25 replies to this topic

[scuba]

So... when we were diagnosed with CML, our bone marrows have a lot of Pluripotent CML stem cells.  These cells make red blood, platelets, & white blood cells and the white cells in particular grow unchecked.  We take a TKI and they kill the progenitor cells but not the stem cells.  So many of us go into myelosuppression because we do not have a large enough population of normal stem cells from which normal myeloid cells originate.  Do I have it so far?

Then - over time - long time - the Pluripotent CML stem cells die off.  They divide to make more and in division expose themselves to the TKI and get killed.  This creates "room" in the marrow for the normal stem cells to divide and re-populate the marrow.  Correct so far?

Over time, the normal cells keep expanding, blood levels return to normal or near normal and the few remaining CML stem cells are killed off EXCEPT those that have been quiescent.  Since they have not divided, they are not killed.  Over many years, even they will divide and then get nailed and a patient like Trey and Susan are functionally cured.

What is interesting is that myelosuppression may be more a cell population dynamic between normal stem cells and CML stem cells than the TKI suppressing normal cells.  In vitro, TKI's don't inhibit normal cells.  Getting the body to re-balance therefore is the trick.  Starting with a lot of leukemic stem cells is the problem.  Some of us may start with a few leukemic stem cells, but a lot of progenitor cells, so when the progenitor cells get killed off, these patients have  a store of normal cells to recover from.

People like Tedsey and myself probably had a lot of leukemic stem cells and not enough normal stem cells.  And it takes a long time for the recovery of normal stem cells to re-populate the marrow.

I am writing this because it is becoming clear that it is the stem cell population in the marrow that is the critical issue.  Kill the bad stem cells and cure is possible (i.e. drink lots of quinine water?).  Start off with a leukemic stem cell marrow and myelosuppression is the result as TKI's kill off the dividing CML progenitors.  Start off with relatively fewer leukemic stem cells and quick remission is possible (mutations notwithstanding).  I have not been able to find any literature on cell population dynamics in the bone marrow. 

It's all about the stem cells in the bone marrow.  Even if CML progenitor cells are dividing - killing the CML stem cells will pull the foundation out and the leukemic population will collapse (progenitor Leukemic cells do die - it just takes longer).  Trey - do you concur?

[CallMeLucky]

Another factor that you did not discuss that could be involved in low counts is if there was any damage done to the bone marrow by the CML.  Isn't it possible for the marrow to become scarred, a type of fibrosis that may diminish the individual's ability to make healthy cells?

I'm not speculating on who's low counts are caused by which factors, I was just curious if this was in fact another possible scenario.

[Susan61]

Hi MIchael:  I am such a idiot with all the terms used, but I read your post and understood somewhat of what you are saying.  I believe I was diagnosed early, but not sure.  I worked in the medical office where they found my CML.  We used to get complete blood work every 6 months if we wanted to, and no charge to us because we had our own lab on the premises.  I took advantage of it,and always had my blood work done.  I think they caught me in the 6 month range from my previous blood work.  I do remember my doctor telling me that they could kill off all the leukemic cells, but not the root of the cells.  He said its like your lawn and you could kill all the weeds where you could see them, but they were all underground getting ready to sprout up again   He said  if I stopped my Gleevec I could be okay for awhile, but in the meantime the root of those cells are rejuvenating and could spread into a full blown condition again.  This is the only way I can explain what I was told.  Now that is how it was told to me back in 2000.

I appreciate all the research that Trey, You, Lucky , and Phil always comment on.  You all have good answers for a lot of our questions.

Like I said I am bad at a lot of the terms that are used in the explanations, but I feel good about all that is being learned everyday about this disease.

Keep up the good work in trying to figure all this out.

[ChrisC]

I too am enjoying reading all the research presented, though I may be only "getting" a fraction of it. A couple of things in the "Scottish university reveals new drug to combat leukaemia" posting by CallMeLucky caught my eye:

". . . CML stem cells avoid the impact of Tyrosine Kinase Inhibitor treatments by going into a state called autophagy in response to the drug. This means that they begin to shut down and use nutrients from within the cell to survive in what is effectively suspended animation. In this state the drug cannot kill them and so later they can initiate a resurgence of the disease. . . ."

