Female patient, after an initial excellent response to imatinib, she had a rise in bcr-abl on imatinib 400 bd with appearance of G250E and Y253H mutations, switched to nilotinib with good effect, but then had a recrudescence of Y235H mutants and withdrew from the study. She started dasatinib 100 mg/d but due to a variety of possible dasatinib-related adverse events, the dose was reduced and she has been taking 50 mg/d for the last 12 years. 

Her last detectable bcr-abl was in Nov 2016 and I am thinking about a trial of cessation of treatment. Obviously, I am concerned about the prior mutation history.

Do you have advice about her suitability for a trial of treatment cessation? Would this be a bad idea? 

Dear David,

We published a couple of cases maybe 10 years ago including a patient who had successful TFR after prior TKI failure with a kinase domain mutation. There was a series at ASH last year of people stopping ponatinib, some of whom had prior mutations, including T315I, and their chance of TFR was not obviously inferior to the run of the mill.

I am still apprehensive about stopping in these patients, but the limited anecdotal evidence suggests that it is safe and may be as effective in people without prior resistance. If the patient is keen to stop, I wouldn’t have a problem with trying, but I would caution the patient that the data on outcome are limited.

We have confronted this issue a few times over the past decade - 4 out of 180 TFR patients – with no bad outcomes. My impression is that the risk is not high. In your case, the resistance you have seen so far has been BCR-ABL driven on both imatinib and nilotinib, and well overcome with dasatinib.

We are still cautious in this setting – we wait a lot longer after DMR has been achieved before contemplating TFR. This lady has been in a DMR, probably MR4.5 for over 7 years now. I don’t think it is unreasonable to start talking about TFR – the reality is that the risk of very long-term exposure to dasatinib (even half-dose) is significant, so it is not a question of taking a risk versus not taking a risk, it is a question of weighing up the risks of long-term dasatinib against the risks of TFR.

4 patients in our 180 TFR patients.

• 1 patient each with G250E, F359V, M351T, E450K
• 3/4 have been in long-term TFR. The 1 relapse was the patient G250E who had molecular recurrence at 11 months.
• Median TKI exposure 10.6 years (range 5.6-15.7 years)
• Median MR4.5 prior to TFR 4.1 years (3.2-10.4 years)

Hope that helps

This is a very pertinent question. Indeed, very few studies have reported cases of patients with a previous history of kinase domain mutations who have attempted discontinuation.

Of the 60 patients recruited in the STOP 2G-TKI trial, 13 had a suboptimal response to imatinib, 4 of which were due to a kinase domain mutation that conferred imatinib resistance [doi.org/10.1182/blood-2016-09-742205]. In univariate analysis, suboptimal response to imatinib or TKI resistance was a baseline factor associated with molecular relapse, although the impact of TKI resistant mutations alone was not reported.

In one small-scale study from 2020, of the 10 patients who discontinued TKI treatment (9 of which had detectable mutations, including T315I), 5 maintained TFR [doi.org/10.3324/haematol.2019.234179].

Whether patients with a previously reported domain mutation can maintain TFR with TKI discontinuation remains to be confirmed by larger studies. A clinical trial is definitely in order to address this question.

We only have experience with 1 patient with kinase domain mutations who permanently ceased TKI treatment. She was diagnosed with CML in 2006 aged 34. She received first-line imatinib but was switched to dasatinib 18 months later after losing initial MMR, with the subsequent identification of a F359V mutation by Sanger sequencing. She discontinued dasatinib in 2014 after a sustained deep molecular response. She remains in TFR to the current day.

With close molecular monitoring, and if dasatinib can be restarted promptly following potential molecular relapse, permanent TKI cessation in your patient could be attempted. Another option might be further dose de-escalations of dasatinib prior to a full-blown TKI stop to “test the water”.

We would be interested to hear how this patient gets on if you do go ahead with the permanent treatment stop.

Dear colleague,

Last year at ESH iCMLf, I presented a series of patients with a history of resistance or suboptimal responses who gained sustained DMR on salvage treatment and attempted TFR. This series included about 35 patients, including some enrolled in STOP 2G and new ones.

Obviously upon long lasting salvage treatment duration and DMR, TFR rates were at least as high as in optimal responders and molecular relapses did not seem more aggressive.

However those with a history of BCR-ABl mutations had only one mutation (except one case).

In conclusion, I personally don't find it unreasonable to attempt TFR in this patient after clear discussion about what is known, what is not known, and potential risks and stringent molecular monitoring.

We clearly need to grow such a series of patients and gain experience for them but not take unreasonable risks.

Best regards,

Dr Delphine Rea
Paris, Saint-Louis Hospital