74 replies to this topic

[story]

I am excited about this new TKI stopping trial. I have wanted to join the ranks of the the "TKI stoppers"

(we need a better name for this, creatives please step up) for a year or more but my onc will not go along if I am not in a trial. Thanks for mentioning the trial, just called to begin the process. I have been PCRU since Nov 2011. Taking Tas and tired of feeling like shit all the time.

[scuba]

I am excited about this new TKI stopping trial. I have wanted to join the ranks of the the "TKI stoppers"

(we need a better name for this, creatives please step up) for a year or more but my onc will not go along if I am not in a trial. Thanks for mentioning the trial, just called to begin the process. I have been PCRU since Nov 2011. Taking Tas and tired of feeling like shit all the time.

 

I just came back from M.D. Anderson today and asked this very same question - why TKI stoppage has to be in a formal trial. I was told this is not the case (at M.D. Anderson) - she told me they have many patients who are now off their TKI for a variety of reasons including stopping because they achieved complete cytogenetic response, MMR or PCRU (undetected). Most, however, stop because of side effects that are too burdensome and they are more concerned about lack of compliance without proper monitoring.

The only requirement is monthly PCR testing. I thought I was alone in this (i.e. stopping because I wanted to after only six months of PCRU instead of the normal two years). The admin told me, "no - you are not alone". And I thought I was special.

 

I asked about the European trials and was told in an email response:

 

"Thanks. I am well aware of the French and other trials. Also, as I mentioned, this is not a trial of one. We have good experience with this issue ourselves."

 

I feel I am in good hands with my "experiment". Apparently not an experiment of one.

 

So far so good - month 3 no TKI, just my extra Curcumin and vitamin D3 - I will get my next result in a few days. I still feel I have a 50-50 shot I remain MMR/PCRU.

[Frogiegirl]

Beleive me scoobs.....you are berry berry "special".....fingers are crossed for ya

[AllTheseYears]

I appreciate this discussion. I've been contemplating stopping my Gleevec for a while now. I've been undetectable for years. No decision yet, but plan to open the discussion again with my doctor. I particularly appreciate the links about the trial. Thanks.  BTW, I have a proposed name for this thread/discussion:    "GoodbyeTKI."  

[story]

GoodbyeTKI, I love it! Heading over soon for the initial consult for the trial, thanks Mikefromillinios for mentioning it. I used to research the trails but got kind of apathetic. I am excited to see what happens...

[Pin]

I'm interested in people's opinions about stopping (or dose reducing) when not technically 'undetectable'.

 

Here's my history:

 

 graph.png   10.49KB   0 downloads

 

Note: I used to ask for the 'exact measure' below 0.001, but I don't bother anymore given they are not that accurate, and I never seem to be undetectable anyway. I had a blip around 15 months which lasted 8 months where I had monthly testing (0.013, 0.032, 0.021, 0.01, 0.014, 0.016, 0.026, 0.041), and I then dropped back down again after that (data omitted from the table).

 

Would you ask for a dose reduction in my case? My doctor is not keen on that, or on stopping - unless I promise to try and get pregnant...Personally, I'd rather try stopping first and see what happens, and then think about whether I'd be happy to do it for a full 9 months (or longer!).

 

Reducing would be about side effects for me - I think it would greatly improve my life. But I am nervous given my history. Stopping would be purely experimental.

[gerry]

Pin,

Have you tried splitting the dose, 200mg in the morning 200mg at night to see if that reduces your side effects?

 

They are trialling people stopping who are only MMR in the UK, but you'd need your doc on board for this as you need monthly testing, particularly for that first six months.

 

There is aways switching to Tasigna, though it it a bit harder for us if you want to switch back to Gleevec. Though I don't really know of too many people who have gone back to Gleevec from Tasigna.

[scuba]

I'm interested in people's opinions about stopping (or dose reducing) when not technically 'undetectable'.

 

Here's my history:

 

graph.png

 

Note: I used to ask for the 'exact measure' below 0.001, but I don't bother anymore given they are not that accurate, and I never seem to be undetectable anyway. I had a blip around 15 months which lasted 8 months where I had monthly testing (0.013, 0.032, 0.021, 0.01, 0.014, 0.016, 0.026, 0.041), and I then dropped back down again after that (data omitted from the table).

