This is an important area that needs more study, ie TFR in the resistant patient, including those with T315I. I like others have anecdotal success in this setting (a young woman wishing to concieve with CP CML and T315I several years of deep MR) and all is well with mother and baby with sequential TFR then pregnancy.

I would add that the ponatinib may continue to pose risk beyond exposure (earlier study showed a 'lag time' effect of AOE risk) and with the evolving vascular disease in this patient i feel there is a sense of action needed to reduce risk. I firmyl believe asciminib can provide this so that would be the conservative yet safer approach if available and feasible.

TFR would be an option I feel as many have suggested, with more uncertainty; if undertaken the most careful of monitoring would be best. I like to leave the TFR decision to patients, simply stating that there is a window of opportunity, either to jump through or simply gaze at and stay put.....

This is a very intricate case and you will only get opinion here and not a lot of data to make a decision.

First examine the response to ponatinb. It has been excellent and stable on 15mg daily. Even in the dose reduction OPTIC study, there was some relapse of t315i after dose reduction to 15mg, but this does not seem to be the case here. Relatively long-term stability is seen.

Secondly, the adverse events. Can they be attributed to the ponatinib? Again the OPTIC study showed a reduced incidence of vascular events, the stenosis could very well be ponatinib related and discontinuation should be considered, although some patients were able to go back on the drug after correction of the problem. There is no data on 10mg in the t315i arm, but I expect that if the culprit is drug, 10 is not much different from 15. The peripheral neuropathy is less well defined and it is not clear that this is ponatinib related. I hope that alternate etiologies have also been investigated.

What then are the options, most of which have been reviewed by others here?

1. switch to full t315i dose asciminib - patient has undetectable disease and is a full therapeutic dose necessary? Would a "maintenance" dose of 80mg daily suffice? Again, although quite rare, vascular cases with ASC have been reported and would it be safer in patients with established disease? Not a lot of data here, correct me if I am wrong.

2.ponatinib dose reduction to 10? Discussed above.

3. TFR attempt? Some cases have been reported and successful. It makes me wonder that with a long 15mg period without recurrence, this patient may be a success. If a relapse occurs, then there are 4 options.
a. restart PON with maximum co-morbidity support if relapse is with a t315i clone

b. asciminib full dose if relapse is with a t315i clone

c. treatment with another TKI - it should be remembered that t315i clones have a slow growth potential and recurrences can be with other clones, WT or a different mutation. This thought raises the idea that this patient could go on maintenance with a different safer TKI such as IM or BOS and have ASC or PON reintroduced only if a t315i clone materializes

d. allograft - an option but very risky with observed co-morbidities

Personally, I agree with Jane. I do not think that immediate intervention is necessary. I would favor a TFR attempt and then depending on what recurs if it does, ASC for a t315i case or other if not, something else depending.

Dear colleague,

If the patient is in sustained DMR, no hurdle to attempt TFR with careful monitoring.
Best regards

Dr Delphine Rea

We had a very similar situation some years ago in a woman in her 70s. She had originally been in PACE, and after several years on ponatinib she developed PAOD. She had been molecularly undetectable for a couple of years. We had no alternative but to stop treatment. She is now in her 80s, fit and well, off treatment since 2017

It would be entirely reasonable to stop, continue molecular monitoring and introduce asciminib if there is evidence of recurrence

I would also switch to asciminib but would consider a TFR attempt first as a possibility, there are some data of sucessful TFR with ponatinib, although in patients with T315I the experience is limited. doi.org/10.1182/blood-2023-187230

In this case I would recommend a switch to asciminib. Considering T315I mutation, this patient is not candidate to TFR.