15 replies to this topic

[CallMeLucky]

I got my latest test results and it looks like I am dancing around between detectable and undetectable on the PCR.  My last one was negative, this one was slightly positive.  My thinking all along was that the last one might have been a false negative.  Fortunately my FISH went back to negative.  My last FISH had shown 1 out of 500 positive, which was largely considered to be a false positive.  The FISH was negative this time around so I think I am done with that.

I'm having trouble really understanding how to calculate my log reduction given the way the lab is reporting the results.  They are not using international scale and basically they are giving me the percentage of BCR-ABL detected when comparing to a control line.  When it went negative on the last one, I just let it go as it didn't seem worth while trying to figure out how to calculate the true log reduction when it was negative, but now that it ticked back up a little, I am trying to really get a clear picture on what the trajectory has been and how to properly calculate the log reduction.  Overall the trend is downward so that is good, but I would just like to understand how to really calculate this once and for all, now that I have a good sample set.

So here is the test history with the latest being at the bottom, with the exact verbiage they use on the report.

Trey, Phil, Gunner - anyone up for giving another math lesson?

Thanks

7/7/2010
Specimens submitted: Blood(Paxgene)
Test Performed: Quantitative RT-PCR for detection of minimum residual disease.
RNA quality: good
Methodology: Real-Time Reverse Transcription Polmerase Chain Reaction using TaqMan assay Design
Primers: TBP (control) BCR, ABL
Diagnostic Interpretation:Positive for BCR-ABL (P210) transcripts, indicating presence of a CML-type Philadelphia chromosome, consistent with CML or a subset of ALL.
After normalization (comparison) with positive control cell line K562, the level of positivity for BCR-ABL is approximately 1.2%

10/25/2010
Specimens submitted: Blood(Paxgene)
Test Performed: Quantitative RT-PCR for detection of minimum residual disease.
RNA quality: good
Methodology: Real-Time Reverse Transcription Polmerase Chain Reaction using TaqMan assay Design
Primers: TBP (control) BCR, ABL
Diagnostic Interpretation:Positive for BCR-ABL (P210) transcripts, indicating presence of a CML-type Philadelphia chromosome, consistent with CML or a subset of ALL.
After normalization (comparison) with positive control cell line K562, the level of positivity for BCR-ABL is approximately .25%

12/13/2010
Specimens submitted: Bone Marrow
Test Performed: Quantitative RT-PCR for detection of minimum residual disease.
RNA quality: good
Methodology: Real-Time Reverse Transcription Polmerase Chain Reaction using TaqMan assay Design
Primers: TBP (control) BCR, ABL
Diagnostic Interpretation:Positive for BCR-ABL (P210) transcripts, indicating presence of a CML-type Philadelphia chromosome, consistent with CML or a subset of ALL.
After normalization (comparison) with positive control cell line K562, the level of positivity for BCR-ABL is approximately .367%

3/14/2011
Specimens submitted: Blood(Paxgene)
Test Performed: Quantitative RT-PCR for detection of minimum residual disease.
RNA quality: good
Methodology: Real-Time Reverse Transcription Polmerase Chain Reaction using TaqMan assay Design
Primers: TBP (control) BCR, ABL
Diagnostic Interpretation:Positive for BCR-ABL (P210) transcripts, indicating presence of a CML-type Philadelphia chromosome, consistent with CML or a subset of ALL.
After normalization (comparison) with positive control cell line K562, the level of positivity for BCR-ABL is approximately .0081%

6/13/2011
Specimens submitted: Blood(Paxgene)
Test Performed: Quantitative RT-PCR for detection of minimum residual disease.
RNA quality: good
Methodology: Real-Time Reverse Transcription Polmerase Chain Reaction using TaqMan assay Design
Primers: TBP (control) BCR, ABL
Diagnostic Interpretation: Negative for BCR-ABL (P210 type) RNA transcripts, indicating absence of cells with CML-type Philadelphia chromosome
Diagnostic sensitivity: This assay is negative in <1% of CML cases.
Technical sensitivity: A clonal cell population <0.003% may not be detected by this assay based on the RNA quality of the sample

