31 replies to this topic

[r06ue1]

I was reading a little on the My PCR website and found this interesting tidbit of information:  

 

 

 

 

Q.5 Is PCR the only test I should have done during my treatment?  

 

PCR is a powerful tool in CML but it is not the only test needed

during treatment. A bone marrow test is recommended at

diagnosis to look for 'accelerated' (more aggressive) features in

the marrow. A bone marrow test is also the only way to obtain the

'karyotype', where the chromosomes are examined in a number

of cells to count the number with the Philadelphia chromosome

(the 9:22 swap, which appears as a long chromosome 9 and

short chromosome 22) or to see if any other genetic damage is

visible.  

 

The karyotype and FISH (fluorescent tagging of cells to count

the number with the Philadelphia chromosome) studies are

recommended to be repeated until they turn negative (this is

called 'complete cytogenetic remission' - or CCyR).

Once this milestone is passed and confirmed, the PCR test is the

only test that will show residual levels of CML and becomes the

main way of monitoring.

 

 

So it sounds like once you hit CCyR, BMB's and FISH are no longer required.  I found this very interesting because my Oncologist told me that after my BMB at diagnosis I wouldn't need another one as long as I was making good progress which contradicted much that I had read in the past.  Is this new information which some Oncologists haven't gotten yet or bad information?  

 

Also, there appears to be a movement to new PCR levels (MR 4, MR 4.5, no more MR 5?) for the deeper responses and they don't want to use CMR any more as it gives patients the idea that they are cured.  

 

 

 

This threshold for a period of time
was called 'CMR' or complete molecular remission but based
on the somewhat misleading nature of that name (as it implies
complete response, which to many would mean 'zero' remaining
leukemia) there is movement towards simply using the names
that describe the level (MR4, MR4.5).

 

http://mypcr.org/fre...sked-questions/

 

[scuba]

The only reason that the term "complete molecular remission" abbreviated as CMR was and is used is because the PCR test gave the false impression that no bcr-abl proteins were present. The reality is that no bcr-abl proteins were "detected". And that is a big difference from "not present". Non-detection does not mean zero. So it is proper to simply refer to levels of residual bcr-abl proteins as far as the test will measure them.

 

Research into greater testing precision and accuracy are providing ways to measure lower and lower levels of bcr-abl protein concentrations. So all this means is that people who thought they were "PCRU" (for years even) will no longer be "PCRU". The PCR test got better, So now what does it mean to be CMR?

 

It is my belief it doesn't matter. Once your PCR falls below 0.1% you are in the home stretch. In fact, once your FISH falls to zero, you are in the home stretch. Likelihood of progression is reduced dramatically. PCR testing is the canary in the woodshop. It is a monitor to "verify" that all is going well. And that's it.

 

So what does it mean to be "cured". I for one do not believe that zero bcr-abl "cells" or the presence of one bcr-abl molecule means you have CML the disease. Normal non-CML disease free people almost certainly are making bcr-abl proteins because they had/have Leukemic stem cells form naturally - here and there in their bone marrow. Just look at how the number 9 and number 22 chromosome are packed in the nucleus. They are so tightly wrapped around each other (vs. the other chromosomes) right at the infamous bcr-abl break points. It's any wonder that there are not more people with CML than there are.

 

But this is where it gets interesting. We're here - us people - because nature found a way to "check" bcr-abl cell creation. When these aberrant cells get created (spontaneously a few at a time), the body has the ability to recognize it and kill it. Our bodies do not have to kill it all the way, just enough so that they don't do harm - just like Herpes. The level of "residual" CML which does not cause disease is probably a few more log levels below current testing capability. In fact it may even be as high as MMR (PCR < 0.1%).

 

One CML stem cell creation does not mean one gets CML. We get CML because our bodies for whatever reason have lost or never had the ability to kill off these cells when they occur. Normal people do. And that is where a cure lies. A cure lies in immunotherapy. Research to re-activate again or for the first time, our bodies own ability to recognize CML stem cells and kill them.

