Clinical Case Discussion Forum
To share and enhance best practice management of CML, experts and interested clinicians can discuss difficult or interesting CML cases here. Physicians submit a brief history of the patient and the case for discussion using this forum.
Resistant Pediatric CML
Treatment 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
My thoughts for next steps
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)
Questions
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.
Thank you! Zach
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.
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.
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 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.
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…
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.
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.
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.