Dear Colleagues,
after CML diagnosis our patient was started on Imatinib. Because of a suboptimal response he was started on Dasatinib and transplanted with MUD Bu/Cy/Campath. Three months after BMT BCR/ABL PCR became postitve, his donor was not available for DLI and he was started on Dasatinib 60 mg/m2. At that time care was transferred to our center.Dasatinib was very well tolerated but now 18 mos later BCR/ABL did show a 1 log increase to 0.05 % (international scale). If BCR/ABL continues to increase our plan would be to do a 2nd transplant, he does have several options for a 10/10 MUD and is clinically doing very well
My questions are:
Would you do a 2nd transplant or try a different TKI ?
For a 2nd transplant would you use TBI/CY/ATG or Clofarabine/Melphalane/ATG or a different type of conditioning ?

Many thanks,
Ulrich Duffner

Difficult case. I presume that you have confirmed compliance with his dasatinib? Have you confirmed that there is no kinase mutation leading to the loss of response?
I have questions about the original allograft? How long did he remain on immunosuppression? Was there any GVHD, acute or chronic? What was the best molecular response post transplant and when? Did he seem to lose response while on immunosuppression or when off?
Given his age and the obvious desire to be aggressive, I think you will need to transplant him a second time. The fact that this is a second MUD donor may not be such a bad thing, as I do not get the impression that he had much GVH and hence much GVL. Personally I would use CyTBI. There is more experience with this regimen I think. I would be hesitant about using ATG as I am worried that the in vivo T-depletion may be in part responsible for the post-transplant relapse.
I do not think that a switch in TKI in the absence of a mutation would help, unless it might be ponatinib, but using this post allograft might be potentially problematic.

Thank you for this interesting case. To summarize, this is CP CML transplanted after imatinib resistance and salvage with dasatinib. Post transplant there was very low MRD treated with dasatinib once again at what sounds like standard doses (BSA dosing) but 18mo hence there is molecular persistence/increase to a level approaching loss of MMR on the IS.

My reaction:
1/ I might try to work with TKIs a bit more- is there room for dose escalation of dasatinib? His MRD has been well controlled from either a partial GVL effect or a TKI effect or both. I am impressed by the very low level of MRD and might wonder if slightly more TKI effect might bring deeper MR in the presence of any residual GVL.
2/ Mutation testing may be of benefit. Given IM resistance and somewhat longer dasatinib exposure this may help in the decision to use more dasatinib, consider switching to nilotinib if a select mutation (DAS resistant/NIL sensitive) or another choice, etc. (see #3)
3/ Ponatinib is an option; one may be concerned about AEs and there is only persistent MRD; I would consider ponatinib if the disease were to continue to proliferate or a t315i mutation was noted.
4/Overall it is the case that GVL has not carried the day for this case; of course DLI if available may benefit in this MRD setting although the timing is late and full chimerism and full immune reconstitution of donor hematopoiesis is likely in place. Hence consideration of a second transplant, if feasible, could be weighed against the option of stable MRD on a TKI if manipulation works (dose increase, switch, etc). If the disease is proliferating, there is a t315i mutation, or for patient choice there is a reasonable case to consider re-transplant.

I will open the floor up for comments on the conditioning regimen while I poll some colleagues; I would not be the right person to help choose that….

Comments? Suggestions? Agreement? Disagreement?

2nd transplant looks quite toxic. I would try a new TKI if I had the possibility. In my country I won't have a different TKI than the tree well know so I would have no other choice than to transplant him. So good chance Alicia

Hi Ulrich,

I presume that he was allografted because of imatinib resistance, not because he transformed to AP or BC. I would be cautious about making any change based on a 1 log increase in BCR-ABL to a level of 0.05% (IS) on a single assay. This could just be assay-based fluctuation. I would continue to monitor closely (monthly if possible) and confirm a progressive loss of response before considering a change of therapy. Drug adherence should also be carefully reviewed. If there is a steady rise in BCR-ABL to a level >0.1% then a mutation screen would be critical and would help determine next line therapy. Nilotinib, bosutinib and ponatinib are all worth considering in this setting. I would probably try nilotinib first if the mutation profile was favourable but move to ponatinib if there was a poor response after 3-6 months. I would not consider a second allograft unless there was evidence of transformation to AP/BC or the patient was refractory to all available TKIs and had no molecular control of his disease.

Regards


Tim