9/19/2011
Specimens submitted: Blood(Paxgene)
Test Performed: Quantitative RT-PCR for detection of minimum residual disease.
RNA quality: good
Methodology: Real-Time Reverse Transcription Polmerase Chain Reaction using TaqMan assay Design
Primers: TBP (control) BCR, ABL
Diagnostic Interpretation:Positive for BCR-ABL (P210) transcripts, indicating presence of a CML-type Philadelphia chromosome, consistent with CML or a subset of ALL.
After normalization (comparison) with positive control cell line K562, the level of positivity for BCR-ABL is approximately .00084%

[scuba]

Gary - The variation you report here is well within the margin of error for these tests.  The results indicate to me that you are essentially at the detection limit of the test and will probably continue to drop (albeit slowly) over time.  Eventually no test will detect the transcripts even if they are there.  As Trey often points out - even at PCRu - there are likely some million Leukemic cells still in the blood.  At PCRu, their presence - although undetected keeps going down if the drugs are working.  And Gleevec seems to be working in your case.

The concern would be if the detection jumped one or two logs upward - say from .0008 to .08  (two log jump up).  A one log change is simply moving the decimal place on digit over left or right.  A two log jump is two decimal places (factor of 10).

You seem to be using the same lab - so the results are probably consistent.

Personally - anything below .000  is probably the best you can do.  As far as I would read this - you are still "PCRu". 

Go have a cigar!

[CallMeLucky]

Thanks Michael, I appreciate the comments.  I can honestly say that I am not stressing it.  I was surprised when the last one was negative and I was expecting this to bounce back into detectable.  I'm actually pleased that when it bounced back it was a whole decimal place lower that the previous detable test so in trying to look at the big picture of trends, I like the way it is going.  Psychologically the nogetive is a plus, it just makes you feel like there is a chance it is gone.  When I think about stopping drug someday, I think it would need to at least be negative for a long time.  I know some studies are looking at stoping with MMR and seeing if the body keeps it in check, but that spooks me.  So seeing a little detection makes me aware it is still there for certain and I am that much farther away from the day when I can stop treatment.  On the other hand, there is the part of me that is resigned to this being life long and that is not so bad, and I am just happy it is under control and I get to go about my life.  So either way it is good enough.

Still, I would like to get the math down.  I did some calculations and this is what I came up with.

Date	MSKCC	Log Reduction
7/7/2010	1.20000%	-
10/25/2010	0.25000%	0.68
12/13/2010	0.36700%	0.51
3/14/2011	0.00810%	2.17
6/13/2011	0.00000%	#DIV/0!
9/19/2011	0.00084%	3.15

This appears to be correct, but it throws me off because the nurse had said I was at a 4 log reduction and my doctor told me I was MMR (3 log reduction) based on the 3/14/11 results.  If my calc is right, I was only a little over 2 log at that time.

I know I am probably splitting hairs here and I think the fact that different people are calculating this different ways lends to the confusion.  For instance my log reduction is based on my personal starting point of 1.2%.  How that percentage is calculated appears to be different at different labs and it also brings up the biggest issue I have had with this whole 3 log reduction thing to begin with.  If I start at 1.2% and someone else starts at 10.2% when we both reach .00084% they will have a larger log reduction than me, but in theory we should have the same leukemic burden.  So what good is log reduction?

I think in my case, what they are basically saying is that out of every 100,000 cells in my body, 84 carry the BCR-ABL gene.  At leass I think that is right, unless I am not converting that percentage correctly .  Do I need to first divide the percentage by 100?  Should have paid more attention in math class.  Either way, I guess we'll see what happens in 3 months.  Perhaps it is time to start taking some curcumin!

[Trey]

The log reduction issue is an exercise in measuring with a micrometer after cutting with a meat axe.  It is merely a rough measure of progress.  Personally, I would prefer to use my diagnostic PCR as the starting point, but using the lab standard is fine.  Both have Kentucky Windage in them.  Maybe even Aussie Windage, but that is a different matter.