 

Would you ask for a dose reduction in my case? My doctor is not keen on that, or on stopping - unless I promise to try and get pregnant...Personally, I'd rather try stopping first and see what happens, and then think about whether I'd be happy to do it for a full 9 months (or longer!).

 

Reducing would be about side effects for me - I think it would greatly improve my life. But I am nervous given my history. Stopping would be purely experimental.

 

Pin - It would be wise to have your doctor on board with your "experiment". It's possible he is not familiar with the rates of success and risk associated with trying to stop when a patient is in MMR or PCRU. You achieved MMR quickly and remain so - one log lower in fact overall which is excellent. But you need your doctor to agree to monthly PCR testing during your cessation. Explain the importance of you wanting to get pregnant and that you understand the risk of stopping. Explain, if he doesn't know, that the risk of non-controllable progression while you are in MMR is very very low (I call it zero). Ask him if he is familiar with the cessation trials now underway.

 

Alternatively, you could reduce your dose first and see how you respond (also will need doctor support). This can be a time consuming process as you will have to wait 3 months between tests, but is a very viable first step. I was on 1/5th the normal dose and was able to achieve MMR/PCRU very quickly once I got things under control. Going from such a low dose to no dose was a pretty straight forward decision for me. But I am a prudent risk taker. 

 

My last sentence above is an important point (which has also been driven home to me by members of this forum - that stopping therapy does have emotional if not physical risk). It is not for everyone. Even I - a risk embracing, stare danger in the face kind of guy - had a thought provoking second guessing of myself that first night I went without my TKI. Waiting for my first PCR result was even more intense. I even had a one time feeling of "I must be nuts to do this". These feelings were fleeting for me and has long since faded of course, but that has come with experience.

 

You have to be confident in yourself with family support that you are making the correct decision  for you and are at peace with it. You have to feel you know what you are doing. A member of our Forum, Trey, is as close to expert as one can get when it comes to CML, its treatment and results. He has been PCRU for 10 years with an excellent profile (reached PCRU very quickly). He is a perfect candidate to try cessation and would be accepted into any 'formal' trial - but even he won't try stopping his drug therapy to test durability of cessation. He did reduce dose and continues to do fine. Side effects for him are not a consideration when compared to the "danger" he feels he will expose himself if he were to stop.

 

The good news is that cessation can be a viable path in dealing with side effects for patients who have had excellent drug responses (at least MMR - preferably PCRU) and there is growing data and experience with it. More doctors are prescribing cessation as a treatment for side effects - even temporary interruptions (as in pleural effusion for Sprycel) without fear of progression. What is important is monthly PCR testing and monitoring. You must be vigilant and watchful for that upward tick in PCR should it occur. Trey believes I will have an inevitable uptick - and he may very well be right. But to have a month of no TKI is a reward in itself for me. I'll take it a month at a time. In your case you would like 9 straight months of no change during your pregnancy and perhaps you'll never have to take a TKI again.

[Trey]

It is a personal choice.  If you really, really want to get pregnant and feel you are running out of time, that would drive a decision which otherwise would not be as acceptable.  If the pregancy is important, this might be the time to take a prolonged drug break and do that because of your time constraints, but the risks are not certain.  The natural higher levels of interferon that come with pregnancy might help. 

 

If you never split dosage as Gerry asked, that is always a good idea for Gleevec.  I would do that first (unless you prefer the pregnancy route).  It also seems from your history you could reduce dosage, and if you get the 100mg pills that is easy to reduce in 100mg increments over time. 

 

Cessation is the highest risk approach.  The one blip may be lab error, or it could be real.  And the < "less than" results are uncertain whether they are real or false positives.  Overall it depends on your risk profile.  I also answered your question about patience and remaining on longer term low dosage to exhaust leukemic stem cells, so that is a factor to consider. 

 

You have options, and they would all seem to be acceptable, but with varying levels of risk. 

Edited by Trey, 22 May 2015 - 10:54 AM.

