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Could Fasting + TKI 'cure' CML?

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4102383/?utm_content=buffer...

Prolonged Fasting reduces IGF-1/PKA to promote hematopoietic stem cell-based regeneration and reverse immunosuppression

A key reason why TKI's fail to cure CML is the fact that non-dividing leukemic stem cells avoid TKI induced cell death (via apoptosis). TKI's work by binding to the energy site of dividing cells (ATP socket). Only when a CML cell is dividing is energy demand high enough that without ATP fuel, the cell dies. That is how TKI's work (for the most part).

Leukemic stem cells, however, can remain dormant for years. In the absence of a TKI, when they start to divide under various signals, our CML disease relapses and we have to start taking TKI again. Some of us while PCRU are able to exhaust CML stem cells (LSC's) while taking a TKI and can move on to treatment free remission (~40% of PCRU patients). And that is great news, but for the rest of us, apparently, enough LSC's stay dormant long enough to always escape TKI assault. So when our TKI is stopped, CML soon thereafter relapses (often within six months).

This is where fasting comes in.

Apparently, fasting (3-5 days, water only), triggers blood system renewal. First, during the fast, older white blood cells are autophaged (i.e. destroyed and recycled). This process provides necessary proteins and building blocks to keep the body healthy during no food intake and also depletes the blood of white cells (mostly non-functioning anyway so you won't miss them). Various hormones and protein signals are changed which primes the bone marrow stem cells to divide rapidly in order to restore blood function. Essentially old blood cells are replaced with new ones directly derived from the stem cells (and this would be both LSC's and HSC's). The actual renewal occurs during re-feeding. When food is re-introduced (fast is ended), blood stem cells (leukemic as well as normal ones) are triggered to come out of quiescence and rapidly divide. This is key.

If we can cause (through fasting) a forcing of LSC's to divide on "cue", then in the presence of a TKI, they will be killed. LSC's are not immune to TKI's. They die when they are dividing and can't get ATP (TKI blocks it). There is evidence that depleting LSC's is key to treatment free remission. Getting at the LSC's cures CML.

My thinking is to put myself into a series of 3-5 day fasts over a year (maybe two or three times) as a way to force 'en masse' a coming out party for the LSC's - where my Sprycel drug is waiting for them to kill them. This way I can more quickly deplete this population of cells while my normal cells take their place. It's a theory that I am testing right now. (I have done one fast during Lent so far). I will do this two more times and then stop taking Sprycel to test if my CML doesn't return. I tried cessation once and it didn't work for me (I never lost MMR, but I did lose PCRU, so I went back on drug).

Interestingly - there is also evidence that fasting alone could weaken CML on its own. This is because T-cell population (killer cells) are modified and become more aggressive against cancer cells - especially on low carb, high fat diets. Key here is to keep the body in Ketosis which starves cancer cells (solid tumor as well as blood) of necessary sugar.

What I am describing above is no formal "cure" or even scientific (need clinical trial under strict mathematical control). But it's my body and any "idea" which doesn't cause undo harm that can be tested easily is worth it to me. And there is the side benefit of fasting - better metabolic health, less weight, lower blood glucose - all good to have anyway.

Not eating chocolate, however, will be tough.

 

Great experiment plan. Let us know what happens!!!!

I wonder if they ever look at dietary habits in the 40% of patients who can stop TKIs without recurrence? Maybe the weight or the Body Mass Index could be significant?

I think it is mostly avoiding sugar (simple carbs) and fasting periodically. Fasting was a way of life for our ancestors. Some because they had no choice (food especially carbs were scarce and mostly seasonal) and others as part of religion. Our modern society has gotten away from fasting as part of living.

Recent research articles are clearly showing the positive effect fasting has on the human blood system.

I'm curious about this and may give it a try.  If I understand correctly, a three day fast (approximately 84 hours) followed by normal diet with TKI will possibly reduce the LSC population and should be reflected by lower BCR/ABL numbers.

I'm currently taking 300 mg imatinib per day, but I have some leftover 100 mg dasatinib that I could take one dose of upon ending the fast.  I would then resume the imatinib therapy.  I tried dasatinib earlier this year but it caused a strange sensation in my chest and some mild arrhythmia that I really didn't like.  I'm currently waiting for my current PCR results.  Here's a link to my history: https://communityview.lls.org/users/kirk

I'm wondering what would be the best timing of the fast in relation to my next PCR test?  I suppose it might be instructive to do the fast now and then there would be a couple of months until my next PCR.  What do you all think?

Do you continue to take your TKI during the fast period?

Absolutely. That is the key part.

During the fast CML stem cells (as well as normal stem cells) will start to rev up and begin self renewal by dividing in preparation for blood cell expansion (progenitor cells) and differentiation. You want your TKI hanging out and available so that when CML stem cell division occurs, the TKI is there to enter the cell and binds to the ATP (Adenosine Tri-phosphate) socket leading to cell death. It's like the last scene in Butch Cassidy and the Sundance Kid where Paul Newman and Robert Redford are safe and sound as long as they stayed in the building (Leukemic stem cell not dividing) - but as soon as they make a run for it outside - the posse is waiting and not just one guy - but the whole army (i.e. Tyrosine kinase inhibitors)...fade to black. Dividing CML stem cells don't stand a chance in the presence of a TKI. The key is to get them to divide (i.e. ... come out of hiding).

