4 replies to this topic

[scuba]

We have been taught that TKI's do not affect Leukemic Stem Cells - the origin of our disease.

But this is not correct - TKI's do impact LSC's.

http://www.cancernet...e/10165/2132178

TKI's can, in fact, eradicate LSC's. I have suspected for some time that cure is possible if a TKI is taken long enough to allow the LSC population to die out. As LSC's divide, they get killed - and the population of the bone marrow steadily reverts to a normal LSC population. As the article above points out, the starting load of LSC's can be prognostic. But I don't know of any test that currently measures LSC burden at diagnosis so we know from where we are starting?

I believe the key to potential cure using TKI's alone is to find ways to encourage LSC's to divide (blood draws?). As they do so, they are wiped out and eventually (according to population dynamic computer models) extinguished. Apparently for those who reach PCRU within 18 months and remain so for another 24 months, LSC extinction can and does occur (STIM study: http://www.ncbi.nlm....ubmed/20965785)

Susan: You are cured. Lowering your Gleevec dose will increase your quality of life. Taking Gleevec gives you peace of mind I fully understand and appreciate. But there are no more LSC's in your body. They have long been extinguished. You too Trey. Congratulations to you both.

My LSC's are more difficult to eradicate, I can't get below detection let alone maintain it there on just 20mg Sprycel. I need a stronger dose I believe to continue to put downward pressure on the dividing LSC's.

[ChrisC]

I have to agree: TKIs do — under the right conditions, I assume — impact LSCs.

How else did I go from 459k WBC to PCRU in 11 months, switching TKIs in the process?

I've been PCRU consistently for 3.5 years, and of that time, for the past 1.5 years I have been completely without TKIs.

In my view, the entire drama is between the TKi and the LSC, and has nothing to do with me. There must be some physical condition or environment that has not interfered with the process of eliminating the LSC.

Why do TKIs sometimes work so efficiently, and most of the time why don't they work so swiftly, even with less of a "burden" or CML challenge? And how can the efficiency be increased? What conditions allow the TKIs to work more efficiently, and what conditions hamper the process?

It's science, right?

I am WAITING for more of us to be off our TKIs: it's frustrating as could be that more can't be done for everyone. No more suffering!!

ChrisC

[CallMeLucky]

Let the bloodletting begin, I'm going to find some leeches!

[LivingWellWithCML]

Thanks for sharing -- this is very interesting.  For those of us that have been on treatment for a bit, is there a reasonable way to deduce where we might've been on the LSC median curve at diagnosis?  They correlated LSC %-age to WBC, spleen size, and blast count - many of us were diagnosed with ~ 100% FISH but might've been < 79% LSC, which could explain the quick response to treatment that the article is suggesting.

I've been trying to translate this to my own case -- on Gleevec 400mg, my response down to CCyR and MMR+ was fast, but then it ticked up a bit at the 18 month point and leveled off at MMR (2 year PCR blood draw coming up this week).  It makes me wonder if I had a lower LSC burden at diagnosis, but perhaps I need(ed) a stronger dose or different TKI choice to hammer LSCs while the burden was in the lower-risk range, but my PCR ticked up because 400mg wasn't enough and it gave the LSCs an opportunity to strengthen a bit.  But I have to think that my LSC burden is much lower now than it was when I was diagnosed, even though I was at 0.1% IS at the 18 month mark.  My last CBC in January had WBC around 3.6, so still slightly below normal -- and is that because of my current LSC burden, or another reason?  Not in the danger zone obviously, but not in the normal range either.

Should I ask the nurse to take a few extra vials this week while they have the needle in me?  Maybe induce some LSC splitting ...

[Trey]

We discussed this article previously, that there are multiple levels of "stem cells", and TKI drugs affect the lower levels but probably not the upper level stem cells which continue the disease.  Also, the researchers made numerous assumptions which are unproven since no one knows which stem cells are leukemic just by counting certain types of cells using a Flow Cytometry test, and combining with FISH testing requires assumptions which are not necessarily true.  And the highest level leukemic stem cells hide (quiescence) from such tests in the marrow stromal layers, and it is unknown if they can be killed off by TKI drugs directly if they come out to divide.