Dose Reduction 5 Week PCR Test Result (.01 to .04)

Hi John, and welcome. 

I know the feeling. You're thinking "this has bloody well quadrupled!" and it's easy to get anxious.

BUT, you have to remember that 0.01% is 1 in 10,000. So a rise to 4 in 10,000 doesn't sound so bad now, does it? Only 3 extra. Another way to put 1 in 10,000 is 10 in 100,000 - and 4 in 10,000 is the same as 40 in 100,000.

And after that might have helped a little, you then have to look at the quality of the test. A good one will have 100,000 assays to report on. That'd be ideal, but often isn't the case for various reasons. Let's say there were only 25,000 assays to report upon (not that uncommon, but a low quality test) - in this case the sensitivity is way down and you are pushing the boundaries of the test so errors can creep in. So it's always worth looking at how many assays were used to build the final figure. Not every patient gets that level of detail from their doctor though.

The pessimist might look at your results and say you just got lucky at 27 months. But even if you take that pessimistic view, your trend is still downwards. So that all looks pretty OK to me.

David.

Hi John and welcome,

My first reaction to your latest PCR result is this - the last 4 results since your 0.05% at 21mths would be considered, certainly by my clinician and expert Lab here in the UK, as showing no significant change.

The apparent change in your last 4 PCR % does not seem to me to be significant enough for you to worry -  you are not looking a molecular relapse here, and certainly not a reason for you to worry at the moment. You need to compare more than 1 result - pref. 2 or even 3 consecutive results.     

Should your next couple of results show a significant rise - particularly the loss of a zero, then that would be a reason for you and your doctor to seriously consider re-introducing your therapy at the original dose. It's the zeros that are important when PCRs get below 1%...ie. into the molecular world. A reason to be worried would be the loss of a 'log' or 1 zero - which equals a 10 fold increase in BCR-ABL1 transcripts.

To put de-escalation into perspective in patients who have responded well to TKI therapy results from the UK DESTINY trial, (de-escalation to half dose for 12 months, going on to stopping treatment) as well as other stopping trials, showed that a good proportion of these good responders with stable MR3; MR4 and lower PCR results, achieved sustainable TFRs. Of those who had a molecular relapse (not to be confused with disease relapse) after either de-escalation or stopping, all regained their original molecular responses within 4-9months after the reintroduction of their original TKI at full dose. 

As David has said, samples need to have enough normal gene transcripts used as controls, if they are to generate a PCR result that is meaningful. At very least, any sample needs to contain at least 10,000 control gene transcripts (copies) such as ABL1, BCR or GUSB.

Labs typically use one of the following normal genes, ABL1, BCR or GUSB, as their control genes in order to measure the amount of abnormal BCR/ABL1 fusion gene transcripts present in any given sample. A PCR result is a ratio of the normal gene transcripts (ABL1, BCR etc.) to the abnormal fusion gene transcripts (BCR-ABL1). A PCR result is a ratio between the two, expressed as a percentage.

Factors that can affect qPCR results.

If a blood sample has been in transit for several days or has been stored for too long after sample collection, the cells it contains will already be in the process of dying as the mRNA (protein) will have started to degrade. This means there is a greater chance of an inaccurate result. Many labs will not report results from samples where the control gene is too low i.e below 10,000 transcripts (copies).

So the main points to consider are:
• The lowest acceptable level for a control gene in any one sample is 10,000 copies (transcripts).
• Test results will show a relative proportion, expressed as a percentage, of how many BCR-ABL1 transcripts are present over the total number of cells analysed in the blood sample.

What may be relevant in your case is that as you have responded very well to therapy, your level of BCR-ABL1 gene transcripts is low:
• A sample taken from a patient who is responding well to TKI therapy is more likely to contain a good amount of the normal ABL1 gene transcripts and a much lower amount of abnormal BCR-ABL1 transcripts. This is because cells containing the abnormal fusion gene will have been killed during therapy and would be very few in numbers compared to the numbers at diagnosis or during the first months of therapy.

Sandy

Hi David,

Great to meet you and thanks for your response! After reading you response I checked my test results for number of assays. Unfortunately mine do not report the number of assays, I really wish they did. The only mention of assays was this one generic sentence "The assay is sensitive to 0.0001% IS and can detect p210 BCR-ABL transcripts ranges from 10 copies/ul to 1,000,000 copies/ul."  I too wondered if my 27 Month test result was wrong and I have simply been at a stale .04 for the last 5 months. Not exactly a pleasant thought but certainly better than thinking my disease is advancing as a result of my dose reduction or even worse not as a result of the dose reduction. If they dont end of curing our disease in our lifetimes I sure hope they come up with some more accurate and faster resulting testing methods :)

Hi Sandy,

Thanks so much for your response. I have been a long time lurker of this forum and I have read many of your previous posts over the last two years since I was diagnosed and have found them very useful! It is very interesting about the control genes hopefully this or some other factor had something to do with the difference between my 27 Month and 28 Month PCR result. Of course it would be nice if this latest result was the invalid one but I would rather have the previous result of .01 had been incorrect than an actual rise in my results. I guess I will have to wait another 4 weeks to find out.

John - Stay the course. You are doing fine. As long as your measurements are within one log (factor of 10), you are within the noise of the test.

I know it's difficult psychologically - but then again Italian priests had a problem when Galileo proved the earth was round.  PCR science is not that accurate at levels  you are at currently.

Two things - you're good as long as your PCR is at or below 0.1%.

Second - Your goal is for you to get your PCR to go below 0.01%. Anything below 0.01% is indistinguishable from PCRU. You are that close.

So enjoy yourself. You are on 50mg Sprycel  - 1/2 the normal dose. Next stop - 20 mg.

(by the way - I just received my six month PCR test result today ....  "undetected" - and I am on 20 mg. - soon I will be off all Sprcyel. That is where you are headed)

Happy for you Scuba - keep it up