19 replies to this topic

[lseaturtle79]

Everyone with CML has the Phiadelphia Chromosome,

[pamsouth]

Billie, I would like to hear the answer to that myself!!!

As far as I know, officially I have CML +PH. and so does everyone else so why do they always had PH+ (CML =PH) ?

CML being the CML Stem Cell that is at the root of the problem or started the whole mess. That is why I had 2 million platelets because the defective CML stem cell is making all the blood on the myeloid side, however platelets and red blood cells are not nucli like white cells, they don't have chromosomes and divide and multiply like PH+.   PH+ being her children or the white cells which are make up granulates,  that are nucli or have the 23 pair of chromosome, of which #9 & # 22 chromosome chose to break into and fuse together at various degrees.  That is the best I can understand it. 

That is why I always say until they can find a drug to kill the mother Stem Cell the TKI are just putting out or killing her children. I think I read something from Trey that if he kill enough of the PH+ maybe the CML Stem Cell will exhaust herself, who knows, lots of theories. Even though we may be PCRU we may still run under the radar and have million of PH+.  Even in transplant they can't always eradicate all the PH+ and CML stem cell, that is why it takes time for donor cell to go home to roost and kill off the remainder of your stem cells, if not then eventually the CML shows back up. That is why I would never agree to do a transplant of my own Stem Cells.  When I flew to MD Anderson they said don't let them do that to you in Indiana it would be a waste.  I met a few people in some seminars who had that done, used their own stem cells for a transplant don't remember if that was called autologus or something else, some patients had full radiation and older patients without radiation.  None of them were happy campers, it was just a matter of time before the  CML PH+ multiplied back.  The ones that had radiation, the younger ones, were real unhappy, because they were in worse shape them before the transplant, because their CML was back like it was, only now they had bad liver/kidneys etc due to the radiation, so they had less to fight with. That is why MD Anderson said don't do a transplant for unless you have donor, so the donor stem cells can multiply and kill off the remainder of yours, which may take a year or two.

When I worked for Electronic Data System a Sub of General Motor, we were always taught to get to the root of the problem instead of just putting out fires.

I could be wrong about parts of the above.  If so, Trey, Lucky, Scuba, or anyone, would appreciate your thoughts as well.

So Billie I am so....... glad you asked that question.  How are you doing?

I fell twice last week and sprained my ankle, but have been going to Physical Therapy and almost as good as new.  Got to have a root canal Thursday and then another one next month.  I think as long as I get patched up I will hold out a few more years, who knows.  But my spirits are up today, for some reason, could be weather, I don't know just woke up feeling really good, except a few aches and pains, but for a 64 year old I feel good today, and I am taking advantage of every bit of it.  Just chili out. Makes me think somebody must be praying for me and God said Ok lets give her a break, I needed it, in a bad way. 

[pammartin]

Billie,

This summer we will get that hula hoop, tennis racket, and bike out of your garage and put them to good use.  We will take them straight to Goodwill.  :-)  We cannot be doing tempted to try these things while under the influence, with our luck we would be the only people in history who get arrested for drunken hula hoop maneuvers.

[CallMeLucky]

Technically not everyone with CML has the Philadelphia Chromosome.  There is a rare subset of CML that have what is called PH- CML (Philadelphia Chromosome Negative).  This is a rare and some would argue is not truly CML.  If you had PH- CML you would know about it from diagnosis.  I'm fairly certain TKI drugs do not work for PH- CML.  Most people with CML have PH+ CML (Philadelphia Chromosome Positive).  Philadelphia Chromosome causes BCR-ABL gene which allows the CML to spread.  TKI drugs block BCR-ABL and eventually the PH+ Chromosome becomes undetectable by tests (CCyR).

I'm not sure what being in CCyR has to do with lowering dosage, usually most doctors would look to PCR test to ensure you have at least a Major Molecular Response (MMR) before considering lowering dosage unless it was for something serious like myelosuppression.

[scuba]

from: http://www.pnas.org/....expansion.html

Pam - It's actually quite simple once you get the terms down. At the bottom of the picture are the cells that do the work - our red blood, platelets, white blood including T-cells, B-cells, etc. These cells have finite life spans in the blood which reduce their number under normal conditions and require renewal from the top two levels.

At the very top, as you like to call it - is the mother cell - the LT-HSC otherwise known as a Long Term - Hematopoietic Stem Cell. A LT-HSC has the unique ability to both self renew (make an exact copy of itself) and differentiate into the next daughter cell (ST-HSC).

