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TFR report May 2025

I had my routine PCR check in March of this year and for the first time in 4 or 5 years (I lost track) of treatment free remission with no TKI drug and "undetected", seeing a positive result no matter how small was thought provoking. I was no longer "undetected" .....

My PCR came back at " < 0.01%".

It was time for me to "believe my own research" and know that this was likely a false positive within the noise of the test. I wanted to take another bcr-abl blood draw immediately, but my Oncologist suggested I wait six weeks to verify a trend if there is going to be one. We both felt this was a fluke.

Six weeks later at the end of April, I retested and my bcr-abl came back "undetected" once again. Fascinating.

As much as I know about the biochemistry and oncology of CML - I was nevertheless "surprised" to see this "blip". A result of <0.01% is indistinguishable (statistically) from undetected in terms of the precision and accuracy of the PCR test. Still, I reacted ..... what if ....

I am confident that even if CML returned for an encore, my immune system is in far better shape than it was during those fateful days back in 2010 when I was diagnosed. There is no way CML can get break out I thought. But seeing a detection is a useful reminder to stay vigilant.

Hi Scuba

Glad to hear you are back to undetected. I'd love to see the results of BCRABL testing on a large number of the general population. I think it is likely that a few people would have very low levelsof BCRABL mutation and be unaware of it, and it would not develop.

While it would be interesting for us, I don't think it likely that anyone would fund the research.

Biernaux et al. Study: In a study conducted by Biernaux and colleagues, 117 healthy subjects were tested, and 23 were positive for the BCR-ABL mRNA, indicating a prevalence of approximately 20%. The study noted that individuals aged 20 to 80 years were more likely to express the BCR-ABL transcript, while cord blood samples from newborns showed no positive results.
JSciMed Central+1ASH Publications+1

Gambacorti-Passerini et al. Study: Another study found that BCR-ABL hybrid genes are formed and transcribed in leukocytes from more than two-thirds of healthy adults. Specifically, fusion transcripts with b2a2 or b3a2 junctions, characteristic of chronic myeloid leukemia (CML), were detected in 27% of the subjects tested. Moreover, when using an additional PCR protocol targeting the e1a2 junction, typical of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), BCR-ABL fusion transcripts were detected in the majority (69%) of normal individuals.

I have long believed the mutation(s) creating bcr-abl is "natural" and occurs all of the time which can lead to detection of the protein. But for most people, this presence likely comes and goes.

Thanks Scuba. A much larger study would be nice, but this is a LOT better than nothing.

I have come to believe that everyone "creates" bcr-abl as they age. And that the only reason some people progress to disease and others do not is because of natural immune surveillance and other factors preventing bcr-abl enhancement or the rate of bcr-abl cell production (as can happen with radiation exposure) is sudden and dramatic leading to immune system being overwhelmed. Leukemic cells express the vitamin D receptor. This causes leukemic blast cells to differentiate into daughter cells which then go through apoptosis and/or caught by NK T-cells. Low vitamin D has been documented with poorer outcomes for CML patients.

Right now the PCR test commonly used is sensitive to about 0.005%. PCR-D (digital) test is more sensitive and will pick up bcr-abl down to 0.0001%, but is not routinely used in the clinical setting (more for research purposes). I would bet many more people walking around would test positive for bcr-abl if the digital PCR test is used.

Hi Scuba,

Good to know that your “blip” was just that, and you are undetected again.

Great news!

David

Awesome, this is something for everyone to be happy about, I can't find your previous post, can you share your treatment and tfr process again? Thank you so much.

Hi Scuba,

Congratulations on continued TFR! I've been reading your posts throughout the years because you also had a rare case of trisomy 8 and monosomy 7. My doctor was convinced that it's only a matter of time until they lead to AML or myelodisplasia and that HSCT is the only option. I decided to play chicken (i.e. do nothing) and for the last two years FISH test has been clean. Presumably helped by a large dose of vitamin D3/K2 supplements. This summer I'm taking a scuba diving course! (CMAS R1*)

With that digression aside, a question - if 20% of general population can have some BCR-ABL and seemingly be no worse for the wear, why can only ~50% of diagnosed CML-ers maintain TFR, despite also having a same, tiny percentage of BCR-ABL cells for years at a time? Is it really just because of some fluke with immune system?

