I agree with the thoughts of others- that any CML case such as this, allografting is a consideration when the patient is younger and fit and a donor is available, as there has not been a protective remission (MMR) established. In the pediatric cases as i know allografting is favored even earlier as later line therapies are not as developed and the risk/benefit may be more favourable. I agree with the lean away from the venetoclax; I agree with the lean towards access to asciminib (or potentially ponatinib, in that order) once dasatinib dose was exhausted. Best wishes to this young CML warrior...

Although a certain degree of response has been observed, it has not been optimal. Therefore, the chances of achieving an optimal response in future that would enable us to consider TFR are very limited. Given the present results and the low mortality associated with allotransplantation nowadays, I would opt if possible for this option rather than continuing with TKI therapy, given the uncertainty surrounding its results and the long-term toxicity.

The pediatric world is completely different and I'm not aware which type of drugs they can be used.

I believe that the switch dasa+ven is a little too much for a resistance still in chronic phase.

In third line, considering the type of response, if this case could be translated to an adult, would be a perfect candidate for asciminib.

Some data in pediatric patients are now produced. Probably better, without specific toxicity in the long-term. In the meantime, I would activate a search for a donor.

Best regards

Massimo

I have a bunch of paediatric CML patients under our care and we don't see any peculiar behaviour of their cases. I am not conversant with these combinations including hydroxycarbamide or venetoclax in CPCML. I have not seen any resistant mutation in this case that precludes the use of nilotinib, bosutinib, ponatinib or even asciminib, and I don't know their contraindications in paediatric practice.
It appears this child may be going the way of autografting sooner rather than later.

I also assume compliance is not an issue, and the child is not receiving concomitant medications such as antacids or H2 blockers that could affect drug exposure. I also agree that the role of venetoclax in this context is questionable and would not recommend its use.
The impact of ASXL1 mutation at diagnosis on treatment response in pediatric patients remains to be established.
Although the BSA is not provided, based on the child’s weight and height, I estimate it to be approximately 0.7–0.9 m², depending on the calculation method. If the dasatinib dose is below 60 mg/m²—the standard pediatric dose—consideration could be given to increasing it. An increase to 80 mg/m² may be also considered. In the pediatric phase 2 study of dasatinib (J Clin Oncol. 2018 May 1;36(13):1330–1338), the 80 mg/m² cohort was closed early due to lack of efficacy in patients with blast crisis or accelerated phase disease, but the dose was found to be safe.
In this case, I would consider switching to either ponatinib or asciminib. For a young child like this patient, the pediatric formulation of asciminib currently being studied in a phase 1/2 trial (NCT04925479) would be ideal, though I suspect it may not be available in your region. Novartis may be able to provide the drug through their compassionate use program, and I would be happy to help facilitate that connection.
Ponatinib is not currently approved for pediatric use, but a few studies have demonstrated its safety (Br J Haematol. 2020 Apr;189(2):363–368; Eur J Cancer. 2020 Sep;136:107–112). If you are able to obtain the medication off-label, I would consider using it. There is also a pediatric phase 1 study of ponatinib (NCT03934372), although it is limited to Europe.

Nobuko Hijiya
Pediatric Oncology
Columbia University, New York, USA

I am concerned that given the counts during the therapy, that the patient may have been underdosed. That said, the mutations are not clear and I am concerned about trying other TKIs. I agree completely with the plan for allograftng if a donor can be found. This needs to be done before the disease transforms