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TFR didn't work

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Hi,
I am long time lurker posting first time here.
History:
Detected in 2015. Been on imatinib 400mg till Nov 2021. I was at consistent PCR zero for over 4 years at that point.
Started TFR in Nov 2021 and was testing 0 every 2-3 months till July 2023 when it rose up to 0.005. Doctor wanted to restart imatinib
but negotiated testing again in a month. The latest test came at 0.02 and have an appointment coming up.

Now, I am debating what I should do:
1. Test again in a month and not start medication right away? This will be a hard sell to the doctor.
2. Restart imatinib 400 mg since I am used to it and then switch to 200mg later? Or restart at 200mg?
3. Consider dasatinib? It will be hard to convince doctor to start at 20mg. Maybe start at 50mg? Are the side
effects more tolerable? I was used to imatinib 400mg but on TFR can feel the difference in energy levels.

Is another TFR attempt a possibility?

Thanks for all your posts all these years!

max1ml7, loss of MMR, 0.1, is considered relapse during a TFR attempt with restart recommended after you exceed that point. That standard was set during the Stop Studies

I recently posted that I have been TFR since October 2016 but haven't had an undetectable test since October 2017. The highest result I have had during that period was 0.015+. My doctor wanted me to restart Imatinib after my first positive detectable, in July 2017, which was 0.001. Fortunately I had read through and compiled the Stop Studies before starting TFR and knew differently

If you need to restart, after loss of MMR, 0.1, Imatinib 100mg should be all that you need to quickly regain undetected status.

Wishing you the best,
Buzz

Why you just dont just restarted the same dose and meds you have reached TFR?
I'm not sure what is the question exactly. You do the same dosage and meds and you might reach TFR again.
If not you change

Thanks for the responses.
Update - I took 200 mg imatinib for a month and that got it to 0.016. The side effects weren't too bad on 200mg.
I met with the doctor and we have decided to do 400mg till it goes undetectable and then try 200mg again.

The results of the Destiny trial indicate a correlation between holding BCR ABL stable at 200mg imatinib and the likelihood of success of TFR. Results discussed in this video by Prof Clarke from Liverpool who was the lead researcher. https://cmlsupport.org.uk/videos/reducing-or-stopping-treatment-who-and-...

Thanks for the link - very informative. I am hoping to be back on 200mg at some point and see if that holds like it has for you.

Update - I switched to 400mg imatinib and it went back to undetectable after 2 more months (so 3 since resuming).
I will continue with 400mg for some more time and then consider going back to 200mg.

I followed the Destiny protocol of 1 year on 200mg with sustained MMR before starting a TFR attempt. After 17 months of TFR my BCR-ABL rose above 0.1% so I restarted on 400mg imatinib and regained undetectable in 4 months. I stayed on 400mg until 1 year after restarting then reduced to 200mg and am still there and undetectable, and with little in the way of side effects.

Hope that is useful.

Alastair

De-escalation of tyrosine kinase inhibitor dose in patients with chronic myeloid leukaemia with stable major molecular response (DESTINY): an interim analysis of a non-randomised, phase 2 trial

Summary

Background
Discontinuation of tyrosine kinase inhibitor (TKI) therapy is feasible for some patients with chronic myeloid leukaemia with deep molecular responses; however, patients with stable major molecular response (MMR), but not MR4, have not been studied, nor has the effect of treatment de-escalation rather than outright cessation. We aimed to examine the effects of treatment de-escalation as a prelude to complete cessation, not only in patients with MR4 or greater, but also in those with MMR but not MR4.

Methods
We did this interim analysis of a non-randomised, phase 2 trial at 20 hospitals in the UK. We recruited patients (aged ≥18 years) with chronic myeloid leukaemia in first chronic phase who had received TKI for 3 years or more and were either in stable MR4 (BCR-ABL1:ABL1 ratio <0·01%; MR4 cohort) or in stable MMR (BCR-ABL1:ABL1 ratio consistently <0·1%) but not MR4 (MMR cohort) for 12 months or longer. Participants received half their standard TKI dose (imatinib 200 mg daily, dasatinib 50 mg daily, or nilotinib 200 mg twice daily) for 12 months. Molecular recurrence was defined as loss of MMR (BCR-ABL1:ABL1 ratio >0·1%) on two consecutive samples. The primary endpoint of this interim analysis was the proportion of patients who lost MMR on de-escalation and regained MMR on TKI resumption. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01804985.

Findings
Between Dec 16, 2013 and April 10, 2015, we enrolled 174 patients into the MMR cohort (n=49) or the MR4 cohort (n=125). During the 12 months of half-dose therapy, 12 patients (7%) had molecular recurrence, all of whom regained MMR within 4 months of full-dose TKI resumption (median time to recovery 77 days). Recurrence was significantly lower in the MR4 cohort (three [2%; 90% CI 0·2–4·8] of 121 evaluable patients) than in the MMR cohort (nine [19%; 90% CI 9·5–28·0] of 48 evaluable patients; hazard ratio 0·12, 90% CI 0·04–0·37; p=0·0007), but was unrelated to previous TKI or TKI therapy duration. Adverse events (eg, lethargy, diarrhoea, rash, and nausea) improved during the first 3 months of de-escalation, though not thereafter. 16 serious adverse events were reported, including one fatality due to worsening pre-existing peripheral arterial occlusive disease in a patient who had received only imatinib.

Interpretation
TKI de-escalation is safe for most patients with excellent responses to TKI therapy, and is associated with improvement in symptoms. These findings show that lower TKI doses might maintain responses in these patients, implying that such patients could be unnecessarily overtreated.

Studies of more ambitious de-escalation are warranted.

https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(17)30066-2/fulltext

The primary reason I posted the previous article on the UK Destiny Trial was to highlight the very last line in the report, that being: "Studies of more ambitious de-escalation are warranted."

200mg, or half-dosage Imatinib, was never meant to be the stopping point in dosage reduction, especially when the Destiny Trial TFR attempt lasted for a prolonged period of time, providing a very strong indication that it would only require a very minimal TKI dosage to maintain an undetected status in the future.

"TKI de-escalation is safe for most patients with excellent responses to TKI therapy, and is associated with improvement in symptoms. These findings show that lower TKI doses might maintain responses in these patients, implying that such patients could be unnecessarily overtreated."

Buzz