 

That's why vaccines work so well. It doesn't matter if you get exposed to measles again - your body kills it when it pops up. Herpes - we don't get cured of Herpes, but we don't die from it either - why? Because Herpes, just like leukemic stem cells is able to become quiescent and "hide" sort of speak from the immune system. But when Herpes (or LSC's) become active, an immune response occurs. For many people with Herpes that response can be quck (they never have "symptoms") or response takes  long time to manifest (they get blisters and pain before it goes away again). So it doesn't matter if your body creates a bcr-abl cell, Your body would destroy it. Discovering a way to create an immune response to bcr-abl for us is where a cure lies. But it probably doesn't require LSC eradication. I don't believe LSC eradication would work long term anyway. Not without an immune system working to kill the cells also.

 

Our friend, Trey, strongly disagrees with me on this. He believes all it takes is ONE leukemic stem cell to create CML, the disease. And unless there is a way to truly eradicate all of them, a person is not cured. I believe that even if every LSC is destroyed, what's to prevent a brand new occurrence - that random shot where a blood stem cell translocates and creates a new LSC. Following Trey's thinking, all it takes is one cml stem cell and disease starts. Perhaps - but I keep getting drawn back to how that 9 & 22 chromosome are packed in the cell and that translocations happen all of the time with other chromosomes.  Without immunity established, we probably can't be cured. And that's why for many of us taking a TKI for the rest of our lives is a necessary substitute for an immune system that can't control CML. But all is not lost.

 

It is encouraging that upwards of 50% of people treated with TKI's who achieve deep levels of remission (PCRU as it is currently defined), do not redevelop the disease even when residual levels of bcr-abl protein re-appear. That is remarkable. It reinforces the idea that getting the population of CML cells down (the LSC's in particular) is all that is needed to re-acquire immunity control. Killing off enough LSC's in the damaged bone marrow niche so that sentry duty can be effective again and normal stem cells re-populate. Maybe even be effective enough to finish killing CML off naturally without a TKI. (keep in mind that TKI's kill LSC's - but only when they divide. It's that quiescent capability that frustrates TKI destruction of the cell).

 

My theory is that when something bad happens in the bone marrow - for example, a shot of X-radiation that blasts a whole niche area of the bone where blood stem cells are located that a surge in the amount of LSC's are induced to be created in multiple areas at once. It's not one or two cells that are translocating the 9;22 chromosomes, but thousands or millions. These cells start dividing and produce cytokines (other proteins) that encourage T-helper cells to shut down the body's natural defense of NK and related cells*. The sudden increase in these bcr-abl cells overwhelms the body's ability to defend and off we go - CML disease. But once these cells are brought under control with a little help from our TKI's, it does seem - for a lot of people, that they are functionally cured.

 

So PCR testing will continue to improve and more and more people will be discovered that they are not PCRU and who knows maybe everyone has bcr-abl in their blood. When the test can detect a single molecule I bet you bcr-abl is in everyone.

 

Disclaimer: This is just my opinion based on the reading I have done to put this idea together. We'll never know until a test is invented that can detect bcr-abl down to one molecule.

[snowbear]

My doctor continued to do the FISH test after I hit 0 which was at six months.  It went back to positive even though my PCR continues to trend downwards.  I'm still making progress, but not impressive (to me). 

[scuba]

My doctor continued to do the FISH test after I hit 0 which was at six months.  It went back to positive even though my PCR continues to trend downwards.  I'm still making progress, but not impressive (to me). 