Then there was this in the article GerryL posted in response to the "Scottish university reveals new drug to combat leukaemia" posting above, where it said:

"With current treatments for CML, a tiny population of stem cells remain in the bone marrow which can't be killed. . . . This means that patients have to continue on drugs for the rest of their  lives and quite often, if you take them off the drugs, they will get a relapse."

What I'm thinking about is how over time the resting/hiding CML stem cells are not dividing, so they aren't being zapped by the TKI, but eventually they either have to divide (and be exposed to the TKI) or they will run out of inner nutrients and they will die as well.

So it seems that it might be reasonable to suppose that with even a low dosage of the TKI and sufficient time, all the CML stem cells would be "gotten," right? That is why we discuss the possibility to be cured?

[CallMeLucky]

Chris - I think you are spot on.  In fact, I believe there was a model created by a mathematician that showed TKI treatment would lead to cure over a long enough period of time.  http://www.cmleukemi...e-leukemia.html

The only question is how long?  Who is going to outlive who in this scenario?  I think if we are lucky enough to get on top of the disease and get it to that low level, the incidence or relapse gets pretty low, so in a way that becomes a type of cure but the obvious is that we are still taking the drug with side effect.  What I like about this research is that they are looking at the treatment in two phases.  A drug like Hydroxychloroquine may not do much against full blown CML, but the idea that the TKI could knock it down and send it into this quiescent state and then the Hydroxychloroquine could be introduced to mop up those last stem cells, sounds very encouraging.  I'm sure it won't be that simple, but it sure seems like they are getting close.

Unfortunatly we have to remember we are dealing with a formitable advisary.  These CML stem cells are willing to eat their own crap to survive - that is hardcore!

[ChrisC]

Thanks for all your input and knowledge, Lucky, it helps us grow in our understanding of this thing we live with.

I can't access the link you posted, but I get the idea and I applaud the researchers investigating the issue. I wish them all speedy success!

My inner resources tell me that there is a vast store of intelligence governing the functioning of our bodies; sometimes mistakes happen, though. Nonetheless, that intelligence continues to work together in all ways to try to restore balance.

Our TKIs are a great boon and are doing a wonderful job of filling in where the CML mistake has happened, resulting in the Philidelphia Chromosome. The CML-correcting TKIs do disrupt other functions, however, and we call the results "side effects." Ooooh. Don't want those.

So perhaps I will someday, without waiting for full scientific validation of the plan but with the careful supervision of my onc, ask my body's intelligence to let me know when/if it's time to let the inner systems take over flushing out the hidden CML stem cells, if in return I agree to stop feeding in the TKI that is causing the disrupting side effects.

I'm working on getting this message to all my inner intelligence to ask for full cooperation and agreement: it's a plan that beats giving in to fear, for me anyway.

I am a work in progress : )  Thank you to everyone on this board for your continuing sharing of questions, ideas, support, enlightenment. It is all helping and healing.

[Trey]

Most info is covered in my posting "Genetics of CML Leukemia: An Overview"

http://community.lls.org/docs/DOC-1272

There are many levels of WBCs.  The TKI drugs can kill most levels of leukemic WBCs except the highest level leukemic stem cells way up the chain.  Even if they are not quiescent, it is unclear that TKI drugs can kill them due to their enhanced survival skills.  All stem cells are harder to kill as a protective mechanism to prevent being killed off, since they are so important to the body.  Leukemic stem cells may have even more sophisticated enhanced survival skills than normal WBC stem cells.

If trying to explain anemia associated with CML, it is certainly related to the stem cell compartment.  But it is NOT true that "TKI's don't inhibit normal cells".  TKI drugs do inhibit normal functions in cells, including normal ABL.  In reality, TKI drugs do not inhibit the BCR-ABL in total, but inhibits all ABL, including the ABL associated with BCR-ABL.  Inhibition of ABL can suppress normal blood cell formation, more so in some than in others.  In that way, both the CML and TKI drugs affect the normal blood making process to some degree or another.