My theory is that fasting (which we now know) forces blood stem cells to divide at a time known to you so that they take a big hit - maybe sufficient hit that their population is so reduced they are no longer able to initiate CML disease (T-cells become effective again and mop up residual). It may take several rounds of fasting over a year to "pulse" the CML stem cell level down enough to be effective.

By the way - blood letting (as in donating a pint of blood if we were allowed) should cause the same thing. A sudden loss of blood also triggers the same biological response and forces blood stem cells to divide (to help quickly replace lost blood). Of course fasting is with its side benefits of weight loss and metabolic improvement is probably better for you than losing blood deliberately.

Just curious, when you stopped Sprycel, how long before your pcr went up?

Hi Karinne,

It took nine months and it never broke above MMR (i.e. 0.1% PCR). For the first three months off Sprycel, there was no change. Then in month four, I had a slight increase (i.e. 0.01%). In month five, it went up to 0.04%, then in month six it fell back to 0.02%. In month seven, PCR rose to 0.08% and in month 8 it fell back to 0.06%. My doctor suggested I continue my personal trial as long as I was below 0.1%, but I was tired of getting tested every month. Driving and PARKING at M.D. Anderson cancer center is not fun. So in month nine, I decided to resume my 20 mg Sprycel and see if I fall back right away. I did - within two months I was back below 0.01% and now PCRU.  It was a good test and I will try again except I won't test every month since I am confident that my CML will not "erupt" suddently - but only slowly if at all next time.

I came to my own personal conclusion that taking Curcumin plus maintaining high normal vitamin D blood level was (and probably still is) keeping CML suppressed (very slow growth). I felt that my own immune system is still overwhelmed by the high leukemic stem cells I no doubt still have. I believe if I can get my leukemic stem cell population reduced below some threshold level, then I feel can be functionally cured (immune system takes over - don't need Sprycel anymore).

That's my hypothesis in any event. I am on day two of my 3 day fast to coax LSC's out of hiding and into division so Sprycel can kill them.

P.S. - I told this story to a friend of mine who has CML and wanted to get pregnant. She used my story and shared with her doctor so she could stop taking her TKI (Sprycel). She became pregnant and her PCR slowly rose during the nine months (she also took Curcumin and kept her vitamin D level elevated). She delivered twins and is now back taking Sprycel and her PCR is falling back down.

 

Hi Michael,

I was just wondering if you're taking any supplements during your fast, or just TKI and water?

Thanks, Kirk

Hi Kirk,

I do take a few supplements during a fast - mostly Magneisum, Himalayan salt water (1/4 teaspoon per glass per day), Curcumin and vitamin C.

Fat soluble vitamins which require food (K2 and D3), I don't take until after the fast ends.

Although my main driver for fasting and Ketosis is to drive CML stem cells out of hiding, I have to admit, losing weight has put me in range of my grad school days. I now have a 32 inch waist. Imagine that. I am much lighter on my feet and feel a heck of a lot better (in terms of energy and mind clarity).

And to think it doesn't cost anything to not eat.

Fasting is not for everybody and I would not recommend it for people who take prescription drugs for their heart, blood pressure, etc. (TKI's are fine - except perhaps Gleevec.) without a knowledgeable doctor's oversight. Once fasting is complete and weight loss is achieved, most people no longer need blood pressure medication or diabetes drugs. Sad that the medical establishment does not embrace this.

My fasting glucose dropped 20 points from 110 to 90 - and it's still going down hopefully to the mid-70's, my A1c is solid normal, my other metabolic numbers are all like a 20 year old. Key to this is not the fast itself. The fast just jump starts the process. What causes metabolism to reset is the elimination of sugar and refined carbs. Carbs are important to health, but not every day - and you can easily go without carbs for months at a time.

Humans were not designed to eat sugar/carbs every single day. But humans were designed to go without food from time to time - only because they had to ... no choice.

By the way - I very much look forward to that bowl of ice cream. It's just that it will be a one time treat when I hit my weight target.

This is awesome. I ve just started fast since 30 hours and felling great. I am curious regarding the outcome. I am also on Dasatinib 100 for almost 2 years now, since diagnosed. I am trying 3 days first and after this maybe move to 5 days after couple of weeks. What do you think about having tea and coffee near water? How do you feel and what are your test results lately?

Ciprians...

I do drink coffee in the morning and tea during the day during my fasts. I fast one day a week now.

Twice a year I will do a 3 day fast. My last PCR test was "undetected" and my next one is in September. I'll probably fast my next 3 days at the end of August.

I would avoid back to back long term fasts. You want your body to recover - especially recovering blood counts. It takes about two months for blood to regenerate - so after your current fast, when you start to eat again, your body will start rebuilding your immune system. You would want that to complete before hitting a long term fast again. One day fast doesn't matter.

