) at this stage, even though this wouldn’t explain her primary resistance - she is at high risk of acquiring an ABL mutation.