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Any consequences of Gleevec dosage shuffle?

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Hi, group. I've been on Gleevec for 15 years. Most of that time I was on 400mg. For the last two years though, I dropped down to 300mg. However...

For the past month I jumped back up to 400mg because of concern about PCR results, but because of increased side-effects (and my likely overreaction to those PCR results), I'm considering going back down to 300mg. My question is: Does spending a month at 400mg and then dropping back to 300mg create any potential for resistance or mutation issues? In other words, does shuffling dosage levels in such a short timeframe create a situation that could give the disease a new advantage on me?

 

Hi William,

No it should not cause any issue. The DESTINY trial showed dropping dose, then later increasing it again was safe. There’s no particular problem with the time-frame this is in.

David.

Thanks for pointing me to that trial. Much appreciated!

I understand what DESTINY is showing, but does anyone know if TKI resistance has ever been shown to be caused by too-low dosages or noncompliance with rx (similar to what might happen with antibiotics)? Or is TKI resistance only caused by genetic factors?

Really good question - there seems to be a great disparity of belief about this issue.  I for one would love to know the correct answer.

TKI resistance is ONLY caused by genetic factors (mutation). There is no such thing as 'resistance' when it comes to cancer. It is in no way similar to bacterial resistance.

As it is, our TKI treatment is not a cure. Enough CML cells, particularly leukemic stem cells, remain that can restart disease. If response to a TKI is lost - it is most likely due to either a dormant CML clone dividing or a genuine mutation changing the nature of the disease. Fortunately, for most mutations that can occur, there is a specific TKI.

Lowering and or raising dose of a particular TKI once CCrY is achieved will make no difference in terms of mutation. Finding the lowest effective dose which works for you is a best practice.

Keep in mind - even at "undetected" levels of residual CML disease there is a probability of a million CML cells still alive. If resistance was possible, we would never have remission let alone 'renewed' response when the same TKI is re-introduced.

Cancer - all cancers - is a failure of our immune system. TKI's pick up where our immune system has failed. There is evidence that for some patients, (45% of PCRU patients), reducing the initial CML tumor load is sufficient for their immune systems to regain CML control leading to treatment free remission. A true cure lies in immune oncology where cancer is checked every time it appears.

Thanks Scuba, but please advise whether or not the chance/risk of mutations increases if one drops below the threshold level of their TKI, in other words, if there are more CML cells circulating, dies this increase the probability of mutations occurring? 

CML cell growth is a population dynamics problem (which can be mathematically modeled). In a healthy / normally functioning immune system, CML cells are likely formed spontaneously in small numbers. Population is very small and proteins they secrete trying to tell the body's immune system - "hey - i'm part of you - don't attack" are too little to be effective.. A normal immune system recognizes the bad cell and either kills it directly (T-cell attack) or circulating proteins enter the cell and cause it to self-destruct (apoptosis).

When CML cells grow in population, however, they emit a sufficient amount of protective protein that causes T-reg cells to protect them from the immune system. This is how CML expands (and most cancers as well). It creates a cocoon of T-regs which run interference against T-NK cells.

Under normal conditions, CML population is controlled by the immune system and normal people would never even know they have bcr-abl circulating around. It gets created and then destroyed.

We, who developed CML disease, did so either because a sudden spontaneous large population of bcr-abl cells were created all at once (radiation can do this - that is what I believe happened to me) or it's possible, the immune system weakened enough so that the few CML cells that were created were able to expand and the population was too great to be controlled on its own.Either way, the population of CML stem cells became great enough in number to be self-sufficient and evade immune surveillance.

Enter TKI's.

TKI's are like a flea bomb. They augment the body's CML cell population control precisely by entering the CML cell, attaching to the ATP energy site which causes the CML cell to self-destruct during division.

By having enough TKI present to cause the population of CML cells to trend down, a new population equilibrium is established. If the new equilibrium is around PCR ~ 0.1%, data suggests, CML does not progress. Keep in mind, CML cells are always dividing; in the presence of TKI, some, not all LSC's, get killed. As long as we take our TKI, the population of CML cells is greatly controlled at a very low residual level. The reason it is not zero is because Leukemic CML stem cells re-populate the killed daughter cells. TKI's do not affect dormant LSC's.

