Below are 2 examples with similar problems :

Case 1.
11 year old boy, diagnosed with CML chronic phase at 6 years of age.
No siblings.
Treated with Imatinib from the outset, switched empirically to Dasatinib , after 2 years, not having achieved MMR at that point.
3 months RQ-PCR FOR BCR - ABL(RNA) :29.21 (IS not standardized at the time)
6 months BCR-ABL1(p210)/ABL1 % IS :3.05
12 months % BCR-ABL1(p210)/ABL1 % IS :0.85
Since then (now 5 years post initiation of TKI therapy) the IS has stayed between 0.22%- 0.47%
No pathogenic variant identified in the tyrosine kinase domain of the ABL1 gene.

Case 2 :
12 yr 7 months old girl, diagnosed as CML Accelerated phase at presentation , at the age of 8 years.
Commenced on Imatinib (did not have easy access to 2nd gen TKIs for Pediatric patients at the time),
switched to Dasatinib after 12 months.
6 months RQ-PCR FOR BCR - ABL(RNA) : 14.40
1 year% BCR-ABL1(p210)/ABL1 (% IS) : 3.05
4 years post initiation of TKI IS has stayed between 0.4%- 0.67%
No pathogenic variant identified in the tyrosine kinase domain of the ABL1 gene (tested twice).
5 siblings , but none are HLA matched to the patient.

The non-attainment of MMR in both these cases, is possibly related to mutations in non kinase domains.

Q1. What would be the therapeutic strategy for children in these cases with non attainment of MMR?
Q2. Both children have TKI related growth faltering. Can growth stimulation measures be considered while on TKI therapy?

I think that in both cases MUD transpant should be considered. Could they stay for long and for the rest of their life in TKI therapy? Is the MUD transplant toxicity and risk in children worse that what they are already experiencing with a long and not curative TKI therapy?

For case 1, He is close to MMR, but not there after 5 years. The only other approved TKI for children is nilotinib, but switching to another 2G-TKI will not be so effective. I have had similar cases and continued dasatinib as long as the number is very close to MMR. If ponatinib is available, it may be tried, but we do not know the doses for children yet while phase 1 studies are ongoing. We have published a case series. ( Br J Haematol 2020 Apr;189(2):363-368). I do not know how big the 11 yo is, but you may want to try 15-30 mg initially depending on his size. I would not take him to BMT from MUD.

Although Case 2 initially had AP, after so many years with PCR close to MMR, I would do the same as case 1. Children who present with AP do reasonably well as long as they achieve the response milestones. (Eur J Cancer. 2019 Jul;115:17-23. ) I might have considered BMT for this child earlier in the course, but after so many years with stable molecular level, I might take the same approach as case 1.

For both cases, asciminib would be a consideration, if the study is available in your area (NCT04925479) and they meet the criteria for failure or intolerance.

About the growth question, I have discussed use of growth hormone with some endocrinologists, most of them are reluctant to use it. There is little experience in the literature.
(Pediatr Hematol Oncol. 2020 Mar;37(2):99-108.) From my observation, children on TKI may have catch up growth in puberty, if the height ends up lower than the mid-parental height. We are hoping that the current asciminib study will show positive results for growth issue.

Thank you.
Nobuko