Our disease occurs at the LT-HSC. At the very top. It is here that a translocation occurs crossing the number 9 and the number 22 chromosome which creates a new fusion gene called bcr-abl. Once it is created at this level, then subsequent divisions into new LT-HSC's as well as the daughter cells leads to more and more cells with the fusion gene: bcr-abl. When the lower level daughter cells are made, the inherited fusion gene has its highest negative impact by pumping out tyrosine kinase (a protein) with abandon which signals the other white cells to make more of themselves without limitation.

As a direct result of this, the normal cells become fewer in number because they are signaled to stop dividing (after all - there are plenty of white cells now). The bcr-abl cells just keep going. By the time disease becomes apparent, i.e. we feel sick - our bone marrow has lots of leukemic stem cells (because they duplicated the bad chromosome that now has the bcr-abl gene) and tons of Leukemic dividing white cells to the detriment of normal blood composition. We feel anemic (less red blood), feverish, and other bad things. If this keeps up - we die.

When a Tyrosine Kinase inhibitor such as Gleevec, Sprycel, Tasigna, etc. is introduced - it blocks the action of the bcr-abl gene especially when the cells are dividing (high energy requirement) and leaves our normal cells alone (that's the magic). It is at this point that the dividing Leukemic cell - needing energy in the form of Adenosine Tri-Phosphate (ATP), dies. It's energy source is blocked (quite ingenious actually!). The cells that die are largely the GMP's - the ones that make white blood cells. The higher order cells are affected also, but to a lesser degree. Normal cells are largely unaffected because the TKI doesn't bind to their energy site as I mentioned earlier.

It is not correct that the Leukemic LT-HSC's (i.e. have the bcr-abl gene) are not affected by a TKI - they are. When an LT-HSC divides it exposes itself to our drugs and can get killed. If this didn't happen, then our bone marrow would forever be filled with bad stem cells and little or zero normal cells (very bad). The reason why gleevec and the other TKI's do not eradicate the LT-HSC's is because they can be quiet - non-dividing - for a very long time. So if we stop taking our drug, when they do divide - they are not stopped and the disease begins again. Also - the bone niches that LT-HSC's live in are real sequestered - and the drugs we take may not penetrate successfully these far away places. For some people - as many as 40% in the Europe trial, these people were fucntionally cured using a TKI alone (Gleevec) most likely due to the fact that their Leukemic Stem cells were exhausted. These lucky people (no relation to our Lucky) had all of their Leukemic stem cells come out of hiding to divide and got nailed - or their remaining Leukemic stem cells are staying quiet and not dividing yielding the same result.

Over time, the population of LT-HSC's decreases, the population of normal LT-HSC's increases and our blood begins to normalize again. But we have to keep taking our drugs so that as Leukemic daughter cells of the few LT-HSC's that are around pop out - they get killed.

In a normal system - when a Leukemic LT-HSC is created due to bad transcription (i.e. formation of the bcr-abl gene for the first time), the body's own defenses recognize it as bad and kill it. But we CML'ers have lost that ability for whatever reason. In many ways, the TKI's are a man-made version of the natural process (sort of ...).

(A true cure (my opinion) lies in restoring the natural killer system that protects the body from transcription errors.

It is my belief, that even if we can kill every single Leukemic stem cell, what happens when a normal stem cell divides and screws up again? It happens all of the time in our bodies - cells divide and screw up creating bad cells. Our immune system recognizes them as bad and kills them. When it doesn't - then cancers are formed. DNA is tough, but not bullet proof. So down the road, after "cure", we have a normal stem cell divide and create the bcr-abl gene and start the CML process all over again.).

Our bodies are magical places. The balance that must be maintained so that life continues is pretty awe inspiring.

Trey has an excellent summary of the biology of the Leukemic Stem cell somewhere around here. Someone should re-post it so it is fresh again for others to read - especially the new members who may not have seen it yet. It should be a "sticky" at the top of the forum - required reading for all who are new to this chronic disease.

[pamsouth]

Thanks Scuba,

I did a copy and paste to my email and saved it.  I also printed it out.  Got a physical Therapy appointment but as soon as I get back I will study this in detail.  I am going to get this thru my thick skull.  Then I will laugh at myself and say why did I make it so hard!

Ok Scuba it is 1pm I have to be at physical therapy, at 3pm.  However I got intrigued at reading your reply so I took a few minutes to digest.

Yes I can definitely see why you would think the cure lies, "in restoring the natural killer system from transcription errors", otherwise a normal stem cell can screw up again.  Darn!  

