Gender – female
DOB : 21/09/21
Wt: 12.8kgs
Ht: 94cms

K/C/O: - Chronic myeloid leukaemia in chronic phase
Date of diagnosis: 22/04/2024

Signs seen at the time of diagnosis:
>spleen palpable(4cm)
>hb-8 TLC- 2 lakhs with 2-8% blast cells
>active and alert
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Treatment: PHASE 1 – tab IMATINIB (Glivec)
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- Dose: 200mg (4 times a week) daily alternate with 100mg OD on 23rd April 2024 alongside cap hydroxyurea for 8 days

- Dose increased to 200mg for 5days a week and 100mg on sat & sun OD daily on 26th October 2024

RESPONSE TO IMATINIB
- Hematological response achieved by 21st may 2024
- Cytogenic response - biopsy on 26th October 2024 showed normocellular bone marrow with erythroid hyperplasia and absent iron stores
- FISH on 26th October 2014 showed evidence of minor clone of BCR::ABL1- t(9:22)(q34.1:q11.2)(Freq.8%)
- Signal pattern showed no evidence of trisomy of chromosome 8, trisomy of chromosome 19, trisomy of chromosome 21and 17p deletion.

Molecular response - BCR-ABL quantitative p120

24th Apr 24 | 125.36 | Time of diagnosis
31st July t 24 | 33.94 | 3 months post imatinib
26th October 24 | 9.97 | 6 months post imatinib
1st December 24 | 8.61 | 7 months post imatinib
Conclusion: NO MMR

ABL1 Kinase domain mutation test by Sequencing analysis done on 1st December 2024 showed two variants of uncertain significance in ABL1 Tyrosine kinase domain: c.1086_1270del185 p.R362fs*21 and c.823_1270del;p.E275Hfs*29.

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PHASE 2- tab Dasatinib (Dasnat 20)
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due to sub-optimal molecular response to Imatinib (warning as per ELN) and tyrosine kinase domain variant mutation were detected; she was shifted to Dasatinib since 9/12/24, dose 40mg OD daily till date

RESPONSE TO DASATINIB
- Hematological response is good

- Molecular response - BCR-ABL quantitative p120

1st December 24 | 8.61 | Start of Dasatinib
10th February 25 | 2.605 | 2 months post Dasatinib
17th April 25 | 1.44 | 4 months post Dasatinib
17th April 25 given to tata memorial lab | 6.426 | 4 months post Dasatinib
17th May 25 | 8.6554 | 5 months post Dasatinib
17th May 25 given to tata memorial lab | 7.998 | 5 months post Dasatinib
Conclusion: NO MMR

 -   Kinase domain mutation status of BCR-ABL1 Fusion transcript is negative by tata memorial hospital done on 17th may 2025

- Cytogenic response- marrow biopsy done on 23th may 2025
> FISH – 3%
> Minimal residue disease for AML- flow cytometry analysis doesn’t show any abnormal myeloid blasts
> Karyotyping – normal diploid female karyotype 46XX in all 20 cells
> Bone marrow aspirate- paucicellular marrow

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PHASE 3 – tab Dasatinib + VENETOCLAX
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Due to loss of response to dastatinib, she was started on Dasatinib 40mg OD daily and Tab Venetoclax 100mg OD for 7 days on 25th May 2025 (prescribed on 23th may)

- Molecular response - BCR-ABL quantitative p120
25th June 25 | 1.6917 | 6 month post dasatanib, 1month post venetoclax
28th July 25 | 1.1956 | 7 month post dasatanib, 2 month post venetoclax
Conclusion: NO MMR

- Hematological response is good
- LFT, KFT, electrolytes, USG abdomen and chest Xray show no significant abnormalities

- FISH panel

Date | Frequency | Phase of treatment
22/04/24 | 95% | Diagnosis
31/07/24 | 28% | imatinib 3 months
26/10/24 | 8% | imatinib 6 months
23/05/25 | 3% | Dasatinib 6 months

Haematological Response Chart

Date | Hb | WBC Xcu.mm | Platelet X10^9/L | Phase of treatment | Lab
22/04/24 | 8.3 | 2,99,000 (8%blast) | 859 | Diagnosis | h.n
29/04/24 | 8.6 | 2,27,760 (2%blast) | 704 | 1 week imatinib | h.n
06/05/24 | 9.4 | 86,300 | 487 | 3 weeks imatinib | dekhne
21/05/24 | 9.0 | 8,900 | 389 | 1 month imatinib | dekhne
29/07/24 | 9.8 | 8,470 | 200 | 3 months imatinib | Metropolis
26/10/24 | 9.9 | 8,910 | 238 | 6 months imatinib | H.n
01/12/24 | 9.5 | 10,920 | 414 | 7 months imatinib | lilac
15/12/24 | 10.7 | 13,350 | 269 | 1 week Dasatinib | H.n
10/01/25 | 10.1 | 12,290 | 291 | 1 month Dasatinib | p.h
10/02/25 | 10.2 | 5,950 | 275 | 2 months Dasatinib | lilac
10/03/25 | 9.8 | 8,270 | 284 | 3 months Dasatinib | P.h
17/04/25 | 9.8 | 8,450 | 377 | 4 months Dasatinib | h.n
17/05/25 | 10.6 | 10,720 | 365 | 5 months Dasatinib | Lilac
23/05/25 | 10.3 | 9,910 | 229 | 5 months Dasatinib | h.n
03/06/25 | 9.8 | 6,190 | 292 | 1 week venetoclax | P.h
26/06/25 | 10.09 | 9,520 | 336 | 1 month venetoclax | Lilac
28/07/25 | 9.58 | 9,060 | 258 | 2 months venetoclax | lilac

Thoughts please. 

Obviously, I am going to start with the caveat that I am not a paediatrician.

Molecular results are available until July.

This 3 y.o. girl failed imatinib and had two mutations of uncertain clinical significance.

Has switched to dasatinib, initially 20mg, and then 40mg and when no molecular response after 5 months, venetoclax added at a dose of 100mg od.

BCR::ABL1 now just over 1%, but not improving. No clear evidence for benefit of adding venetoclax.

Some of the BCR::ABL1 results are a little discrepant between local lab and TATA Memorial Lab. Are either (or both) reporting to International Scale?

My initial thoughts would be:

I am assuming that compliance with treatment is not an issue.

Stop venetoclax as I’m not sure what it is adding to dasatinib.

Review dasatinib dose, especially if child is growing quickly and assess whether further dose increase is possible/appropriate - will also be dependent on side effects.

I think I would be considering allogeneic stem cell transplantation here and would be asking about family donors and doing tissue typing. I would still try to optimise TKI therapy first. I would give the dasatinib up to 1-year and if no improvement in response would consider a switch to an alternative TKI or go straight to transplant, depending on the options available.

Is it possible to assess Myeloid Cancer Gene Mutations, e.g. ASXL1? If this was present I would be more in favour of early alloSCT.

Happy to discuss further.

Best wishes
Mhairi

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

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 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.

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