[LivingWellWithCML]

Sounds like an interesting double-whammy from both CML and TKIs.  So, the benefits of inhibiting BCR-ABL are obvious for CML, but what other "issues" are inherent in the inhibition of ABL in general?

Dan

[rct]

Trey wrote:
Most info is covered in my posting "Genetics of CML Leukemia: An Overview"
http://community.lls.org/docs/DOC-1272
There are many levels of WBCs.  The TKI drugs can kill most levels of leukemic WBCs except the highest level leukemic stem cells way up the chain.  Even if they are not quiescent, it is unclear that TKI drugs can kill them due to their enhanced survival skills.  All stem cells are harder to kill as a protective mechanism to prevent being killed off, since they are so important to the body.  Leukemic stem cells may have even more sophisticated enhanced survival skills than normal WBC stem cells.
If trying to explain anemia associated with CML, it is certainly related to the stem cell compartment.  But it is NOT true that "TKI's don't inhibit normal cells".  TKI drugs do inhibit normal functions in cells, including normal ABL.  In reality, TKI drugs do not inhibit the BCR-ABL in total, but inhibits all ABL, including the ABL associated with BCR-ABL.  Inhibition of ABL can suppress normal blood cell formation, more so in some than in others.  In that way, both the CML and TKI drugs affect the normal blood making process to some degree or another.

Chaps my a$$ seriously.  This stuff is available, it is known, it is facts.  TKI pushes counts down.  Period.  I don't understand why people come up with this stuff, make it up outta vapor apparently, and then put it on the internet.

"TKI's don't inhibit normal cells"?  Really?  Here's something to inhibit:  Internet Bee Ess.  Go see a doctor, and for crying out loud PLEASE listen to what he or she SAYS, not the answer in your head that you hope they say.

In five years, when quinine and hot peppers from India haven't made anyone one step closer to anything resembling a "cure", MAYBE some folks will understand the crapshoot this is.  MAN if it was that easy, and if it is?  Why do we have this web page?  Why do people go from just plain old fantastic to deceased in a couple months?  Why is bazillions of dollars needed to figure all this stuff out when all we REALLY have to do is give our loved ones gin and tonics, which we do by the way, and some spices?

Denial is fine, I live near that river too sometimes.  Hope is Eternal, we live with it and for it every day.  But really, this is serious stuff. It won't ever be "cured" by postulating some theory as to the whys and wherefores, and then dumping it on the internet.  Substituting hopes for facts and then putting them out there as though they actually ARE facts is just a disservice to everyone going through this.

Last year we drove exactly as far from our house as we possibly could and still be in this country in order to see the guy that started it all.  His answer?  That beautiful shrug of the shoulders that only he can do, hands up, "it's a crapshoot".

Words to live by.

I think of you all every day, and I get sadder and sadder as what seems to be the facts just get lost in a morass of non-, mis-, and dis-information.

rct

[CallMeLucky]

rct wrote:

"In five years, when quinine and hot peppers from India haven't made  anyone one step closer to anything resembling a "cure", MAYBE some folks  will understand the crapshoot this is"

I'm guessing many felt the same way when Druker and Lydon first started working with Gleevec, in fact according to the history people did feel exactly the same way.  Fortunately the nay sayers were wrong.  More often than not, the nay sayers are right, but every so often they are wrong and that is when something amazing happens.  Hope is a dicey thing.  Sometimes we tell ourselves not to get our hopes up so we are not let down when things don't work out.  I've always found this line of thinking odd (particularly since it was entrenched in my psyche from a very young age).  I've been disappointed when I had my hopes up and I've been disapoointed when when I did not get my hopes up, the level of disappointment was pretty much the same regardless.  However, when my hopes were up, I generally felt better about the period leading up to the disappointment.  Was I living in ignorant bliss?  Perhaps, but I did feel better in the aggregate.  If we try to live by the motto that life is about the journey and not the destination then shouldn't we try to focus on things that keep us hopeful and help us to better enjoy life rather than dismiss hope for the sake of mitigating the pain of the disappointment that may or may not ever come?  I certainly don't subscribe to a policy of walking around with unrealistic expectations, it is important to pare our enthusiasm to the point it keeps us based in reality, particularly when planning for the future.  I hope to be cured, but I plan to be sick.

