8 replies to this topic

[cousineg]

See New abstracts about CML  at ASCO 2013

http://www.cmleukemi...---chicago.html

[Pin]

Some very interesting research in there.

I have to say though, I was rather alarmed at Figure 1 in the article by Dr Mauro on resistance (see below for image: from p. 307, Mauro, 2013, Overcoming Resistance in Chronic Myelogenous Leukemia, Knight Cancer Institute, Oregon Health & Science University, Portland, OR.).

Can anyone confirm if this is the dominant current viewpoint amongst researchers on how mutations arise? I ask partly for personal reasons as this is something I am worried about, but also as this does not really agree with the theories or ideas that are usually discussed on this board - i.e., that mutations would likely show up anyway, that the newer TKIs may simply address mutations before they have the chance to arise if they are used first etc.

[rct]

I don't have CML, my Mrs does.

It is my experience with all of the oncs we have ever seen, including out where Mauro works, that they relate to me that the number one problem not only with CML but virtually all medical work is non-compliance, or in this case, poor adherence.  Number one.

It should be above both TKI limitations as we know them today and drug interactions/uptake problems caused by other medications.

When we saw Druker, the key, the number one thing, the absolutestestest mostestest ever important answer she had to give him was a truthful and honest answer to "Do You Consistently And Regularly Take Your Gleevec"?  It all went from there, and if she was not honest with her answer she could have changes to her regimen that might not otherwise be needed.

There was a guy here in this area, gave a sorta seminar, pep talk if you will, at the Gilda place.  He was on the team that helped move Gleevec from GIST to CML, worked with Druker, all that stuff.  Number one consequence causer during all of their work: Non-compliance.  Single biggest thing to overcome to get this to work: Non-compliance.  They had people with devastating, fast moving cancers suffering because of non-compiance, they didn't hold out much hope for such an indolent, slow moving form as CML.  From the time we started this whole thing in 2006 I have heard nothing but the words non-compliance, it can't be tolerated.

So we here on this forum, which is but a handful of the slightly larger handful of people that do this every day, we may have our views and what we think and then repeat are the reasons for mutation or failure of a drug, but the docs, whether they are saying it to patients or not, believe otherwise.

rct

[LivingWellWithCML]

So if a CML patient is compliant (i.e., consistent and regular with TKI dosing), and have a low risk of drug-to-drug interactions, then what other factors can contribute to "Altered Absorption"?  We, on this board, have talked about things like promoting an acidic environment in the stomach to -increase- absorption (like taking a Vitamin C supplement, which is something I now take along with Gleevec each morning), and perhaps there are other factors as well.  What are specialists like Druker and Mauro saying about this?

I (and I'm sure other CML patients) still get worked up about the things that I cannot control, but if there are recommendations/research that supports a way for us as patients to have at least some level of control around maximizing TKI absorption, then I'm always willing to try it.

Come on cells, please uptake this stuff......

[rct]

In my wifes case altered absorption happened because of the interaction of Gleevec with her thyroid replacement.  The Gleevec was messing up T3 uptake, took us a long time to get that sorted out because they don't think of that problem going the other way, but it happens.  Other than that, the PCR will tell you if there is altered absorption of TKI, or reason to suspect it.  If all is good with the PCR, all is good, that's what Druker would tell you.  "You can't get any gooder than good".

rct

[Trey]

Sad to say that is a dumb chart from Dr Mauro.  He is essentially saying that both kinase mutation and non-mutation resistance (i.e., all forms of resistance) are directly caused by "below threshold" drug levels in the leukemic cells.  There is no evidence to support his theory.  Do all leukemic cells have the same amount of drug in them?  Of course not.  Patient evidence from about 15 years of Gleevec use supports other theories, especially that the mutations or the predilection to such mutations exist from the beginning.  But none of the theories are proven or even provable.  Most people  who develop a kinase mutation do so within the first couple years, which strongly implies that Dr Mauro is incorrect in my opinion.  I have also seen some of the best TKI drug experts change their minds about this issue in recent years, meaning that Dr Mauro is still pushing an outdated theory (again, my opinion based on observation). 

If Dr Mauro were truly worried about this issue he would push drug intake at least twice per day instead of only once per day.  Leukemic cells are exposed to a constantly cycling level of drug in the plasma, and there is no evidence to suggest that there is a lower "threshold" for drug levels which will prevent kinase mutations. 