Regarding mutations.

TKI's are designed for a specific gene arrangement of CML which kills that cell type only.  Those cells on their own do not mutate. They are already differentiated. It is the stem cells and daughter stem cells which can mutate. Either a pre-existing population of mutated stem cells already exists or a new population of mutated cells gets started. The fact that LSC's can stay dormant for years is a likely source of mutation. Fortunately this is rare.

The reason the 'odds' of CML mutation and subsequent relapse is unlikley when CCyR levels drop to zero (i.e. FISH = zero; PCR ~ 1.0%), is because LSC population is also reduced. Keep in mind, every time an LSC divides, it is killed in the presence of TKI. So by the time FISH = zero occurs, the originating LSC population is also greatly reduced - just not eliminated. And that becomes the steady state most people achieve. A balance between LSC's that are dormant coming out of dormancy and creating replacement CML cells which are then killed by TKI. Each of us has a different population equilibrium - many will achieve MMR, some will only achieve a stable PCR ~ 0.1%.  And that is sufficient to keep CML in check.

Over time - for 45% of two years of  PCRU - enough LSC's are killed off that treatment free remission is possible. This doesn't mean that all LSC's are gone - just that the population is so low that the persons immune system can keep it in check.

Hi Scuba, thanks for the post and an excellent explanation in my view. One of the best, in terms of layman ish speak, yet relatively short, I have read in a while. I would like to copy paste this into a Facebook group I run as well if you are happy for me to do so ?

Nigel

Absolutely a wonderful explanation - thanks Scuba.  But, and I might just be a bit dense here, I don't see a simple direct answer to the question I posed:

"please advise whether or not the chance/risk of mutations increases if one drops below the threshold level of their TKI, in other words, if there are more CML cells circulating because the TKI does is too low, does this increase the probability of mutations occurring?"

Thanks for humoring me :) 

The chance of mutation always exists. When it does happen, the mutated cell is  a new condition that the body may or may not recognize as aberrant and destroy it.  In the case of TKI being too low to keep CML cells in check (i.e. population control), this naturally leads to an expanding CML population of a particular clone. Is it possible for these cells to mutate? Yes. But it would take a lot of cells to establish itself.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2898591/

So it is important that a decreasing trend and or low level equilibrium be maintained. If PCR increases by a log or more during TKI treatment, then response is probably lost and a new clone may have established necessitating a different drug.

Keep in mind that CML in chronic phase is a slow disease (even though billions of cells are produced every day! - hi-lighting the population dynamic equilibrium at work). There are many patients who stop treatment for one reason or another (pregnancy),  and experience a significant rise in both PCR and FISH and immediately respond back to pre-stopping levels when their TKI is restarted many months later. So the key is to catch any PCR increase WHILE taking a TKI. Protocol suggest 3 months is enough  (between PCR tests) and even longer periods when a long term trend is established.

The article above describes blastic transformation of CML chronic phase. This is what makes CML disease particularly dangerous and is what kills. The mechanism of blastic transformation is not well understood and involves DNA damage that goes beyond mutations. What does seem to be clear is that the amount of bcr-abl kinase activity is a prerequisite for blastic transformation (amount being produced by the CML cells). And that at FISH levels = zero (CCyR) and PCR ~ <0.1% blastic transformation is exceedingly rare - to the point where progression does not occur when this low level is achieved.

(Also - not mentioned in the article above, vitamin D is known to be critical in differentiation of blast cells.- including leukemic ones. Patients with high normal vitamin D levels usually test with no blast cells. In my own case, I have always had blast cells present (one-two percent). At diagnosis, I was borderline 'accelerated' phase. I also had very low vitamin D. Once I elevated my vitamin D status significantly - my blast cell count disappeared. I have had zero blast cells measured since. (it's been 5 years now). I wonder if preventing blast crisis is as simple as taking a vitamin D supplement to keep vitamin D levels above 50 ng/ml. )

 

OK - so my take away for me is that the answer to my question is yes if for no other reason than the fact that the CML cells of the current close exist is greater and increasing numbers. The good news is that even though the answer is yes, the probability is very low.

Hope I've got this right - thanks again Scuba

Thank you, scuba!