When I read the article about the research in Scotland, it made me hopeful.  Will this be a cure for CML?  Possibly, probably not, but maybe.  Regardless, I felt good that day when I read it.  It made me feel for a short period that maybe the future wasn't as bleak as I sometimes think it is.  So regardless if this ever turns into what we hope it will, it still served a purpose for me, for that day.  I also noted that unlike some of the various things out there that claim to someday become a cure, this had a little more meat to it.  The doctor running it is a highly regarded CML researcher, there is a trial already underway and it is an established drug.  So there was more than just the usual "well we put this stuff on a CML cell in a petri dish and it killed it, but we have no idea what is going to happen when we try to give it to a human or if it will work".  This at least had some facts behind it that to me made it worthy of my hope.  So for me, I choose to be hopeful when I can, I try to be realistic, but in what is a different way for me to think then I normally do, I am finding that by trying to look for positives it helps me in the moment to be more at peace and have a better overall outlook; and for me, that is the benefit of this forum.

It is important people remember that there are no doctors here, just other people going through the same thing they are.  We all have advice and opinions and we all know what they say about opinions.  So yes, I agree, you shouldn't have a plan that is based on you being CML free in two years because of an article you read on a CML forum, nor should you alter your treatment basd on something someone else is doing, but at the same time I don't see anything wrong with reading an article on an internet forum that helps to lift your spirits, even if just for a few moments that day, when you would have otherwise been down.  Regardless if it ever amounts to anything, at least you had a moment to dream, even if only for a moment, and that spark of positivity can sometimes turn a bad day into a not so bad day.  These days I'm keeping track of my good days vs. my bad days and I am more interested in having good days and less tolerant of bad days.

Peace to all.....

[rct]

CallMeLucky wrote:
rct wrote:
"In five years, when quinine and hot peppers from India haven't made  anyone one step closer to anything resembling a "cure", MAYBE some folks  will understand the crapshoot this is"
I'm guessing many felt the same way when Druker and Lydon first started working with Gleevec, in fact according to the history people did feel exactly the same way.  Fortunately the nay sayers were wrong.  More often than not, the nay sayers are right, but every so often they are wrong and that is when something amazing happens.

Druker was working with research already begun by people hip deep in GIST.  There is a very big difference between nay sayers and just substituting hopes and thoughts and conclusions drawn from one very personal point.  Nay sayers can be presented with the facts, what is known as the facts, and the extrapolations outward from those facts, and they can Nay, that's why they are Naysayers.

I am the farthest thing from a Nay Sayer there is, but I do and will continue to say:

If it was really that easy...

rct

[CallMeLucky]

In reference to Druker, I was really thinking more about the idea of targeted therapy in general, which was something that admittedly was being pioneered by some others like Slamon with breast cancer before Druker.  Regardless of who the players were, my point was that the idea of a specialized drug that could be created to target a specific oncogene was considered fantasy by many.  They said it just couldn't be done.  There were no facts yet because it had not been done, they were pioneering a new concept.  Was it easy?  Absolutely not, but they did develop a new paradigm that shifted the way cancer is being treated.  So all I am saying is that if a cure is ever discovered, I expect that most people will be doubtful about it until it is proven to work.  That is to be expected given the many disappointments there have been.  For me however, none of that is really the point.  For me it is about trying to find things to be positive about in the face of a very negative thing in my life.  I try to use articles like the one out of Scotland as a basis for hope when I often find I don't have much.  Is this misguided?  Am I delusional?  Perhaps, but it is a means to an end.  Occasionally I need something to cheer me up and give me hope that there is a chance some day I will be cured and I feel better than I do today.  The day I read that article, I felt pretty good that day.  I shared it with my wife and my mother and they were both very excited.  It doesn't matter if it doesn't turn out to be the cure, for that moment we felt hopeful and to me, that was worth it.

