8 replies to this topic

[Widgeonus]

Sort of like what Scuba is doing. Although the program is for people over 65, it shows that there is a possibility that the body will keep CML in check when taking Gleevec on intermittent schedules. All those that lost response resumed taking their normal dose on a normal scheduled and regained optimal, and sometimes deeper responses.

 

http://www.nature.co...bcj201575a.html

 

 

[scuba]

No surprise to me. Next we'll be reading how they went two months off, one month on ... then three months off, one month on.

Almost as if the body is getting conditioned like a prize fighter to fight CML via the immune system.

 

I did receive correspondence last week from Dr. Druker regarding my personal trial of complete cessation. He told me that my not losing MMR after 8 months reflects an immune response taking hold. It may not be perfect and perhaps by letting CML "pop" its head up may enable the immune system to strengthen its attack on CML - hence the deeper response when Gleevec was re-started for some cases as reported above. 

 

It's all guessing to a large degree. The take away is that for those of us who have achieved at least MMR/PCRU - stopping and then starting does not lead to disease progression. As this study and other research has reported, the risk is zero. This is why I undertook my personal trial. I felt the risk was worth it.

 

So - Trey - does this give you a higher level of comfort to give this approach a try? One month on - one month off? These are the "clinical" results you have been waiting for .... 

Edited by scuba, 28 September 2015 - 04:16 PM.

[Trey]

About 50% lost MMR and about half of those also lost CCyR.  Losing CCyR in that many participants is not a very impressive result.

 

Pulse therapy has been tried for years as a concept and works for some.  It is one of several sub-options to complete cessation, and could have better results for some than a complete cessation.  But I would prefer a shorter pulse cycle than in this test (one month on / one month off).  Shorter pulses might have better results. 

[scuba]

About 50% lost MMR and about half of those also lost CCyR.  Losing CCyR in that many participants is not a very impressive result.

 

Pulse therapy has been tried for years as a concept and works for some.  It is one of several sub-options to complete cessation, and could have better results for some than a complete cessation.  But I would prefer a shorter pulse cycle than in this test (one month on / one month off).  Shorter pulses might have better results. 

 

Shorter pulses is certainly worth considering - but another way to look at the results - 21% lost CCyR or 4/5th's maintained it! That does seem more impressive for patients to be able to "discover" if this approach can work for them and if it doesn't:

 

"In optimal and stable responders, a policy of intermittent imatinib treatment is feasible, is successful in about 50% of patients and is safe, as all the patients who relapsed could be brought back to optimal response."

 

In my own case, I was going to re-start Sprycel if my PCR broke above MMR and stay on for two years. In light of this study, I will probably just go back on for a month and then go back off again and see what happens? I may be able to go that route. Hopefully my current approach is working and I won't have to go back on at all. But the article above is intriguing. 

 

You have been PCRU for so long and had a quick response to Gleevec - you very likely would succeed (no drug) were you to try.

[Pin]

About 50% lost MMR and about half of those also lost CCyR. Losing CCyR in that many participants is not a very impressive result.

I agree with you, not that impressive. I wonder why they recruited those in MR3.0 though, you'd have to think less ccyr would have been lost if they were in MR4.0 or better to begin with.

[Pin]

I did receive correspondence last week from Dr. Druker regarding my personal trial of complete cessation. He told me that my not losing MMR after 8 months reflects an immune response taking hold. It may not be perfect and perhaps by letting CML "pop" its head up may enable the immune system to strengthen its attack on CML - hence the deeper response when Gleevec was re-started for some cases as reported above.

I find this so hard to understand! I thought the immune system either wins or loses categorically. It's clearly not like that though, more like an ongoing battle maybe?

I would much prefer it to be gone, just like a virus - with only the memory of what it looks like etched into the killer T cells memories

Also, I think we need to be careful saying zero risk - whilst I would love to believe this, I think the risk is still there - just predicted to be low based on the research so far

[scuba]

I find this so hard to understand! I thought the immune system either wins or loses categorically. It's clearly not like that though, more like an ongoing battle maybe?