[Pin]

Well, I had a fascinating conversation with my haematologist about this. I really thought she would not be on board with the whole idea of testing out stopping. Boy, how things can change in 3 months! Last time I asked, I was told a flat out no to stopping (without the immediate intention of getting pregnant). This time, she was really open to the idea - she said that at my level, they consider it to be essentially equivalent to not detected (interesting - she's told me this before, but this time I actually believer her), and that I've almost been at that level for 2 years, so if I wanted to try stopping for pregnancy - or taking a medication break (as she called it), I could. In 3 months. I nearly cried. Actually, I did, but just a little bit.

 

She said loads of patients are now having short breaks in medication (for side effect reasons) who have my level of response, and they put them back on after and they regain their response. The risk, from what they can currently tell, seems to be minimal.

 

Interestingly, she was more interested in letting me have a full break, rather than reducing (only "because there is more data on this" though). I hope soon, there can be more data on reducing. We all know that so many of us (who are not in trials) can successfully reduce e.g., Trey. And I do enjoy Trey's theory about why that works, and why it's not like antibiotics. She said there is still debate about that in professional circles - the whole resistance issue and reducing medication - so I thought that was interesting. I think I would feel more comfortable reducing personally, but who knows. I guess I have to have a real think about this now!

 

I do kind of think that being patient is the way to go - I'm very lucky to have the response that I have and I'm not in any rush to get pregnant, despite my age. What I'd really like to know is a prediction of how long we need to wait in order to exhaust all the stem cells, but I imagine there'll always be a chance we didn't wipe them all out...need more research I guess!

 

Ps. Unfortunately, splitting the dose has never really helped with the types of side effects that bother me Fluid retention, cramps, skin issues, dry eyes, stomach pain, none of those things seem to really be helped. I think that it can work better with the short term effects like nausea and diarrhoea maybe.

[pammartin]

Pin, I had tears when I read your post.  You have been through the wringer and back again.  It is wonderful to realize and to hear there are options. 

 

I still find it interesting Cleveland is on board with stopping a TKI but not as interested in lower dose for maintenance purposes.  Like you mentioned, there is information on people stopping, I guess not as much for lower doses and remaining undetectable.  e

 

It is wonderful to have options.  I am sorry you still have so man side effects from the TKI.  That has to be horrible, and with no end in sight very frustrating.  Hang in there.  Lot's to think about.

 

Take care

[kat73]

My oncologist is a CML expert.  In fact, he is on the committee that writes the NCCN guidelines.  When I recently asked him if I couldn't reduce my dosage of Sprycel, he said no.  When I asked why, he said, "How do you think we create resistance in the lab when we want to study it?  We underdose, let the leukemic cells grow out, then underdose again, and so on until we have created resistance. The most difficult cells are the ones that are left."  He further said he would be more comfortable with a complete break than a reduced dosage, the logic being that there is no specific selection of extra strong surviving leukemic cells involved in that.  He's not a jerk.  He believes in a balance, for every individual patient, between reducing troublesome side effects by reducing TKI dosage and making sure they're getting enough to be therapeutic.  Shortly after I came to him, he reduced my Sprycel from 100 to 70mg to see if my counts would come up and side effects lessen.  (This was after a couple of years on Gleevec at another place, and after the initial Sprycel had given me an impressive immediate drop.)  My counts came slowly up to just under normal or low normal, the side effects did lessen a bit, and my PCR continued to slowly but continuously drop.  In other words, he was willing to reduce the dosage for me under these circumstances, but not just because I wanted to try and get as little TKI in me for the next decades as possible.  I'm glad to hear that there are some professional differences about this, but it has always worried me that Trey feels TKI's are NOT like antibiotics and resistance does not arise in the same way.  Trey, could you explain your reasoning again?  BTW, this is my first post, so I hope I've done it right.  I think I forgot to put in my name in the registration, so I'll sign this.

kat73

[Trey]

Kat,

Welcome.  About 7 years ago every CML expert agreed with your Onc.  This is about when I offered the analogy of resistance and how TKI drugs are not like antibiotics, so low dosage in a stable patient is not a cause of resistance.  Here is a recent discussion where I explain this analogy:

http://community.lls...ics#entry159133

 

Today very few CML experts agree with your Onc.  Dr Druker and Dr Shah no longer believe that low dosage leads to resistance, although I asked both of them that question several years ago and they both said low dosage could cause resistance.  Now they both prescribe low dosage when it is warranted, so they no longer believe that low dosage leads to resistance.  Most CML experts now believe the resistance, if it is going to develop, is in the CML cells from the beginning (not all CML cells are the same), and that over time IF there are resistant cells, they become the ones remaining after the non-resistant ones are killed off.  So the resistance comes to the forefront over about 2 years, but that does not mean it was developed.  This is why I have often said that the first two years of CML treatment are the ones where relapse while taking TKI drugs is most likely.  After two years relapse is unlikely if the patient is stable CCyR or better, but it still occurs in rare cases. 