 

FISH going positive even though PCR continues to decrease can happen. It's mostly a statistical chance that a CML cell got caught on the slide. For those who are at MMR or below, there are still plenty of CML cells moving around in the blood (making bcr-abl protein). When blood is drawn for a FISH count, it's "possible" although very unlikely that one or even more cells are caught in the blood smear used to create the slide. I bet if you had a series of FISH tests on the same sample, your FISH would be zero. And chances are quite high that your next FISH test will be zero. PCR below 0.1% - there are just too few cells producing the protein to have a high chance of being "caught" and detected. But the chance is not 'zero'. Just a really small number...like the chance of winning powerball ... although 3 tickets had the winning combination of numbers this morning! 

 

p.s. we didn't buy any powerball tickets. 

[Melanie]

I also tested positive on my fish test after being negative for a year and PCR continues to decline. I think it happens more than we know because most Dr stop testing with fish after you've reached CCyR. Mine and apparently Snowbear's continued.

[kat73]

I had a karyotyping done at diagnosis, but it was from peripheral blood.  I got the report and I also got a picture of my chromosomes - all little squigglies against a grainy shadow, each in its little numbered frame.  I looked at 9, I looked at 22.  Such pathetic, pusillanimous little dorky-looking things - I couldn't believe this was the portrait of such cataclysmic disaster.  Science is just amazing.

 

I've never had a bone marrow test, so I don't know the answer, R06e1.  I think the updated NCCN Guidelines will tell you what's the normal protocol on repeats.

 

The CMR name change doesn't really matter, I don't think.  Dr. Cortes has said that anything 0.09% IS or under is "outstanding," and "indistinguishable from PCRU."  Many places just don't report out to the same decimal points for "undetectable."  And since the International Standard has become broadly accepted, the log chart has been regularized, too, so that .1 is 3 log reduction (MR3 or MMR), .01 is 4 log, and .005 is 4.5 log, which is GENERALLY as far as can be measured/reported.  So that has become the PCRU or CMR Holy Grail.  I guess they thought 5 log (.0001) was statistically not defensible.  Sort of like sunscreen labeled 80 SPF!  Anything over 30 SPG gets into the land of salesmanship and hype.

 

One thing I have been seeing and wondering about tho' - does anybody know what DMR (Deep Molecular Response) is exactly?  Is it 4 log or 4.5 log?  This comes up as a condition for joining a stop TKI study and then for reading the results.  The abstracts don't always define it. 

[Trey]

Complete Response Analytically Correlated (CRAP) will soon become the new standard for molecular testing.  A variant called Holistic Ovunicular Response for Simultaneous Elimination (HORSE) can be used in combination to create HORSE CRAP.  The patient who achieves DEEP HORSE CRAP is considered to have "exited the barn", meaning they are in Major Tom territory, out of reach from CML's ground control.

 

Until that day arrives, FISH is used until CCyR is achieved (zero FISH) and PCR afterward.  It is good practice to do both FISH and PCR until CCyR.  After CCyR a BMB will not find anything (statistically speaking).  A FISH test can randomly be positive when actually negative since it is a color test, and the colors can overlap to form false positives.  BMBs are still required for a proper and complete diagnosis, but after that the requirements are a bit fuzzy, and generally not needed unless there is a dramatic loss of response.  Karyotype by peripheral blood is not recommended since it is very difficult to find the exact cells required (metaphase WBCs) unless the patient is in advance stage disease.  Although a blind squirrel can sometimes find one acorn, a proper karyotype should look at 20 metaphase cells, and that does not happen for peripheral blood. 

 

So we look forward to DEEP HORSE CRAP while continuing to employ the tools at our disposal. 

[Tucker1]

Trey, thanks for the chuckle!! Looking forward to deep horse crap

[r06ue1]

Thanks for the info Trey

[kat73]

Trey - They did look at 20 metaphases and it was done on peripheral blood. But I will take it to my onc at Hopkins next visit and ask.

 

For the purposes of studies, when they say "DMR" do they mean 4 log or 4.5 log?

