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AML Relapse (May 2008)
"Trojan Horse" Remissions?

WARNING!!! The following are only my own personal speculations
as an uneducated non-medicallly trained individual. I have only gathered information
that I have read or heard (hopefully represented correctly) and drawn my own conclusions.
I have been known to come up with "off-the-wall" ideas and so take everything I say with a large grain of salt.

Note: At the point I wrote this I still hadn't learned where to find peer reviewed studies (pubmed)
- so these were pretty much just my wild speculations that launched me out in search of something else for Jaymun.
I included this here as a curiosity - just to show how I was blundering around at the beginning.
I never blunder about any more (grin) (just kidding).



I'm wrestling with the science of AML relapse - trying to confirm that our plan for Jaymun agressively counteracts statistical history. As I understand, the chemo we use to fight AML (leukemia) is not so much toxic to cells on contact unless they are actually dividing to reproduce. That is why cells of organs (as opposed to bone marrow) that reproduce over a longer period of time (bones, heart, lower skin layers, etc.) are not as quickly affected by the chemo, because a smaller percentage are actually dividing / reproducing during chemo's systemic presence.
Let's say (as an "over-simplified" example) that in 10 days time all your blood cells would have divided and reproduced new cells. So then we can use chemo (including the time it takes chemo to clear the body) for up to nearly all that time (say 9.9 days), leaving .1 % of the healthy immune system remaining to grow back. And since leukemia cells reproduce faster (that is why they over-run the bone marrow) - in our example they would all have tried to reproduce themselves in, say, nine days time. Since chemo was in the body for that entire shorter time - hopefully we kill ALL the cancer.

However, with Jaymun in spite of 3 rounds of chemo and a bone marrow transplant (with it's own chemo - called "conditioning") we still have relapsed leukemia. I suppose before we address increased risk - we should prove that Jaymun actually relapsed, rather than this being fresh cancer (Jaymun's blood or environment just prone to cancer).
So we tested, and genetically proved this to be the same cancer as before. Two other reasons:
*At one point in remission he had 100% donor blood, before it slipped to 99% upon relapse. Since upon relapse there were 2% blasts, the 1% showing up of his old immune system was probably all cancer.
*Since the relapse started in his CNS system (that did not receive radiation last time) (even though last time the stubborn cancer in his skin required spot radiation after three rounds of chemo.)
I believe these reasons are why we conclude this is relapsed leukemia - not fresh cancer.

And relapsed AML is harder to treat (I was told 20% long term survival for Jaymun).
So I am taking these statistical "leukemia" facts to draw conclusions from:
Problem A) After every relapse - it becomes harder to achieve remission.
Problem B) Even if you achieve (post relapse) remission, subsequent relapses become more probable.
Problem C) Even if you achieve (post relapse) remission, subsequent relapses happen more quickly.
#1) To conclude from these stats that Jaymun's (first) AML relapse (after transplant/remission)
is more resistant to treatment
- we first need to:

a.) Disprove that statistically, Jaymun's length of remission (1 year 2 months) shows us that his leukemia was not so much resistant - but just of a quality/quantity that was undertreated last time. In that case as long as we intensify his treatment this time, we should be able to erradicate the cancer. However, even though we are intensifying treatment
(adding the radiation mode), I was still given a lower (20%) hope for long-term cure by the docs. Although some of that bleaker outlook might be due to riskier complications (because of longer recovery?) ...I would need to see studies showing the relapse probability portion of the risk is less than at first.

b.) Disprove that the statistical problems above do not prove relapsed leukemia to be resistant, because statistically relapses aren't diagnosed and treated as quickly as initial diagnosis. That relapse treatments simply start at a disadvantage, and are consequentially less successful, However, my thought here is that this seems patently improbable, because having once achieved remission, it would seem that vigilance for future relapses would grow, not relax.