Take care - hope the Mrs. is feeling ok.

[CallMeLucky]

I don't know if this could have been any more timely.

http://www.current-o...le/view/652/713

cml biology for the clinician in 2011:  six impossible things to believe before breakfast on the way to cure

---

B. Leber, MDCM

ABSTRACT

Chronic myeloid leukemia (cml) is a model disease in oncology: it  is the first human cancer linked to a distinct chromosomal abnormality,  ultimately causing constitutive overactivity of a known oncogenic tyrosine  kinase that represents a drug target. The introduction of the tyrosine kinase  inhibitor imatinib into clinical practice has far exceeded expectations and  resurrected hope that the fundamental insights from the "war on cancer" can lead  to significant therapeutic advances. Nevertheless, the current perception among  clinicians is that imatinib and its newer more potent cousins offer superb  long-term disease control for most patients, but that cure without  transplantation has remained elusive. However, several important  laboratory-based observations over the last few years have changed those  perceptions. Several of those developments are discussed here, including direct  manipulation of the apoptosis pathway in cancer cells and prevention of disease  progression with the use of antioxidants. Intriguing results from a French study  indicate that, if disease progression is halted, a small but significant group  of patients may be able to stop imatinib therapy without disease recurrence. And  for patients whose disease, because of resistant stem cells, needs a more direct  attack than tyrosine kinase inhibitors alone, several approaches investigated in  laboratory and animal models seem promising, and some are ripe for clinical  testing, including inhibitors of Smoothened and 5-lipoxygenase, and suppression  of autophagy. Thus, there is realistic hope that true cure of cml, without transplantation, may be a  feasible goal in the near future.

[scuba]

I didn't have the energy to take on RCT's comments point for point with citations, references and logic.  It would take too long to put it all together.   I simply disagree with him.

But I am adding Gin & Tonic to my daily regime (albeit less wine).  And I take those Curcumin tabs every day.  So now I will be hitting this disease with Sprycel, Quinine and Curcumin.  Who knows .... At least the Gin will bring back Grad school days when Gin was cheap.

You see - I believe that CML stem cells are damn hard to kill.  They have to go into division in order to get exposed to the TKI and many of the damn stem cells stay dormant (Trey's tons of data on this).  And if you have a lot of CML stem cells - then damn - a TKI that works is sure to cause myelosuppression (they don't know if TKI's directly cause myelsuppession - because they don't in vitro - it may very well be a population issue: Dr. Cortes, pers.comm.).  One has to get those stem cells out of the way in order for myelosuppression to not be an issue.  Curcumin encourages stem cell division and then mucks with the machinery.  It 'facilitates' Dasatinib (colon cancer studies).  There is no magic bullet - but it sure looks like there is something to it.

I was a basket case with myelosuppression.  0.1 ANC doesn't get much worse than that (except zero).  I took a TKI and wham - down plumments my Neutrophils.  I suspect my bone marrow was chock full of PH+ chromosomes.  Start killing off the CML and bamm - I have no white blood.  And then - I start taking Curcumin (BCM-95 to be precise) - along with a much lower dose Sprycel (1/5th as much).  And over two months - what happens.  I experience a dramatic drop in PCR (FISH =zero) AND my counts are recovering.  Didn't happen with Gleevec - didn't happen with Sprycel by itself.  But I added Curcumin with Dr. Aggarwal's encouragement and bingo - dramatic progress.  Cause and effect - who knows.

So I don't give a damn if RCT thinks it's snake oil  - I think it would be stupid to pass up opportuntiies to try a "cocktail approach" (more than two substances) to beating this disease.

I'm not a doctor so no recommendations - but I am damn glad I added Curcumin to battle my myelosuppression and give Sprycel an Octane kick.  And I am pleased to be reading Gary's citations on Quinine.