If the cells have poor drug uptake, then the drug will be less effective.  The various TKI drugs have different methods of getting into the leukemic cells.  Gleevec  uses the hOCT1 pump.  Sprycel and Tasigna use other methods. 

By the way, most drug resistance is NOT caused by kinase mutations.  That is even more reason to doubt his theory that all forms of drug resistance are rooted in low drug levels. 

I have previously discussed this issue in more detail including the following:

1) The NCCN CML Treatment Guidelines authorize low dosage TKI drug dosages. 

2) Leading CML Oncs regularly authorize reduced TKI drug dosages (Dr Cortes at MDA has patients such as our Michael on 15% dosage -- is he trying to induce mutations to perform some evil experiment?  If so, can we watch?)

3) Dr Druker has changed from worrying about low dosage TKI drugs a few years ago to authorizing low dose Gleevec for long term "maintenance therapy" after several years PCRU, as reported by one of our members here.

4) Most kinase mutations occur while patients are taking full dosage TKI drugs (from what I have observed on this L&L website).

5) There are over 100 known kinase mutations, and most do not prevent the TKI drug from working, although they can sometimes reduce effectiveness, and only a very few can prevent the TKI drug from working.

6) Our TKI blood level concentrations change all day long.  Peak concentration occurs a couple hours after taking the drug, then it declines continually until the next dose.  So aren't we all on "half dose" or less most of the day and night?  Why isn't that a problem if the theory of low dosage mutation applies? 

I would want to hear Dr Mauro explain why he believes TKI drugs and antibiotics act the same way to cause "mutations" (hint -- they don't).

[CallMeLucky]

Quite scary indeed.  I guess in two weeks I'll know if I am a supporter of Mauro's theory.  I so regret lowering my dosage.  I feel like I took my foot off the snake's neck and I got bit.  My whole point of lowering my dosage was to improve my quality of life.  My QOL right now is the worst it has been with the stress I am under.  Even if I it turns out nothing is wrong, it will not have been worth it to go through this.  And if something is wrong, then I will only have myself to blame.....

[Pin]

RCT - thanks, I completely agree that medication compliance is a really important issue - it was the first thing they asked me when my results started slowly increasing, and for good reason. It is also, as Dan has said -  the only thing over which we as patients should have total control. I guess what I was wondering about is the concept that this, as well as altered absorption/drug interactions can actually 'cause' mutations. I don't see a lot of research supporting this - and clearly it is because it is a difficult thing to demonstrate - you can't ethically run an RCT where patients are randomised to a condition where they deliberately skip doses and eat interfering medications so we can see what mutations the participants in each condition develop. So we make inferences, logical arguments, and educated judgments based on what we know and what we don't yet know.

Thank you for providing your wife's experience as well - it is always useful to hear of people who have had unusual experiences with things doctors aren't expecting or are simply 'unlikely' so they ignore them.

Trey - thank you for summarising your opinion on this so succinctly. I know I have read these arguments you presented before, I had sincerely hoped that this you had not changed on this issue since this article was only just published - please excuse my (potentially) Gleevec-related amnesia! Maybe Dr Mauro simply republished an old diagram without giving it too much thought - it wasn't discussed in any great detail at all in the paper - hence my question here.

Lucky - that is what I'm getting at - surely we can't blame ourselves. I don't want to - but occasionally things pop up like this article, and what my doctor last said to me - that stick in my mind more than the alternative. Trey's arguments and the opinion of your doctor are both sound. It makes little sense that very small populations of bcr-abl would mutate because they don't have enough drug . It seems more likely that the larger your population of cells, the more likely one of them is going to have a spontaneous hissy-fit, and would be there from the beginning when there were much larger numbers of cells (more chances of a mutation maybe?). It seems logical that the longer you are under treatment, the less likely these mutations are to occur purely on a numbers basis.

[rct]

Trey wrote:
6) Our TKI blood level concentrations change all day long.  Peak concentration occurs a couple hours after taking the drug, then it declines continually until the next dose.  So aren't we all on "half dose" or less most of the day and night?  Why isn't that a problem if the theory of low dosage mutation applies?  

Remember the brew ha ha about level testing?  heh.  What am I asking, of course you do.  Paranoid old guy conspiracy theorist in me chuckles now that you ask and they just look at you blankly.  Whatever agenda somebody wanted to push on the poor sufferers of this stuff didn't work out, and you just don't hear about it anymore.

rct