c.) Disprove that we shouldn't use statistics to measure relapse risk - rather simply count remaining cancer cells upon remission. This does not work because our measurement methods are inprecise. We can't measure cells below a certain level, or in every location in the body - meaning remission achieved after second transplant might have more remaining cancer cells than remission achieved after first transplant. However, from rapidity and strength of eventual, measurable relapse we can directly deduce things about the "under the radar" early part of relapse. Alternatively, theorizing consecutive "sinking quality" remissions in the face of intensifying treatment would already be acknowledging increasing resistance to treatment.

d.) Disprove that the statistical advantage of a donor transplant wanes once relapse occurs because over time donor systems have less "staying power" than the original host system they replaced (rather than the leukemia growing more resistant). We would have to argue that whatever the short-term benefits of a transplant, in general, donor systems are not as long-term vigilant against cancer - that the "graft versus leukemia" benefit from a donor system is front loaded and short lived (because the donor system "learns" to accomodate the rest of the body - and cancer along with it). And so likewise we would argue the initial GVL effect of a 2nd transplant is weaker than the 1st. In order to test this point, we would have to study only persons who actually had a first relapse and a second relapse - and then find a lower rapidity of second relapses of "non-transplants" as compared to the rapidity of second relapses for "transplants". My guess is the data would disprove this.
#2 So let us agree that relapsed leukemia (after each transplant) grows more resistant to treatment.
How? Well... with each treatment regimen, if we leave some cancer cells that avoid destruction, we facilitate natural selection in some form. The resistant cells can smoulder through successive remissions because of our imprecise ability to detect low levels of cancer. It is possbile to have either thousands or ten-thousands of cells without detecting either - so successive levels of remission could easily be twice as dangerous. The relapsing cancer is then an expanded growth of a particular subset of original cancer cells that was already resistant and evasive to the treatment.
Why? Due to natural selection because of one (or some combination) of the following possibilities:

a.) Not because we killed the cancer cells dividing consistantly faster - leaving ones dividing consistantly slower.
That would have explained problem A)
(harder to get back into remission) because an increased amount of the cancer cell population would be slower reproducing cells (the original ones evaded chemo by slow reproduction).
That would also have explained problem B)
(future relapses more probable) because if earlier treatments (including transplant) allowed the evasion of slow reproducing cancer cells - then it is probable later treatements would also.
However - that would NOT explain problem C)
- because if the new cancer was a slower growing cancer, future relapses should happen LESS quickly. In fact, then successive treatements should eventually select the cancerous blasts to the point where their growth speed would approach normal blood, and so not threaten overgrowth of the normal blood system, or at least relapses would space far between.

b.) Possibly because we killed the cancer cells that were easily penetrated by the type of chemo we used, that were able to be killed in one reproduction generation, or that were somehow not physically sheltered from treatment (chemo/radiation). That would explain all three relapse problems A), B), and C) because each remission would retain a larger population of these drug resistant, stronger, or protected cells to seed the next relapse.

c.) Theoretically we killed the "predictable" cancer cells - that there exist erratically reproducing cells which go to both extremes. Most of the time they grow more rapidly than usual - but sometimes they pause longer than usual. When we were doing chemo - a certain small percentage of them were exercising the ability to be dormant. However - now the entire popluation of cancer cells has that ability - to "sleep through" chemo.
This would also explain all three of the relapse problems A), B), and C) - because each remission would retain a larger population of these "erratically growing" cells to seed the next relapse.

