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Hi everyone, i was diagnosed with CML July 23, 2018. I am 44 yo two kids, wife and the whole pkg!it was a painful reality but as all of you did... i learn to live with it. I was on Gleevec 100 mg at first, but then messed up my platelets and my doc decided to  switch after three weeks of holding to sprycel 100 mg. unfortunately Sprycel dosage was too high and still messed with my platelets so now im at 80 mg Sprycel again. It looks like my platelets are going to be too low to  continue ( 49) so i will wait for Monday CBC to confirm, but, in the meantime anybody had a similar issue? I am with Kaiser Permanente here in the US and  ot sure if my doctor is well informed of any other way to control my platelets! Im getting frustrated, but patiently

pls help

Gian

 

What is your PCR level?

Last month was 13% 

when i was diagnosed was at 65%. Scuba, i am also intrigued and interested on your supplement diet, Vitamin D, Curcumin+ pepper and i was hoping for some directions on the matter, i order them last night, and they are 500 MG size C3 Complex by Bioperine...how many should i get daily? You think thy will help me?

 Thank you man!

Gian,

I was diagnosed around the same time as you, started on Imatinib, and my platelets steadily dropped to the 70s (not a worry), then after 4 months and my PCR still at 20%+ I was switched to a high dose of Nilotinib. Platelets crashed with 3 weeks, stopped treatment at 34 but they continued to drop to lowest count of 21. Stayed very low for weeks and weeks so stayed off treatment. I was worried as I expected the count to come back after two weeks but instead all blood counts dropped and stayed low. My consultant kept promising the counts would climb if I gave it time, and hey presto after 9 weeks they jumped rapidly. Restarted Nilotinib but on a very low dose, down from 400mg twice a day to 150mg twice a day. Platelets began to drop again but got to lowest 60 and then climbed slowly over two weeks to 69. Next test is next week but i feel pretty good. I just hope it’s continuing positively with the PCR count on the lower dose.

Hang in there, take a lower dose if needed and if you have a treatment break give it time. I’m not a doctor by any means but I hope my journey helps you 👍🏻

Edit: should add i’m UK based treated under our NHS. My case has been discussed at conference at The Christie which is a world class cancer centre. I’m very lucky.

Thank you David, some reassuring words! I appreciated.Glad you feel good man, i get concern sometimes about the Platelets, but i do feel good...though...  i just want to get my PCR close to 0 as possible.. you know? yhanks again for your time;) Good luck next month!

At 13% form 65 at diagnosis, your trend is good. You should ask your doctor that if your platelets are not stable (i.e. keep dropping), that you re-start on a lower dose at 40 mg. You want to monitor your blood counts closely during  this transition period you are still on. Are platelets the only blood cell affected? Neutrophils are another 'canary in the mine shaft' to watch. As long as your blast cells are near zero or at zero, you can have drug breaks to get your platelet count back up.

Regarding supplements. I am a strong proponent of maintaining a high normal level of vitamin D (70 ng/ml). Vitamin D is necessary for cell differentiation and actually can facilitate cancer blast cells to differentiate. Have your blood tested for vitamin D. You are likely low. I take 5,000 IU's per day of vitamin D3 (which converts to D in the body) in summer and more in winter. I do take Curcumin complex C3 with bioperine (which is a fancy name for pepper). Studies show upwards of 8 grams are needed to ensure enough absorption. I used to take 8 grams when I was at your PCR level. I only take two - four grams now - and only two grams at a time. There are no significant clinical trials that show efficacy for either Curcumin or vitamin D. In fact, a recent VITAL study on vitamin D showed no definitive benefit. I read that study and believe it to be flawed as the dose they used was too low and the blood level was not raised to 70 ng/ml.  Curcumin showed promise in the petri dish, but no study in vivo when it comes to CML. The biochemistry, however, is compelling and since it is good for you - I take it anyway.

I’m no doctor. This is my understanding (correct me if Im wrong): With CML you have these leukemic stem cells that are dividing out of control. There are also normal stem cells. Both divide into what later becomes thrombocytes or neutrophils or other blood cells. Sometimes stem cells also divide into a new stem cell. 

When you start taking TKI the leukemic stem cells stop dividing. Blood cells have short lifespan (days), which may lead to shortage in blood cells since there are only the normal stem cells left to divide.

Stem cells have long life span (years). This is why it may take years before all the leukemic ones die off and your normal stem cells take over. The more the normal ones take over the closer your blood count comes to normal, and finally if youre lucky ”all” leukemic stem cells has died and you may try to stop treatment.

Is that how it works?

Poppert - You would be amazed how many doctors don't understand !hematopoiesis!

