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.

I think it’s too early to change from asciminib. There is some improvement and several changes. I would give asciminib at the very least 6 months, if not more. ASXL1 increases the risk of failure and of developing mutations, but the probability of response is not zero. Many patients do respond. I would follow the response closely with real-time PCR (IS) and look for donors. If there is truly a lack of response, I would be more inclined to go to SCT, whatever the response (or lack of), rather than adding ponatinib, as we do not know what that will do, and this is a young patient who will likely do well with SCT. We should acknowledge that we also do not know the outcome of SCT in patients with ASXL1, but it is likely worse than for similar patients without ASXL1 mutations. That is true in AML, where there is some data, but we do not have data in CML (a project for CML Network?). I hope this helps.

I think it’s too early to switch from asciminib. However, the ASXL1 makes me think she won't respond.

I would repeat BM and switch to ponatinib.

Resistant Pediatric CMLTreatment summary:

• 13yo otherwise healthy female diagnosed with CML, chronic phase on 4/16/2025. WBC 218,000, Hgb 6.9, Platelets 766,000, Peripheral blood with 4% blasts at diagnosis and 18% basophils. Bone marrow with mildly increased blasts morphologically and 2.9% immunophenotypically unremarkable myeloblasts and 10% basophils. Molecular testing identified p210 Major Form (e13a2 or e14a2). Molecular panel notable for BCR::ABL1 and mutation in ASXL1 c.1934dup and USH2A.
• On dasatinib 100mg daily from 4/17/2025 - 8/27/2025
• On bosutinib 500mg daily from 8/28/2025 - 9/8/2025 (held due to skin toxicity)
• On Asciminib 40mg BID from 9/15/2025 - 10/10/2025, and 80mg daily from 10/11/2025 - Present
• Patient reports 100% adherence to medications (witnessed by parents)
• Responses:
  • Hematologic
    • Complete hematologic response (CHR) achieved at 5 months
  • FISH:
    • 3 months: 63% positive (minor cytogenetic response)
    • 4 months: 55% positive
    • 6 months: 28% positive (1 month on asciminib, partial cytogenetic response)
    • 7 months: Pending
  • BCR::ABL Molecular:
    • 3 months: High Positive
    • 4 months: High Positive
    • 6 months: High Positive
    • 7 months: High Positive (2 months on asciminib)
  • Resistance testing:
    • 4 months: No BCR::ABL1 mutations detected

• Obtain a bone marrow to repeat cytogenetics, repeat resistance testing
• HLA typing for BMT
• Add ponatinib to asciminib
• Send to allogeneic transplant once in CCyR complete cytogenetic response or IS <1% (MR2.0)

• What would your approach be?
• Do I need to be more patient and give asciminib more time before adding ponatinib? It seems like obtaining a CCyR at 12 months is an important milestone, so maybe I should be more patient and continue therapy until this point if FISH continues decreasing?
• If I continue asciminib/add ponatinib and patient has an adequate response, would you continue with medication alone and avoid transplant? She is tolerating therapy well currently with no symptoms.