I am eager to try stopping Sprycel again and test for durability. I''m hopeful my fasting program is helping.

Scuba - Is there any evidence that a one-day a week fast disrupts the blood-making apparatus as intended for our purposes?

there is some evidence that even a one day fast starts to stimulate stem cells (in the intestines):

https://www.sciencealert.com/fasting-for-just-24-hours-boosts-the-regene...

Dr. Longo's work, however, shows that it takes 3 days during which time the body starts to consume many of the excess blood cells (many of the old tired ones). How long it takes for this process to get ramped up is probably more than a day. It's takes a day just to get the sugar out of our system before Ketones get started.

I suspect one day fasts do not have much impact ... it's day 2 and 3 that the gene changes kick in (according to Dr. Longo). And then once re-feeding starts, blood stem cells are triggered to re-generate the depleted blood/immune system.

 

Such an interesting line of possibility.  It would be hard to construct a good study for our purposes, but I hope somebody is doing it!

I follow with great interest the scuba issue. It is a fact that the immune system wants three months to come back. I'm a month in keto. I'm preparing for 3 days fasting. The problem in this case is that TKIs because of their toxicity keep the immune system to very low levels. Perhaps he can not help the body and all the work will be done by TKIs. I am of the opinion that you may have to initially stop a drug and after three months when the immune system will recover from this 3-5-day fasting . I believe that after the regeneration of the immune system will attack the problem stem cells. Fasting must be harsh, that is, without food, water, tea, coffee ... nothing from the mouth ... some therapists do not allow a bath to do the healer.

Tom,

You absolutely should be drinking water during a fast! Water is vital for life every day. In fact, during a fast you should be drinking more water - a glass an hour if one remembers, but certainly you need to stay well hydrated. Coffee, tea are fine to drink, just without any cream or sugar added.  The goal in a fast is to remove calories.

During a 3 day fast, the body will begin (after the first day) to scavenge blood cells for their "parts". Most of these cells are older non-functioning anyway. But they do take up space sort-of-speak. As the fast proceeds these cells are recycled. When re-feeding occurs signals are sent throughout the body for stem cells to divide such as hematopoietic stem cells (HSC) so scavenged cells can be replaced. HSC's will re-generate the entire immune system with fresh new cells. This happens quickly - days - not months.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4102383/

You should keep taking your TKI during this time. In addition to their being HSC's (normal blood stem cells)l, a CML patient also has LSC's (Leukemic stem cells). LSC's were formed when an HSC mutated into the famous Philadelphia chromosome (9;22 translocation). LSC's, no doubt, receive the same signal to divide when re-feeding begins after a long fast as HSC's do. Any time an LSC divides we want it to die (apoptosis).

That's when we want to kill 'em (LSC). As they divide, we want our TKI lurking to interfere with their cell division and cause apoptosis. So take your TKI throughout.

There  is evidence that as our immune system re-generates from a fast that it alone can also attack cancer stem cells, but the data is spotty and I am not convinced yet.

The only way we can become functionally cured is when the LSC population is reduced to a low enough level to be rendered useless in re-starting CML. Research is underway with other molecules to cause this to occur. I feel fasting might get us there sooner. And if doesn't work - losing a few pounds is o.k.

I hope this is clear.

*note: non-dividing quiescent LSC's are unaffected by TKI's. Only when they divide are they susceptible.

Very interesting article you gave. What I did not understand is if with fasting only the HSCs are renewed; With LSC what's going on? Can the number of LSCs be reduced only with fasting? Without the help of TKIS. Thanks in advance scuba.

During fasting very little if anything is renewed - stem cells are quiescent. The body is conserving, recycling and clearing.

Upon re-feeding, the presence of food in the system triggers hormones with trigger genes which generate protein signals that travel to the bone marrow and cause HSC's and LSC's to divide and differentiate to re-populate the scavenged immune system. HSC's and LSC's are essentially the same except one leads to cancer if nothing checks it (LSC's).

Also - even without TKI surveillance, cancer killing cells are enhanced (NK - killer cells) so that HSC's are dividing and LSC's are attacked.

https://www.healthline.com/health/fasting-and-cancer

My hypothesis is that during fasting and re-feeding, LSC's are 'triggered' to divide just like HSC's are triggered to divide - and our TKI is present to kill the dividing LSC further decreasing the LSC population. I further surmise that once LSC's are reduced in number sufficiently for our normal immune system to take over, our TKI may no longer be necessary. That's my thinking. It's why I am doing a series of 3 day fasts - so I can try stopping Sprycel and see if I can hold PCRU.

It's just my personal theory with a bit of science behind it.

 

 

Very informative dear scuba. I accidentally found a study about Feverfew. It contains a substance called parthenolide . parthenolide may kill leukemic stem cells according to the following study: https: //www.ncbi.nlm.nih.gov/pmc/articles/PMC1988840/ What a nice thing would be if a flower cared for us! I hope this happens quickly! I hope that science will also help spread its research to other substances in addition to the beloved - necessary TKIs.

do you know where and in what form we could purchase feverfew?