d.) Probably because we didn't kill the "stem cells" - that there exist certain cancer cells (stem cells?) that ALWAYS reproduce more slowly, maybe even more slowly than regular blood. These cells would have to be able to produce both cancer stem cells just like themselves which divided more slowly, and also alternatively at times produce regular cancer cells which divided rapidly.
This would also explain all three of the relapse problems A), B), and C) - because each remission would retain a larger popupation of these slowly dividing "stem cells" to seed the next relapse.
#3 The general approach? ... would seem to be to continue search for more effective/targeted treatment using current modes (chemo/radiation). However, if, as we change drugs and intensify radiation, future relapses are not on a curve to be at least merely as probable/rapid as the first relapse, then I suggest the possibility that we are missing a small essential component - we are simply not "closing the deal" during the regimens we have now. That resistant cancer is merely the result of sequential "almost succeeding" treatments. I suggest the theory that at the end of each induction or salvage round, we are faciliting periods of time for "un-inhibited" growth of the remaining (most resistant) cells. That although the majority of the remaining cancer is severely weakened - and necessarily reduced by several logs, a small unmeasurable resistant seed portion is growing vigourously against the measurable trend. Since our induction/salvage regimen is not followed up with immediate donor infusions, and our induction/salvage treatments severely weaken the normal immune system, a time period of several weeks exists where this unmeasurable resistance can flourish. We currently shut down this opportunity after conditioning/prep (when we transplant) but unfortunatly, after each prior induction/salvage chemo round, we just wait for the immune system to come back.
I argue that since during second transplant we use more intensive chemo or radiation - that should counteract increased resistance from first transplant. But since there is predicted not only a more probable, but also more rapid second relapse - that suggests the scenario that if salvage produces "remission" - it is a "Trojan Horse" remission - that directly during part of the salvage regimen itself is a time of higher than normal "resistant" cancer growth.
#4 So lets speculate about some things we could do to combat Jaymun's resistant relapsed AML: I am proposing to find a mechanism to check the uninhibited growth of resistant cancer cells at the time when the cancer cell count is as low as other means can bring it, but while the recovering weakened/distracted immune system is outpaced by the remaining drug-resistant, erratic, or stem cells. During this time you would not want to use radiation or other toxic means - because the immune system needs to recover ASAP. I am not proposing substitute treatments for chemo / radiation - merely additional modes to:
1) Enable each successive chemo or conditioning regimen to progressivly lower the resistant cancer population. At the very least the treatments would not even have to substantially reduce cancer cells, as long as they held the line on the current population - so that successive chemo rounds could continue to lower the population. At least that way the erratic or stem cells wouldn't have that short period of time of un-inhibited growth that would negate the effects of the prior treatment, and make eventual relapses more rapid and future treatments less successfull.
2) In case of failure to cure, at least you maintain the same percentage risk between successive relapses as you would search to find a donor with the appropriate GVL effect. If a particular (sibling) donor transplant failed to have expected "Graft versus Leukemia" effect, you could later move to haplo or cord transplant without increased risk of relapse.
3) To help radiation truly "overlap", chemo or vice/versa because a lower margin of resistant cells was maintained.
Possible modes?
a.) In the case of the theoretical dormant or stem cells - is there a way to stimulate rapid stem cell growth during the conditioning chemo - so all the cells will be dividing and effectively destroyed by chemo? I suppose the danger here would be if the stem cells were chemo resistant - we would exacerbate the disease - also we would kill more healthy cells.
b.) During the front part of recovery between salvage and second transplant prep) could we use our available donor (who's immune system is already present in Jaymun) to maintain an immune response (some kind of T-Cell depleted Donor Leukocite or (multiplied?) NK cell infusions?)
c.) If b. works - then in other cases - could the same thing be done during initial induction. When cancer is first diagnosed, bank and "multiply" (from the original host) healthy T-cells to be infused after the initial induction regimens.
d.) After re-induction, go (slightly) faster to transplant. (?) (longer recovery?)
e.) Between inductions, and after transplant give cellular repair treatment (mesenchymal cells)?
f.) After transplant give prophylactic DNK/DLI infusions (widen relapses and allow immune system maturation)?
g.) Improve early measurement of the strength of resistance by "Culturing" leukemia cells throughout treatment (comparing with a "baseline" response.) Would this help deciding about the agressivness of individual relapse treatment?
h.) Trigger the immune system to fight cancer harder (vaccination?)
i.) Trigger the immune system to fight cancer harder (supplements?)
j.) Trigger the donor system (pre-transplant) to fight cancer harder (vaccination / supplements?)
k.) Are there substances non-toxic to the body but toxic to leukemia?
l.) Are there substances that will reverse resistance (to chemo AND NK cells)?



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