Case and treating physician are located in Armenia.

63 yo lady who was diagnosed CML CP in March of 2002. Started treatment with busulfan until the 1st gen TKI availability. Treatment continued with Imatinib 400mg daily since Jan 2003.

When the RT-PCR was available, the 1st monitoring was done in February of 2021 by Cepheid GenXpert: 46.83%. Treatment switched to 2nd gen TKI nilotinib 400mg BID, but dose was reduced to 400mg daily because of hematotoxicity and sometimes interrupted. In August of 2022 RT-PCR p210 was 23.93%. We decided to switch treatment to 3rd gen TKI Ponatinib 45mg daily, but unfortunately patient had some complications and we had to reduce dose to 15mg daily and sometimes interrupted treatment. She had unexplained fever 39C and more. So, we decided to stop the treatment and started Bosutinib 400mg daily since July 2024. She tolerated well, but we didn't observe improvement in CBC. She continued to have anaemia and was transfusion dependent. So after 3-4 months of treatment we stopped bosutinib. Now 23.05.2025 CBC: Hb 85g/L, WBC-4.68, Neut.-1.74, PLT-194.0, bone marrow - 3% blast cells, PCR p210 -30.72%.

The problem is that only available (by The Max Foundation) TKI's in Armenia: imatinib, nilotinib and ponatinib. There's no other treatment available in Armenia. What will be your advice for this patient? Return back to Imatinib which was well tolerated and showed stability or prescribe Asciminib?

Very challenging case.

The physician should be commended for managing the patient for the last 20+ years without optimal resources.

If I understand correctly - the patient has never been documented to have achieved MMR.

I note the patient is still of an age where allogeneic stem cell transplant may be considered, but will assume that access is difficult.

Mutation analysis would help, but again, may not be available.

I would also be interested in whether there are additional cytogenetic abnormalities or morphological features suggestive of concurrent MDS, which may contribute to the cytopenia.

In the context of MDS, if the patient has renal dysfunction or inappropriately low epo, supplementation may help. Solving this problem may allow you to increase the intensity of TKI treatment.

If there is no other mitigating factor, and only CML is involved...
The only other licensed agent is asciminib – it would probably have a 30% chance of working in a patient with prior ponatinib exposure. I understand that access is difficult.
In its absence, if it is possible to try ponatinib again, I think that would still offer the best chance of response. But if this is not clinically appropriate due to prior toxicity, choosing imatinib is understandable if this is the best tolerated (consideration may be given to increase the dose to 600mgQD).

Thanks for sharing this case

This is tricky as I’m not sure what the toxicities were with ponatinib? Did she obtain a response to ponatinib?
Does the marrow show fibrosis and does the patient have splenomegaly?
Is it possible to obtain erythropoietin in Armenia? If so, I would try re-starting bosutinib (I can see this isn’t one of the Max Foundation TKIs so not sure how this was obtained) at 300mg with Epo support.
Not sure if asciminib is available, but that could be an option. If it is, I would start at a low dose (20-40mg od), again with Epo support if available.

Very challenging and I agree with my colleagues, and I would:
1. Trial asciminib as the next step. I have been told that Novartis is supplying asciminib through the Max Foundation. Please communicate with us if that is not true.
2. A step up dosing approach starting at 40 mg daily to start is reasonable, but she may need a higher dose to respond. Managing CML with cytopenias on therapy is hard and I agree using ESA, such as epo if you have access is a good idea. Cytopenias often persist until some degree of disease control is achieved.
3. Pursue BCR::ABL1 mutational analysis (we may be able to assist if it cannot be performed locally).

The anemia could be a complication of treating late CP CML or possible evolution to AP. I agree with my colleagues that looking for cytogenetic evolution could be prognostically informative. MDS is a possibility given prior busulfan, age.
If cytogenetics or mutational profile is available from the most recent bone marrow exam, it would be of interest.

Is it possible to sequence for BCR::ABL1 mutations? If sequencing is not possible, you may be able to send us spotted dried blood on Whatman filter paper through the MAX foundation (we can provide instructions) and we can help sequence. I'm happy to share contacts. We have done this in Sub Saharan Africa and SE Asia.

Asciminib among the next line choices makes the most sense and confirming there is no T315I could be important here as the dose used to treat would be different. There are also mutations that confer resistance to asciminib.

I am also curious what were the complications of ponatinib treatment? Was there any response to this potent drug? Olverembatinib is available in China and Macau, but I do not know of availability elsewhere; it is another very potent 3G TKI BUT is not available through Max Foundation.

Often in cases with progression or inability to treat we think of allogeneic transplant. I know there is a small allo program in Armenia, but she is older and I know resources for this are limited.

The lady did very well on imatinib for almost 20 years. Obviously, a CHR without a molecular response still provided her a fantastic survival advantage and problems started when TKI was changed according to modern recommendations.

My view is: either the goal is cure, then transplant. Or the goal is live quite well, then don't try to have more than a CHR on imatinib or any TKI. Epo to treat anemia.

A new TKI is unlikely to change the molecular outcome in such very late CML likely without any normal hematopoiesis.

Patients originally treated with busulphan will very often not respond well to more definitive therapy down the line. Switching to another TKI is not going to work and will delay the only potentially successful therapy – allogeneic stem cell transplant. If this unfortunate woman is a transplant candidate – acceptable co-morbidity, available donor and meets transplant centre criteria, I would proceed ahead rapidly before blast crisis develops.