I would much prefer it to be gone, just like a virus - with only the memory of what it looks like etched into the killer T cells memories

Also, I think we need to be careful saying zero risk - whilst I would love to believe this, I think the risk is still there - just predicted to be low based on the research so far

 

The immune system (and our other systems as well) does not function in a win/lose kind of way. It functions in a 'it's good enough' kind of way. It's helpful to think of immune response as a form of crowd control; a couple of bad actors hanging out on a street corner - no big deal, local police can handle it, but hundreds of bad actors? - need to bring out the Guard. Our immune system responds in a similar way - but via protein signals expressed by the cancer cells (http://www.merckmanu.../tumor-antigens). It takes a critical amount for the immune system to ramp up. And in some cases, for whatever reason, it ramps up too late or with not enough. We're all unique on on how our immune system responds. In some cases eradication may occur (impossible to know for sure) - or in others, a low level residual is tolerated.

 

In the same way that a germ triggers an immune response (as do cancer cells), other triggers are necessary to end the response and to shrink the population of defending white blood cells. This is why our white blood cell count can dramatically change up and down depending on the state of infection. What makes cancer cells hideous is that they have a secret weapon that foreign germs do not. Cancer cells are 'self' and have "inside knowledge" - they produce triggers to tell our immune system to stand down while they proliferate. So the cells multiply and multiply and our immune system ignores it. That's the crux of the problem. But it does take a lot of cancer cells producing the triggers to tell the immune system to stand down. What this threshold is and how to sensitize the immune system to a lower threshold is the subject of much research:

 

http://www.nature.co...ll/ni.2703.html

 

Cancer cells are created by our bodies all of the time. The reason we do not get cancer disease is because at low levels, these cells are not able to stand down the immune system and either will get eradicated (to the extent that eradication can actually ever occur) or go into quiescence. But for whatever reason - over time, perhaps when the immune system is weakened, the triggering threshold for cancer proliferation is crossed - and the cancer grows and is not able to be stopped by the body alone. And keep in mind, cancer cells themselves, including CML, have internal triggers to cause the cells to die on their own (apoptosis) when DNA errors occur. So a lot has to go wrong for cancer to establish. The establishment of CML disease is a perfect storm of a lot going wrong. 

 

In my case, there is no doubt I have CML - I have a positive PCR result for the bcr-abl protein. The only way this protein is made is by a Leukemic cell. It takes a million of these cells circulating in our entire body before there is enough material in a blood sample for the PCR test to detect the presence of the bcr-abl protein. But to put in perspective, our bodies are circulating over 30 trillion blood cells (5 million alone are in a drop of blood). One million out of 30 trillion is a very low number expressed as a percent. This why PCR is so useful - it detects at the molecular level the bcr-abl protein long before we actually have any disease symptoms.

 

In my CML case, I have no apparent expansion of the disease currently - although I am testing one month at a time. My PCR is hovering up and down below MMR - without the use of a TKI for the last nine months. Why? Two explanations are reasonable. One - my immune system is checking the expansion of the disease. It's keeping it at a very low level. Or two - The disease itself is quiescent, more or less, and not triggered to proliferate for whatever reason at this time. It may never proliferate again, or I'll have a big jump in PCR and will have to resume therapy. I'm just fine with one and two working together in order to avoid taking Sprycel.

 

I do wonder, how many "normal" people, if tested for bcr-abl, would test positive? The only people who get tested are the ones who show up at their doctor complaining of painful spleens, high wbc counts, pain, fever and other symptoms. It's my personal belief that there are probably a lot of people in the general population who would have a positive detection for bcr-abl who will never CML disease. Their immune system is doing its job.

Edited by scuba, 04 October 2015 - 09:37 AM.

[scuba]

I find this so hard to understand! I thought the immune system either wins or loses categorically. It's clearly not like that though, more like an ongoing battle maybe?

I would much prefer it to be gone, just like a virus - with only the memory of what it looks like etched into the killer T cells memories

Also, I think we need to be careful saying zero risk - whilst I would love to believe this, I think the risk is still there - just predicted to be low based on the research so far

 

I agree with you - the risk is not zero. It's just really really very small. So small, that I am more concerned about my artery health (family history) and making sure I don't lose sight of diet and exercise than I do CML. I truly believe - 100%, I am going to leave this planet by some other cause - hopefully old age  - and not by CML.

[Trey]

The key is that our immune system needs to fight "self" (our own cells, even though they are changed).  Although leukemic cells are slightly different, they are still "self" and not different enough to trigger an immune response in most cases.  Whether this can be learned over time is the primary issue, and that is unknown.  This is what the "leukemia vaccine" studies are trying to do, but with little success so far for CML.  It is unknown whether the immune system is the key to TKI cessation success, or some other factor(s).  There are several other possibilities.  No one knows the answer to this at this time.