Interesting that I had 2 million platelets at diagnoses and only 21,000 white cells. You said that "largely die are the GMP", but the platelets are on the CMP/MEP side.  Therefore I would summarize the LT=HSC can effect the whole CMP OR MYELOID side, does that sound feasible. As far as that goes the LT-HSC is the defective stem cell also for CLL or even Hairy Leukemia for that matter.

PAMSOUTH

[pamsouth]

Billie only you could make it into some funny, laughing.  I am off to Physical Therapy, will get back with you later.

I told my good friends at Physical Therapy and the good doc, I must like them a lot to re injury myself and keep coming back. I did get some sympathy, but pain wasn't really worth the sympathy.  Got to find a better way!

You mentioned, hula hoop, I used to water ski, haven't been up on skies for a number of years.  Humm

Back at you later,

PamSouth

[CallMeLucky]

The question of the body being able to fight off has different theories.  One theory is that we lost the ability to fight it off.  Another theory is that the body may have been compromised by an evironmental factor (radiation, virus, stress, etc) that allowed the transcription error to get by.  Once it took root, it may have survival mechanisms that allow it to fend off the body's natural defenses.  See below for an interesting article on how the LSC may actually alter the bone marrow to protect itself in CML patients.

In the first scenario, eradicating CML may be more difficult because even if you eliminate all LSC new ones may develop.  I have a hard time with that (maybe just because I don't like that outcome as much) but to me it seems like this was a muti-factor event that led to the transcription error getting by and there is also the chance that it could take an entire lifetime before the circumstances were ripe for it to happen again.

City of Hope researchers show how cancerous stem cells manipulate their environment to enhance their own growth in chronic myelogenous leukemia Contact: Roberta Nichols 800-888-5323 ronichols@coh.org DUARTE, Calif., April 16, 2012 — City of Hope researchers have shown how leukemia stem cells hijack the bone marrow where they live, helping them to proliferate, potentially outlast powerful therapy and return to cause cancer. The findings appear in the journal Cancer Cell. Thanks to modern medications like Gleevec, most patients with chronic myelogenous leukemia (CML) now can enjoy a long life — but as soon as they stop taking these drugs, cancer usually comes back. City of Hope researchers like Ravi Bhatia, M.D., and colleagues at Dana-Farber Cancer Institute and the University of Glasgow are pursuing ways to finish off CML more completely, knowing that current drugs are expensive and cause major side effects that hurt quality of life. Scientists believe CML returns after therapy because drugs fail to kill leukemia stem cells, the primitive cells that produce mature leukemia cells. Work by Bhatia and his team in laboratory and mouse models shows that leukemia stem cells are even more cunning and powerful villains in the CML story than once believed. They actually transform their surrounding neighborhood — what scientists call the bone marrow microenvironment — to give themselves a protected place to hide and grow. Normally, healthy blood stem cells live in the bone marrow and produce the many kinds of different blood and immune cells the body needs. But in CML, leukemia stem cells hide in the bone marrow and start to take the place of healthy cells. The researchers found that the leukemia stem cells do more than call the bone marrow their home, though. "We found that in CML, leukemia stem cells actually change their microenvironment, altering the bone marrow so it selectively supports them over normal cells," explained Bhatia, director of the Division of Hematopoietic Stem Cell and Leukemia Research at City of Hope and senior author on the study. Researchers once believed that leukemia stem cells took over the bone marrow because they naturally grew more out of control than normal stem cells. The new study suggests that the leukemia cells change the tissue around them to block healthy "niche" cells. These niche cells tell stem cells when to grow normally and regulate the number of healthy cells needed. Leukemia cells shut down this communication and alter the bone marrow to enhance their own growth.   When they looked at the bone marrow itself, they found abnormal levels of two proteins that cells use to communicate. These proteins are called interleukin 1 and CXCL12. Higher levels of interleukin 1 and lower levels of CXCL12 appear to help leukemia stem cells grow. Researchers believe that the leukemia stem cells somehow manipulate the tissue around them into producing these protective, abnormal protein levels, even as mature leukemia cells are dying from treatment with drugs like Gleevec. The study showed that new therapies must not only target leukemia stem cells but the microenvironment, as well. "These results improve our understanding of leukemia stem cell regulation in CML and could guide strategies for targeting this resistant population," said Bin Zhang, M.D., Ph.D., staff scientist in the Division of Hematopoietic Stem Cell and Leukemia Research at City of Hope and first author on the paper.

http://www.cityofhop...own-growth.aspx

[Susan61]

Hi Billie:  Love your HUH!  I am right there with you. All the years I have had CML, and I still do not understand it no matter what I read or I am told.  I know the basics, but I was also told by my doctor that there would be a test that they could do on me.  I do not know if she was talking about the same test your getting, but she told me it would not be available for about 5 years.  She explained it, if I remember what she said that it would tell if my CML would return if I stopped my TKI.  She also said it had to be done if you were at PCRU.  I will have to ask her to explain it again.