 

So your Onc's description of how resistance is "developed" actually shows how relapse is brought to the forefront, not developed.  The resistance in lab cells is usually there since most CML lab cells come from blast phase patients such as K652.  But there is a second issue when too little drug does not keep the CML in check and the CML advances, and in that case resistance is actually developed as the cells enter Accelerated and Blast Phase CML.  So I agree with your Onc that resistance can be "developed" by causing the CML cells to mutate and advance in Phase.  But that was not my analogy to antibiotics since I was not discussing encouraging and allowing the CML to advance to Accelerated and Blast Phase.

 

This does not diminish the capabilities of your Onc, since I am sure he is excellent.

[gerry]

Hi Pin,

I'm glad there is some light at the end of the tunnel.

As I've mentioned before my doc was very strong on the "got to keep hitting it hard" when I first started seeing him. I continued to have discussions with him about changes to my treatment as the CML reduced. I wound up being his first patient on reduced dosage and then his first one to stop taking a TKI.

 

I take it you've got three months to work out which way you would like to go. I'd probably still start the conversation with her on reducing dose to see if there has been more data come through the next time you see her.

[jjg]

Hi Pin, One thing to be careful about stopping in the Australian system is how our scripts are approved. I'm not totally on top of it but my understanding is that when our docs send the script off to Tassie for that stamp they have to send a copy of our PCR results (probably some crappy paper photocopy of a dodgy fax, roll eyes) to show that we are responding to the drug the tax payer is funding. I think that they only have to do this for every second script. If the results show an upturn the paper pusher in Tassie may not be flexible to understand that this was because you trialed going off treatment or stopped for a pregnancy and may say that you are no longer responding to gleevec and not approve the script. Possibly your doc can spend a lot of effort to get around this but it's best avoided. When I stopped in 2012 I was soooo over gleevec side effects that I was more happy to switch to tasigna so that upturn in my PCRs didn't need to be explained. You seem to be very keen to stick with gleevec, so the ideal time to stop is just after you get a new script and make sure that that script had a copy of your PCRs with it. Then if you do have an increase above MMR you have a year to go back on gleevec and demonstrate a response before requesting the next script that needs PCR results.

 

Another thing to think about is if you are eventually planning to get pregnant age is unfortunately not something we can ignore. I can't remember your age (late 20s?). The current (not well evidenced) recommendations are to stop treatment before or at least at conception. So depending on how conservative you are (risk to baby v risk to you) you are looking at a min of 2-4 weeks off treatment before confirming a pregnancy. But the main delay is that even young healthy women on average require a few cycles to get pregnant. The older you are the longer on average it takes to get pregnant but this depends on the age of the eggs not the age of the uterus. Ideally you want eggs from your 20's but most definitely before 35. So if you are planning a treatment break it could be an opportunity to store some eggs/embryos that a) in the future can help you get pregnant quicker, are definitely not damaged by the TKI and c) give you time to deal with the CML without worrying about what is going on with your fertility. Unfortunately this is not cheap and it's hard to spend money on IVF when you may be able to do it naturally. At least you will be able to access the PBS for fertility preservation.  In a way this is none of my business but as I was dx at 37 you have options that I wish I'd had and so I wanted to make sure that you had the opportunity to think about it.