Hematopoiesis is the process by which all blood cells are made. Describing it here would take many pages. A good reference is here:

https://en.wikipedia.org/wiki/Haematopoiesis

Essentially - the hematopoietic stem cell (HSC) divides upon receiving a protein signal to divide into two cells, one will self renew and the other will establish the subsequent blood cells lines , both lymphoid and myeloid. CML is a disease of the myeloid line (where neutrophils, red blood, platelets, etc. get created).

During faulty division, a translocating error can occur creating the philadelphia chromosome and bcr-abl gene (9;22 translocation). This new cell is the leukemic stem cell (LSC) and when it divides, it establishes a new line of myeloid projenitors containing the philadelphia chromosome. This chromosome has the bcr-abl gene which codes for a tyrosine kinase (a protein) which tells white blood cells (neutrophils especially) to divide unchecked. This is the disease.

What's important to keep in mind is that HSC's and LSC's  can lay dormant for many years dividing only when the daughter cells are not keeping up with demand. For example, a trauma where sudden blood loss occurs, or a disease triggering a dramatic need for more fighting cells. When CML goes out of control, it's not the LSC's that are causing it, it's their daughter pluripotent cells run amok.

During cell division, however, the demand for energy to divide in the form of ATP is very high. This is how our TKI kills them. Gleevec, tasigna, sprycel, all bind to the white blood cells ATP site and cause cell death (apoptosis). But only the ATP site in CML cells. In normal cells, the ATP site is differently shaped (lock and key idea) and so they are unaffected (for the most part).

The only time leukemic stem cells are susceptible to TKI attack is during cell division - which is rare. This is why (most likely, my opinion), treatment free remission works for some people and not others. Some got their LSC's killed during division while others LSC's were not dividing when they stopped therapy. It is a theory of mine that LSC's can be induced to divide following a 3 day fast so that I can expose more of them to sprycel. Over time, it is my hope, I get them.

One final thought - we don't know what a minimal level of LSC is tolerated by the body that will not cause disease. In other words, one LSC is not enough. There is a need for a population of them so that together they produce enough signal proteins which tell T-cells to not attack them. This process is a whole other topic.

I also had a moment when the platelets dropped a lot. I got spectacular results with beet juice. I did not believe it myself. Drink beet juice 3 times a day, if possible before eating at least half an hour. It does not have the best taste in the world, in fact I hate it.
At this moment , you say you're doing everything to make you feel good. I know because I said the same. Beet juice is fantastic as a result but hard to drink for long periods.
My wife discovered it was losing his gross taste if she mixed it with parsnip or carrot or parsley root. You will see good results in just a few days . You should do your analyzes to monitor your platelet count.
About curcumin . I take curcumin daily. Curcumin is highly indicated as a second-line treatment with Dasatinib. Here are some links :
- Curcumin potentiates the anti-leukemia effects of imatinib by downregulation of the AKT/mTOR pathway and BCR/ABL gene expression in Ph+ acute lymphoblastic leukemia.
- Curcumin derivative C817 inhibits proliferation of imatinib-resistant chronic myeloid leukemia cells with wild-type or mutant Bcr-Abl in vitro.
- Multi-targeted therapy by curcumin: how spicy is it?
- Curcumin synergistically augments bcr/abl phosphorothioate antisense oligonucleotides to inhibit growth of chronic myelogenous leukemia cells.
- Curcumin affects components of the chromosomal passenger complex and induces mitotic catastrophe in apoptosis-resistant Bcr-Abl-expressing cells.
- Inhibitory effect of curcumin on proliferation of K562 cells involves down-regulation of p210(bcr/abl) initiated Ras signal transduction pathway.
These are just a few of the scientific articles on the use of curcumin in CML.
Here's an article about curcumin and vitamin D:
-- Nutritional support for chronic myelogenous and other leukemias: a review of the scientific literature
However, there is still a problem. A big one .
Curcumin has a pronounced antiplatelets character.
-The regulatory role of curcumin on platelet functions
-Interaction study between antiplatelet agents, anticoagulants, thyroid replacement therapy and a bioavailable formulation of curcumin (Meriva®).
-Curcumin, hemostasis, thrombosis, and coagulation.
-Biological and therapeutic activities, and anticancer properties of curcumin.
I realized from my personal experience that I used it when it was not the right time.
My advice is to wait until you stabilize your platelets, then you can use curcumin gradually.Be patient . Learn to be patient .
There are two very important vitamins for platelet formation: B9 and B12 . I did my analysis for vitamins B9 and B12 and I added the appropriate supplements.
Just as important as beet juice is wheatgrass juice .Wheatgrass juice is extremely useful for many others and for increasing the number of platelets. Wheatgrass chlorophyll is essential for blood. I drank wheatgrass juice and still drink.
Keep us informed about your evolution. Do not be afraid, the number of platelets is a fight you can fight and win. I could .

