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.
Diagnosed 11 May 2011 (100% FiSH, 155% PCR)
with b2a2 BCR-ABL fusion transcript coding for the 210kDa BCR-ABL protein
Sprycel: 20 mg per day - taken at lights out with Quercetin and/or Magnesium Taurate
6-8 grams Curcumin C3 complex.
2015 PCR: < 0.01% (M.D. Anderson scale)
2016 PCR: < 0.01% (M.D. Anderson scale)
March 2017 PCR: 0.01% (M.D. Anderson scale)
June 2017 PCR: "undetected"
September 2017 PCR: "undetected"