[jjg]

Hi Pin, One thing to be careful about stopping in the Australian system is how our scripts are approved. I'm not totally on top of it but my understanding is that when our docs send the script off to Tassie for that stamp they have to send a copy of our PCR results (probably some crappy paper photocopy of a dodgy fax, roll eyes) to show that we are responding to the drug the tax payer is funding. I think that they only have to do this for every second script. If the results show an upturn the paper pusher in Tassie may not be flexible to understand that this was because you trialed going off treatment or stopped for a pregnancy and may say that you are no longer responding to gleevec and not approve the script. Possibly your doc can spend a lot of effort to get around this but it's best avoided. When I stopped in 2012 I was soooo over gleevec side effects that I was more happy to switch to tasigna so that upturn in my PCRs didn't need to be explained. You seem to be very keen to stick with gleevec, so the ideal time to stop is just after you get a new script and make sure that that script had a copy of your PCRs with it. Then if you do have an increase above MMR you have a year to go back on gleevec and demonstrate a response before requesting the next script that needs PCR results.

 

Another thing to think about is if you are eventually planning to get pregnant age is unfortunately not something we can ignore. I can't remember your age (late 20s?). The current (not well evidenced) recommendations are to stop treatment before or at least at conception. So depending on how conservative you are (risk to baby v risk to you) you are looking at a min of 2-4 weeks off treatment before confirming a pregnancy. But the main delay is that even young healthy women on average require a few cycles to get pregnant. The older you are the longer on average it takes to get pregnant but this depends on the age of the eggs not the age of the uterus. Ideally you want eggs from your 20's but most definitely before 35. So if you are planning a treatment break it could be an opportunity to store some eggs/embryos that a) in the future can help you get pregnant quicker, are definitely not damaged by the TKI and c) give you time to deal with the CML without worrying about what is going on with your fertility. Unfortunately this is not cheap and it's hard to spend money on IVF when you may be able to do it naturally. At least you will be able to access the PBS for fertility preservation.  In a way this is none of my business but as I was dx at 37 you have options that I wish I'd had and so I wanted to make sure that you had the opportunity to think about it.

[kat73]

Thanks very much, Trey.  As usual, you have advanced my understanding by several logs.  So, in English major fashion, I will make a story for myself - the model is NOT:  you knocked the bully flat, but he woke up madder than ever and came back at you with new weapons and you have only your fists.  Rather it is:  you mopped the floor as clean as you could see, but there might have been a little mold, say, left in the corner which, over one or two years, grows until you can now see it, and your detergent doesn't seem to remove it.  So you switch to a new detergent that kills it and keep mopping. You keep mopping, in fact, for a lotta years!  But the floor stays cleaner and maybe after awhile you can use less detergent and still get the same results.  

 

Personally, I was an immediate rabbit on Gleevec at diagnosis in 2009, then slowed to become a turtle, missing the MMR guideline goal by 4 months, became a rabbit again by switching to Sprycel, and then turtled ever downward to land in limbo - MR3.5 to MR4.5 land, where I've toggled for about 3 years.  I know how good this is and I'm grateful. But as of 2015 the bar is still officially set at PCRU for a sustained period before any talk of reducing dosage to lowest levels or even stopping can be entertained, at least by MY oncologist.  So I plod on.  I follow everyone's different experiences on this dosage reduction/stopping topic with great admiration and tremendous interest, and am amazed at the range there is among the oncologists' approaches.

 

Mop on!  

[Pin]

Thank you for all this info and advice jjg- I will certainly ask my doctor about the script approval. I thought they may have relaxed the strictness around this now, but a very important thing to ask about!
Tasigna has been way better for you hasn't it? I'm not totally against changing, but there are a few things that put me off about it if I'm honest. Mostly that I am afraid of change, especially if I can't go back. Will have to ask about that issue too.
Still not sure what we will do, my head is still spinning a bit from all the info. I probably won't know in 3 months either...well, no rush on stopping for the sake of it I guess. Just the other stuff is a problem. Might be worth investigating if I do have a break, the issue of storage...

[gerry]

Well worth asking about the Tasmanian thing, I checked with my doc when a script seemed to take a long time to get to me. I'm sure the doc told me they don't get sent to Tassie anymore, they were just a bit slack at the doctor's office instead.

[gerry]

Myeloid Derived Suppressor Cells in Chronic Myeloid Leukemia Abstract

The suppression of the immune system creates a permissive environment for development and progression of cancer. One population of immunosuppressive cells that have become the focus of intense study is myeloid derived suppressor cells (MDSCs), immature myeloid cells able to induce immune-escape, angiogenesis, and tumor progression.

http://www.ncbi.nlm....les/PMC4432672/