Hi scuba,i am really interested in the role of exercise(especially running) on LSC.waiting for your enlightening reply.

It's intriguing ... exercise does seem to cause HSC's (and probably LSC's) to mobilize outside of the bone marrow:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830735/

"Exercise as an Adjuvant Therapy for Hematopoietic Stem Cell Mobilization"

https://www.ncbi.nlm.nih.gov/pubmed/22457109

The effect is apparently short lived, but does lead to stem cells getting into circulation and 'homing' back to the bone niche environment. Apart from 'filtering' out LSC's, I have no insight to what advantage this confers. It is reasonable that HSC / LSC mobilization is an evolutionary development to move HSC's to a remote site for damage repair. This probably occurs during a shock event like loss of blood during an accident. In this case, these HSC's are of the differentiating variety to re-start rapid blood cell growth quickly in the area needing blod. Non-differentiating stem cells stay behind in the bone niche.

In the model above, exercise would serve to let loose some LSC's so a TKI can destroy them. Just another quiver to attack them.

Regardless whether exercise can help in the fight against CML, exercising is good for you that's for sure.

Scuba, thank’s for a great explanation! Fascinating!

I just wonder, how do you mean, can white blood cell be created in two ways: Either from a stem cell division or from the division of another white blood cell?

If not, how does blocking the ATP pocket of the white blood cells stop new ones from being created?

Is it the white blood cell that signals back to the LSC to divide? And that blocking the ATP pocket of the white blood cell stops this ”callback”?

Also, how can TKI stop LSC from dividing? Does the LSC also have the ATP pocket just like a leukemic white blood cells?

Study the figures in the article below and you will get a feel for blood cell formation:

https://www.thermofisher.com/us/en/home/life-science/antibodies/antibodi...

Anytime a cell divides - and this is true for all cells, they need energy in the form of ATP to complete the division. The energy helps mobilize and assemble the proteins so that two cells exist when there was one before. Stem cells are no different. Whenever they divide, they too need energy to complete the process completely.

The energy pocket in these cells which receives the ATP molecule are shaped in a specific way (3D geometry) - think of this as a specific lock. ATP will bind to this site and the cell is off and dividing. Other receptors on the cell membrane will receive signalling proteins (called cytokines) which tell that cell 'when' to divide....what to divide into and whether to blow up and die. But without ATP, the sudden trigger to divide will kill the cell. It wants to divide, starts the mitotic process and can't complete it - no energy - so dies.

This is where imatinib, dasatnib and nilotinib come in. These man made chemicals 'bind' to the ATP site only in CML cells (mostly) which are "keyed" differently in terms of shape than normal white blood cells. As a result, when these cells go to divide, they are starved of ATP - and die. This is why we are able to recover within a few weeks after starting treatment following diagnosis - there are a lot of CML cells dying.

(no doubt, this relatively sudden death early in our treatment is what triggers a sudden 'need' for new blood and starts stem cells dividing - so early in treatment a lot of the LSC's are probably killed off too. Over time, normal blood takes over and re-establishes itself as leukemic blood fades away)

Blood stem cells that are not dividing are not affected by our TKi's - and that's how we lose remission when we stop taking our drug. When they do start to divide (they get a cytokine signal to build up the blood for whatever reason), they divide as do normal blood stem cells and then CML is started all over again if a TKI is not present.

The only way to "cure" CML, in my opinion, is to attack the LSC as well as any daughter cells. Some sort of vaccine that 'teaches' the body's immune system how to attack any new LSC that is formed is probably what is needed so that we no longer need to take a TKI. Personally - I do not believe it is necessary to kill every cancer cell - and then we're magically cured. I believe the Philadelphia chromosome is created all of the time in healthy people. They just have an immune system which keeps it to a relatively few cells.

Thank you sir, i will certainly follow your advice and monitor my CBC closely, Platelets is the only test that fluctuate so much especially with Sprycel, i will tak to my Oncologist about reducing the dose, but they are not prone to listen much really...

but thank you again!

i will keep you and everyone posted on any changes, and will add my Vit D test for Monday.

cheers

G

Thank you for your thorough explanation, so much that I don’t know yet:/ 

i will definitely try Beet and wheatgrass... these days flavor is not a priority, and will look into the other Vitamin that you mentioned, my pharmacist is very serious about letting him know of any supplements, and i know that if i would tell him about any of these supplements would say no:( i think i will try and monitor the test results, thats all i can do.

 Thank you again

gian

SCUBA you are great