     Are you at PCRU?  I do not think I would cut back on my dose of any TKI if I was not at PCRU.  Ask your doctor about that also.

     I leave all these intricate explanations to Trey and others who are constantly studying everything on CML.

[Lizzybee]

I remember reading that some people with CML don't have the Philadelphia chromosome, and those patients are not treated with TKIs.

I googled to be sure, and the National Institutes of Health webpage about CML says this: "It is usually associated with a chromosome abnormality called the Philadelphia chromosome." Key word: usually.

[Pin]

I think it is a matter of contention in the field as to whether people who are Ph- actually have CML or not. When I say Ph- I don't mean people who have PH+CML who have been treated with TKIs and are now undetectable (i.e., PCRU or CMR), I mean people who never had the Philadelphia chromosome to begin with.

Billie, in your case - I think what they are looking for is whether they can now detect the Philadelphia chromosome after treatment with TKIs (i.e., they want to know if you are undetectable, PCRU, CMR).

Which I hope you are!

[pamsouth]

Call me Lucky,

Thanks for the info,  I am beginning to read with some understanding.

I just spoke with my oncologist nurse.  She just finished her clinical last week, 5 years of schooling, and will be moving to another facility for internal medicine.  Wanted to give you a little of her back ground.  I took the liberty of taking up some of her tim,e to go over the chart you sent me yesterday.   I have not had time to log back on and see the other articles you sent yesterday, in fact my email had not gotten anything since early yesterday afternoon, not sure what is up with that.

Anyhow I asked the nurse, a few questions.  1 question, how far up do the TKI kill, or do they kill up and including the stem cell.  She said they do not kill the stem cell, they only kill from the myeloid side, which on the chart would be the CMP.  The nurse did agree on the Stem Cell environment as you stated above  ""it may have survival mechanisms that allow it to fend off the body's natural defenses."  only she said it in very professional terms, that i could not write down quickly enough.  Except I understood the factor of the "first flawed stem cell is unable to be killed off in our bone marrow", sorry my laymans terms. 

It is 11:30 am 4/19/12.  I got to hurry got a root canal at 1pm. 

I think she was pretty much on board with everything else, except she believe the TKI only kill on the lower level, the myeloid.  I asked her, do you mean the CMP and down, she said I'm not sure what CMP stand for.  Anyhow she had other phone calls to make, and it was nice of her to take several minutes to talk to me about the TKI and the stem cells and all.  I do understand why my red cells were misshaped and I had 2 million platelets.  OH, I did ask her about the CLL, pretty much same theory except depends on where the STEM CELL At the top of the chain becomes defective.  Wish I could repeat it in her professional language, best I can do for now, I will get better at this. 

At this point in my level of thinking, I still don't think it would work even if you found a TKI that supposedly kills the top level of stem cells that went bad.   Unless the bone marrow environment changes, because the bone marrow would not kill off the defective stem cell. So I think it is much more complicated then TKI'S for a cure.

So I think I still stand by my personal belief in how the TKI's work. At least until I learn more and darn I need to learn how to pronounce these words with proficiency.  Got until May 10th my next appointment.  Going  to get my labs done 2 week before appointment so we will have at least two PCR & FISH, ETC to look at.

Got to go,

Thanks Again, PamSouth

[pamsouth]

Billie,

I had a few of them (douche and an enema) while water skiing also drank a lot of water.  However even in my 40's I loved the water so much I didn't care, I was young and healthy and the sun and water and wind in my hair was so breath taking.  We don't have a boat anymore. We got to traveling to Florida a lot and had a home there for awhile.  My husband is working part time now.  But next year I think I might try to talk him into moving back to Florida.  Well that is if we are up to it.  He will be 71 year old in Jan and I am 64 years.  We built this house and moved in Jan 2008.  We have a full basement where we store all our treasures that nobody else would want.  We tried to part with some of them when we moved in.  Now I can see why we should keep my stuff, but my husband I mean how many hammers do you need.  That wood saw he hardly ever uses. We got enough nails to built another house. geezzzz.

Take Care, Blessing PamSouth

[Pin]

I thought you were - that's great! Hopefully you can reduce your dosage as well