Clear indication for an allogeneic stem cell transplantation.
Deficient underlying Ph neg hematopoiesis.

Thank you Prof for the comprehensive analysis of the situation. I am from Uganda and we face such challenges. However, I wish to be enlightened on why the first line treatment was dasatinib and at a high dose. I think we have not identified any ABL1 mutations in this young patient but what would be the role of other lines of treatment? I am asking this because in low income settings access to Allotransplants is not possible.

Henry

Normal hemopoiesis has not recovered for whatever reason and what does recover here is clonal. All the TKIs are good at shutting down the CML clonal hemopoiesis and switching will not change things. Persistent cytopenias is one of the very few indications for stem cell allografting and as I pointed out in a very recent commentary in Am J Hem, nothing will be gained by delaying and the risk of cytopenia related problems can only get worse. This is a young man and should have a good transplant outcome. I agree with Tim, but would not delay.

Indeed challenging. Would a trial of another second generation TKI like Nilotinib not be useful? He is not a failure as 3 month BCR::ABL RQPCR is 2 %.
Was there any myelofibrosis in BM?

Yes this is an unusual and difficult case. I am worried that this young man is one of the 2-3% of CML patients who develop profound cytopenia and little or no response to their TKI therapy. However his molecular response at 3 months was actually reasonable. I guess there is still a small chance that you will be able to steer through this difficult phase and get some level of response with modified dose dasatinib or another 2G TKI. It has already been 7 weeks with no therapy and looks likely to be a lot longer – this puts him at high risk of transformation. I’m not sure asciminib is a better option at this stage – it has a similar problem with thrombocytopenia as dasatinib has, perhaps less neutropenia and anaemia. Given that he has gone for 6 months with minimal response, it would also be worthwhile to check for a kinase domain mutation.

Given his age and presumed fitness I would be getting prepared to go ahead with an allograft in the next 3 months if the situation doesn’t improve (i.e count recovery and some evidence of molecular response back on TKI therapy). I think if you can’t deliver effective TKI therapy for a prolonged period despite growth factors then an allograft would be the best option – if a suitable donor can be found.

Thank you for your insights. I have been discussing this case with Sarah and suggested that she post it here to gather advice from a broader group as there is likely more experience with adult patients.

As Sarah mentioned, G-CSF has been administered but has not shown efficacy thus far. Romiplostim has also been considered. There are a few case reports of aplastic anemia associated with dasatinib. The key question is how long we should wait before determining whether this is indeed AA, rather than the transient count suppression often observed with dasatinib, which is typically reversible.

Another question is whether it would be safe to introduce asciminib in this context, given the rising BCR::ABL1 level. If this is irreversible, then, he needs HSCT, and he needs disease control while awaiting HSCT. While asciminib poses a lower risk of count suppression compared to ATP-competitive TKIs, its effects in this particular situation remain uncertain.

We greatly appreciate any further thoughts or suggestions.

Nobuko Hijiya
Pediatric Oncology
Columbia University