Patient in late 50s. Very healthy.  Diagnosed CP_CML in November 2024. 

November 2024: BC::ABL1-->1.7
November 2024: Imatinib 400 mg 
February 2025: BCR::ABL1-->15.5
February 2025: BM biopsy-->CCyR
March 2025: BCR::ABL1-->8.8% No mutation
April 2025: asciminib 80 daily
July 2025: PB BCR::ABL1-->9.3
July 2025: BM biopsy --->Karyotype and FISH negative. PCR 8.22 in bone marrow
October 2025:       BCR::ABL1-->4.2
December 2025: BCR::ABL1-->6.5 

Question: 

1-Why discrepancy between PCR and karyotype
2-Would you switch to different TKI despite being in CCyR?
3-When would you consider alloHCT?

Wow! This is a very perplexing case to start the new year. Let me work through it step by step, to show my thinking.

The first point relates to the discordance. I want to go back to what was present at baseline. The first mention of CCyR comes in February 2025. Given the pcr result at that time, I will conclude that CCyR and/or FISH were negative at that time. But what were they at baseline? Were they done? If they were positive at baseline, then there is very perplexing discordance with the 3-month follow up. If I were "presenting" this case, then I would be doing it to point out an issue. Not everyone agrees, CML diagnosis these days is done with a peripheral blood pcr and no cytogenetics or FISH or even bone marrow pathology are done. About 5% of newly diagnosed CML are cytogenetics negative but pcr positive. Was this one of these cases? FISH which is a molecular test and not a cytogenetic test should be positive in this case. If neither were done, then a finding of CCyR cannot be based on anything other than pcr, as there is no comparison possible. As an aside, cytogenetics could also show a complex rearrangement or an additional chromosome abnormality, which might be useful as baseline in the future in the event of poor disease response.

So unless it could be shown that cyto or FISH were once positive here, then I can only rely on pcr. If cytogenetics were positive at baseline and at 3-months negative leading to the CCyR conclusion, then this is a response, although the error bars with cytogenetic testing are not narrow and it may just have been missed at 3-months. If FISH were positive and at 3-months negative, then this too is a response. Here is where I scratch my head. The sensitivity of FISH is about 1%IS or roughly a 2-log response. Given the very consistent pcr levels over a year, FISH should still have been positive and even if not done at baseline but done at 3-months, should have been positive. My conclusion...were they done at either time? pcr mutations or unusual breakpoints may affect molecular testing but not FISH. I believe the chance of a FISH undetectable bcr-abl even in cytogenetically negative cases would be reportable. The CCyR conclusion needs clarification.

We now go by the pcr result. So we are left with a case of EMR by 6-months (<10%) which is on the riskier slow side, but still acceptable. It has however plateaued in this range even with asciminib. Here the question of what is the goal of therapy must be asked. MD Anderson data from more than a decade ago, shows that the survival at 10 years whether a 1% or 0.001% response is essentially the same. This patient has not even achieved this and both the NCCN and ELN would consider this a very risky scenario. Here I think that survival is the goal of therapy and a TFR attempt is not even on the table. So what would I do? This is a two step approach. The first is imperative - a switch must be made and given what has been tried, the only drug I would consider would be ponatinib although drugs such as olverembatinib may be available or consider a clinical trial. Staying with the current therapy I believe, is not an option, unless the only goal here is short term disease control. In a young woman, this to me, would not be acceptable. Response should be obvious by 3 months and if it occurs then stay the course. Meanwhile, search for a stem cell donor should be initiated.

If there is no improvement with this last intervention and a stem cell donor identified and there are no medical contraindications of stem cell allografting, then proceed immediately. Waiting until there is evidence of disease progression or possible other medical issues or risking the donor is not available, makes no sense. As I have consistently stated in the past, if stem cell allografting is on the table, waiting will not improve the outcome and could make it worse.

I hope there is a conclusion to this question. Personally, I am really interested in the process here.

I believe that, if RQ-PCR is standardized, these results can be considered. It's unnecessary to perform PCR on bone marrow because peripheral blood has been shown to be more informative. The conventional karyotype must have a minimum of 20 evaluable metaphases: how many were analyzed each time? I think another mutational analysis is necessary, considering the BCR::ABL1 value. In the case of no mutations or even if mutated (including T315I), I would recommend a switch to ponatinib 45 mg with subsequent reduction after achieving at least a ratio <1%. In case of resistance to ponatinib, I will consider an allogeneic strategy. Please also consider investigating scarce adherence to treatment.