It's a shame that there is negative financial incentive to research more into TFR, since TKI medications are a goose that lays golden eggs. Although today for the first time I was given a generic version of nilotinib, by Zentiva. Didn't expect the patents to expire yet.

TFR failure is due to Leukemic stem cells (LSC) surviving in large enough numbers in the bone marrow niche to initiate disease when they divide. People who fail TFR despite having undetectable status while under drug fall into a category where LSC's are largely quiescent during treatment. TKI's do not attack dormant LSC's. Only when LSCs are actively dividing does the ATP binding sites get locked up with tyrosine kinase inhibitors (TKI) and die. Getting LSC's to divide while in the presence of active TKI is key (in my opinion) to reducing their population sufficiently.

My personal research into LSC's led me to engage and practice periodic prolonged fasting in order to coax LSC's into dividing while taking a TKI. It would be interesting if researchers under controlled conditions would enroll patients who failed TFR and have them try TFR using my approach. I hypothesize that more people would succeed where earlier attempts failed by focusing on the LSC population.

LSC's are the key. LSC's likely form all of the time, but in low enough number that T-cells keep them from disease progression. CML patients who have been treated successfully (i.e. undetected remission), likely have a pool of LSC's in dormancy which if high in number will not lead to TFR success, but if low in number will lead to TFR success. So far the statistic is 50% success. If LSC is in high supply, over time, these cells will divide and initiate new disease if untreated. What is not known is what level of LSC population is needed for disease progression. Some TFR success may simply be luck of TKI's hitting actively dividing LSC's due to bone marrow repair. There is evidence that patients in severe crisis who respond very well a TKI (i.e. leading to rapid non-detection), may have had their LSC's wiped out too.

I continue to take Curcumin and other nutrition support which is anti-LSC in lieu of taking a TKI. The longer I remain in untreated remission, the greater likelihood my remaining LSC pool is no longer big enough to be disease causing.

Regarding trisomy 7 and monosomy 7 - my monosomy 7 disappeared years ago. But I don't know if I have trisomy 8? That's a good question.

Re trisomy 8 - guess I misremembered, or confused you with someone else.

Regarding TFR, it seems like in theory doctors could test bone marrow for presence of LSCs and based on that predict whether TFR will be successful or not? But this is not done in practice, so presumably testing is too expensive or not precise enough?

Scuba which BCR/ABL transcript do you have, e13a2 or e14a2 or e1a2? My guess it’s either e14a2 or e1a2.

b2a2 BCR-ABL fusion transcript coding for the 210kDa BCR-ABL

Interesting. I found a little snippet on the transcripts. See below.

B2A2=e13a2: I have this transcript also, however, my TFR did not stick.
Soon after I dropped from TFR, I found info that generally states that transcript e14a3 is less likely to maintain TFR compared to e14a2.

So that’s why I thought you had one of the other more favorable transcripts like e14a2.
But your case counters the general narrative for e13a2 being less optimal and that gives me hope……

Thanks for sharing your information.

Transcript Findings:
In 20–30% of cases, the breakpoint on chromosome 22 is downstream to BCR exon 1, resulting from the fusion of ABL1 exon 2 on chromosome 9 with either BCR exon 13 or BCR exon 14 on chromosome 22. The resulting fusion transcripts are named e13a2 (also known as B2A2), and e14a2 (also known as B3A2), respectively.

In chronic myeloid leukemia (CML), the e13a2 BCR-ABL1 transcript type is associated with lower white blood cell (WBC) counts and higher platelet counts compared to the e14a2 transcript type. Patients with e14a2 transcripts tend to show more favorable outcomes and achieve higher rates of complete cytogenetic and molecular responses to imatinib