[rct]

Michael wrote:
So I don't give a damn if RCT thinks it's snake oil  - I think it would be stupid to pass up opportuntiies to try a "cocktail approach" (more than two substances) to beating this disease.

I didn't say it was snake oil.

I have said and I'll say it again:  This is far too much a statistical crap shoot for ANYthing that works for one single person being the answer, the "cure", whatever.

Seriously, I'll say it again:  Do you really think a little curcumin is what it takes?  Have you ever looked at the various rates of progression and worse for the various genetic versions of humans?  Do you really think curcumin is helping a population that has a documented hard time such that they have persued legal recourse in order to get Gleevec made affordable for, shocker, all the people that consume more curcumin per person than any dozen people in America?  Do you think curcumin will "cure", keep the nasties at bay, whatever you want to call it, for Asians?  I don't think so.  They have their very own statistical anomalies regarding the very same CML, and brutha it is bad.

Quinine has been known to be "good" for the systems for a long time, nice "nervous pill", good for calming.  As our docs would say, it sure  can't hurt, like anything in moderation.  But really, throw back a gin and tonic a day and...what?  We are where you are headed, have been where you are going.  These things are just anomalies that may or may not help in the long run, but statistically are so insignificant as to be nearly laughable when held up as "facts" for others.  Especially new people.

Dandelions.  B Vitamins.  Only Green Foods.  NEVER Green Foods.  Exercise, can't forget that miraculous cure all.  All these things held up as "facts", that's what chaps my rump.  We been through them all.

Anything that works per individual works.  Just remember that many are walking ahead of you, and have been a long time, and have the scars and failures of it all to prove it.  Just be considerate and careful of your own hopes, and remember what they may return.  Above all, don't substitute your hopes for other peoples medicines, treatments, ways of coping.  It just isn't it, because we  are now back to...

If it was that easy...

I think about you every day Michael, wondering how you are doing, hoping it turns around and stays well for you.  I also don't want you wasting precious time and energy going after straws that prolly won't pan out in the end.

rct

[CallMeLucky]

One other clarification should be made with regard to the quinine (I'm not weighing in on the curcumine), it is important to read the article closely and understand what they are saying.  The media loves to dumb things down to get people talking (i.e. Cancer Cure found in common soft drink IRN-BRU).  The article is actually talking about using Hydroxychloroquine to go after the stem cells.  Hydroxychloroquine is a serious drug used to treat milaria.  This is not some over the counter drug that you are going to pick up and start taking to see if helps your CML along.  Among other things, long term use of the drug can cause you to go blind.  So obviously real trials are needed to see if the drug works on CML stem cells the way the researches hypothesize it will and figuring out how much is needed to get the job done vs. how much a person can tolerate before it becomes unsafe (quantity and duration).  Hydroxychloroquine is not the same as quinine, they are related, but not the same thing, "the beneficial effects of quinine and its more advanced synthetic forms, chloroquine and Hydroxychloroquine, have been increasingly recognized in a myriad of other diseases in addition to malaria." http://www.traveldoc...jEyMjE4NDc=.htm

So based on the article out of Scotland, I see no reason to go out and start drinking tonic water!

As I said before, I'm encouraged by the research into a drug like Hydroxychloroquine and the potential for it to help some people with CML possibly get off TKI and not relapse.

[scuba]

Too late ... sipping a G&T right now.

[rct]

Few years ago, I don't remember which doc we were at, they stopped prescribing the hydroxy blah blah for leg cramps, said it was dangerous in some way or another that I don't remember.  So again, these things come and go, and for some it is old, already disproven "news" that is nothing but hopes wrapped up in blurry and vague facts.

Here's a good one for our bretheren and sistahs in onea the other forums:

http://www.msnbc.msn.../health-cancer/

Hopeful, yes.  Shame about why nobody can get the studies off the ground, but yes, very hopeful.

rct

[rct]

Good gin, I hope.  You deserve something expensive.

rct