I'm failing to achieve optimal responses by a small amount placing me just inside warning territory. My consultant told me yesterday that if I were to move to a second generation TKI, I could not move back to imatinib. I didn't think to ask why this is the case. Does anyone know, please, why there is no return path?
You are here
"Cannot move back to imatinib from second generation TKI"
Here's another paper I had saved that discusses TKI rotation.
The title of the paper is: TKI rotation-induced persistent deep molecular response in
multi-resistant blast crisis of Ph+ CML.
"In conclusion, we present a patient with TKIresistant
multi-mutated blast crisis and a Ph-negative
sub-clone producing severe BM fibrosis, in whom we
induced a continuous CMR with TKI-rotation therapy
complemented by HU, without major side effects. Such
treatment strategies are in line with personalized medicine
[24] and recent developments in the field [28] and may
lead to the design of new improved treatment concepts
in TKI-resistant CML. Eventually, such novel treatment
concepts may also assist in the early eradication of all
relevant CML sub-clones at diagnosis, so that it may be
possible to switch back to a less-toxic TKI at CMR, and
later discontinue TKI therapy in most patients with (even
advanced) CML in the future."
That's nonsense. You absolutely can go back to imatinib after trying a different TKI.
If you strictly follow ELN guidelines you'll find that there's no specific treatment path that allows for this, but that's a quirk of it not covering every conceivable situation rather then any clinical reason you can't go back to imatinib.
David
Thank you, David, for your usual "to the point" response. I think that you're right: it may be that there is a tendency to follow the ELN guidelines to the letter. I think that the consultant was on the pivotable point of deciding between continuation with imatinib and a move to Dastatinib. I'm not quite reaching the ELN targets so dependent upon the nine-month results and mutation tests, the next move remains questionable.
Making a move to dasatinib, in your case, is a good move. Given you already have a response on gleevec (although not optimal), dasatinib is very likely to crush the remaining resistant clones. It works very differently than imatinib by attacking higher order cells (pluripotent) which are causing residual CML.
One thought for you to consider - do not switch to 100 mg dasatinib. That is old thinking. New research suggests strongly that 50 mg is a better starting dose especially since your disease burden is already reduced. More is not better in regard to dasatinib. You may find you have a dramatic response downward with 50 mg providing an opportunity to lower dose further (20 mg). You will avoid many of the side effects associated with dasatnib and have a smooth transition. You can always increase dose if 50 mg is not your threshold (but I strongly doubt that will be the case).
I am on 20 mg dasatnib and this dose alone brought me to PCRU (after imatinib failed). I have no side effects I can feel. And this dose was prescribed to me by one of the four top leukemia researchers (CML expertise) in the field. I asked him why not 100 mg dasatinib and he replied that dasatinib can suppress our normal immune function against CML at the higher dose (100 mg) and by finding the sweet spot for a patient (50 mg typical) he has observed better results. His approach is to start low and work up! (exact opposite from the current protocols). He re-started me at 20 mg and that was it (been at 20 mg for years). As long as you have time to experiment (i.e. few blasts / in chronic phase), finding the lowest dose that works is a wonderful way to help patients minimize side effects.
You can always go back to imatinib if dasatinib doesn't work (David is absolutely correct on this point) although switching to yet another TKI first before going back to imatinib would be better. Cycling through TKI's is gaining traction in research and in the case of the authors cited below - standard practice.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142480/
(The lead author of this research article is my oncologist.)
Thank you, Scuba, for your reassuring response. You have provided a lot of information for me to use when I next visit the haematologist. The decision will now be made when I receive my nine-month results. Personally, I think that I would have opted for the move to Dasatinib at this stage. My haematologist is calling for mutation testing.
I agree, I was on Tasigna, then imatanib, then tasigna again, and stabilised finally on imatanib
Scuba:
Where in Dr. Cortez article does it state that rotating TKI's has become standard practice? As I read the article, it says more study of this needs to be done: "until data become available from prospective trials showing that change in therapy at 3 months meaningfully changes long-term outcome for a significant number of patients compared with continuation of unchanged therapy, or change at a later time point (eg, at 6 or 12 months), changing to a second-generation drug at 3 months for patients lagging behind scheduled efficacy end points (eg, BCR-ABL1 >10% IS) remains investigational.
I am currently on 150 mg/day nilotinib having started treatment in Oct 2016 on 300 mg nilotinib 2x/day. I was a very early responder, reaching MMR in 82 days and have been at <.003% for nearly 2 years now. Nevertheless, mild grade A/E's persist - mild dry mouth, folliculitis, and most recently a re-emergence of persistent heart arrhythmia that is benign but negatively affecting my QOL. I am thinking seriously about 3 alternatives in an attempt to resolve these A/E's, particularly the arrhythmia:
- 1 - 2 week drug break - I have done this once before and it was helpful in that it provided a reset on the heart issue at least for a while. Of course, I'd really like to try TFR, but I haven't been on treatment long enough for my doc to sponsor me in this. Plus, the data from DESTINY and other trials clearly shows that TFR chances improve with length of treatment, so I am thinking I will wait until I have been on treatment for 5 years before trying.
- Swtich TKI's to either imatinib or dasatinib for 2-3 months and see if old A/E's resolve and/or new ones appear.
- Proactively rotate TKI's every 2 - 3 months - imatinib, nilotinib, dasatinib
Would appreciate your comments on this as well as others - thanks
In your case, switching off nilotinib in order to test getting rid of arrhythmia's is worth trying. You should consider a low dose dasatinib (20 mg) which very well could keep you at MMR or better as you tack on the years leading to a TFR test. All TKI's can have AE's related to the heart. Nilotinib is one that has the highest impact in that regard. Getting off Nilotinib is smart.
Also - focus on nutrition that helps your electrolyte balance so you give your heart a helping hand. Magnesium/potassium/calcium and sodium are key (along with Co-Q10). Of the above, Magnesium and potassium are usually in short supply. I take 400 mg Magnesium taurate per day (mostly before sleep). Calcium is usually plentiful in food if you eat dairy (cheese especially). Potassium is fine also if you eat a lot of fruit and veggies. If you use salt, you have plenty of sodium. I find myself taking 1/4 teaspoon of himalayan salt per day (mixed in a glass of water) because it is dried sea water and has the minerals in correct proprotion. I find it calms my heart. My wife calms my heart too - so that helps.
(rotating TKI's is standard practice for Dr. Cortes and his team when faced with difficult cases. In your case, just switching to a different drug may be all you need: Additional info on rotation: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410285/)
Thanks Scuba - I am going to have this conversation with both my GP and my oncologist and see what they say. I already do all the other stuff you suggest plus 2 miles per day 5 days a week on the treadmill. My cardiologist said I have the cardiovascular system of a 30 year old (I turn 66 next month) based on nuclear stress test and treadmill score late last year.
If you work outside watch out with Tasigna. I can't take Tasigna because I work outside in the sun and it gave me very bad rashes and sun burn. i had to wear 70spf sunscreen and find long sleeve tshirts made by Columbia that had SPF protection so that I didn't break out in a rash. Also watch your body wash you use in the shower. I had to switch to a all natural oatmeal bodywash otherwise my chest and neck would be real red and itchy for hours .