[Trey]

Some are trying to change CMR (PCRU) to DMR because they do not like the "complete" word.  I agree that "complete" is not very accurate, so I never liked CMR either and rarely use it.  Personally I prefer "undetectable" as in PCRU since it is more accurate and is also descriptive, and I may have invented the PCRU thingy but can't say for sure.  PCR reports say "PCR negative" but I liked "undetectable" better so I started using PCRU about 10 years ago.  But overall the issue should be giving the patient information they can understand, so DMR works for that purpose which makes it useful for the average patient.

 

All PCR equipment does better than 4 log, but various labs set a cut-off point.  MDA sets a cut-off at 4 log, which seems to me like it does not measure PCRU at the correct level.  Most labs set PCRU at 4.5 log, which seems about right.  Others go beyond that.  If the PCR is allowed to go beyond 4.5 log many believe the accuracy of the result becomes questionable since false positives can occur. 

[Gail's]

What does DMR stand for? And no CRAP from you, Trey!

[scuba]

What does DMR stand for? And no CRAP from you, Trey!

 

DMR = Deep Molecular Remission

[rcase13]

Would you say DMR is ≤ 0.01% or ≤ MR4.0?

[Trey]

Not necessarily either, but it could be both. 

 

Deep Molecular Response (DMR) is not one thing, it is the cut-off where any given lab stops reporting the PCR result.  The PCR would report out to maybe 6 or 7 logs if allowed, but most labs cut off the results at 4.5 log to avoid false positives.  So if a lab cuts off reporting at 4 log, both your values cited above would be correct.  If the lab cuts off at 4.5 log or even 5.0 log, neither of your values is accurate.  I hope you are not a school teacher -- your multiple choice question cannot be answered. 

 

So is it fair, realistic, reasonable, or non-fattening to say there is such a thing as "DMR" if it is defined by each lab?  (See, we can all suck at multiple choice questions.)  One person would be straining for years to achieve the 5 log DMR while all the MDA patients did their happy dances years ago when they met their paltry DMR of only 4 log.  That is an entire log difference in definition of something called "Deep".  So then it becomes a deep philosophical discussion about how deep deep is.  Can there be a deeper than deep?  I have used the term "deeply PCRU" contrasted with "barely PCRU" when discussing who can most likely succeed at TKI cessation.  Would I need to start saying deeply deep?  Barely bare?  Barely deep?  Deeply bare?  Rarely peep....well, you see my point.

 

The real problem is CML patients measure PCRU to the .001's but the entire thing is cut with the meat-axe of lab variations of PCR cut-off, which can be a log different.  Defining DMR to the nanometer when it doesn't even have any rules makes it imprecise, at the very least.  PCRU is self defining as a negative PCR for that lab.  DMR is undefined yet it sounds like it is something clear and precise.  CMR was no better, but is DMR good enough?  

 

If a patient is well served by having a term they can say to their family to explain their response level, that is useful.  I just don't see DMR as that term.  The family will not understand the "deep" or the "molecular" or the "response" -- they will continue to ask: "Well, are you cured?" 

 

Back to square one.

[rcase13]

Sigh... So if I moved to a clinic in some podunk town that cuts off at 0.01% I would be PCRU... But alas I think mine measures to MR5.0 so I may never be PCRU...

[soundoff]

I'll give you credit for PCRU Trey

[rcase13]

DMR is too close to DNR... I think I prefer PCRU. I would hate for someone to get confused and leave me for dead.

[kat73]

Whew.  The only reason I asked, a long time ago, was that the requirement for entry into any cessation trial, formal or informal, seems to be "Patient has been in DMR for at least two years," and I wondered how that is defined. It's not always spelled out in numbers.  When you are waiting around for months and years for your numbers to drop, champing at the bit to quit taking these miserable pills, it makes a difference whether they are going to start counting down your required two years at .005 or .01.  I wouldn't care, otherwise, personally.

[gerry]

They are running trials in the UK (Hammersmith) on people with low levels of CML, under MMR, to see if they can stay at the same level while off the TKI.