It is not unusual to bounce around the PCRU limit for a couple PCRs.

[CallMeLucky]

Thanks Trey.  I think it just annoys me that I don't fully understand how the calc is down.  I get that it is not that accurate, and yes I get that it is silly to try to understand how to properly calculate something that is going to result in a subjective answer.  But, I still want to figure it out.

I have my dianostic PCR as the starting point.  So am I calculating this correctly and am I correctly stating that my personal log reduction is 3.15?

Am I correct in my thinking that if I was had started at a higher diagnostic number and got to the same place I am today I would have a greater log reduction, but effectively be in the same place from a leukemic burden perspective?

[Trey]

It is certainly beyond -3 log.  But I will not fall into the trap of allowing Phil to criticize my maths by agreeing with your 3.15 since he considers himself to be the Exchequer to the Keeper of the Queens Royal Maths & Semi-Solid Waste Treatment Department, and has scolded me on occasions for sullying the Queens Royal Maths.  But it looks close enough to me.

From MR Exchequer Hisself:

http://community.lls...d/4218?tstart=1

[CallMeLucky]

Ok, then if I use the logic Phil had in that post (which is the same gunner had in one of his posts) then it looks like -3.1549 is the verdict and represents my personal log reduction.  Which means my negative on the last test was probably just over a 4 log reduction, which I believe is the level of sensitivity they go to and I am dancing around that line.

No point in splitting hairs any further I guess, although I still feel somehow cheated ironically.  If I understand this correctly, then if I had started at 12% (clearly not as good as starting at 1.2%), today I would be at a personal log reduction of 4.15.  So I'm "penalized" for catching it early according to this system.

I think it is time for me to stop thinking in terms of logs.  It just doesn't seem to make sense to me when I have the ratio, which appears to be a better indicator of leukemic burden.  The lower that ratio the better until it is 0 (or at least sustained undetectable).

[PhilB]

The key thing with log reductions is 'compared to what?'  All a log reduction tells you is how big one number is compared to another number.  Bur if I tell you that I have twice as many pairs of socks as Michael, but Trey has three times as many as Tedsey, that doesn't give you any way of knowing whether Trey has more socks than me - unless you know what the relative baselines were ie how many socks Michael and Tedsey have.

Personal log reductions are perfect for measuring direction and speed of travel, but are meaningless as regards where you actually are.  They give you an idea of how quickly your socks are being eaten by the washing machine, or indeed if your socks are breeding, but they don't tell you when you are going to run out of socks.  Your 'personal' log reduction is indeed 3.15, but all that means is that you have over 1,000 times fewer socks than you started with.  All the diagnostic / prognostic measures like MMR are based on something closer to absolute sock count, and must therefore take into account how many socks you started with.  The piece of information you are missing is what your lab considers to be the 'standard' level of socks a person starts with, or alternatively how many socks do they consider to be MMR.  That's the question you need to ask your onc.

As to your calculation that 'out of every 100,000 cells in my body, 84 carry the BCR-ABL gene', I'm afraid it doesn't quite work like that (and you are a bit out on the maths).  What actually happens is that the lab sends their trained sock hound to have a rummage through your chest of drawers and see what it finds.  What they have found in your case were 84 socks and 10 million handkerchiefs.  Again you need to know what their standard sock level is for this to be fully meaningful as a number (because otherwise you don't know what the normal ratio of socks to hankies is for that particular sock hound), but unless you have a lab that is way, way off the normal reporting scales, what you can say for certain is that you have very, very, few socks indeed and will probably get frostbitten toes come the winter.

Phil

[CallMeLucky]

Thanks for the analogy.

I have to figure out how to get that missing piece you are talking about.  But I'm not so sure my Onc has it.  Anytime I ask her she talks to me in terms of log reduction and has always looked at it in terms of my personal log reduction.  I may have to make some inquiries to the lab.

So what exactly would I ask them?   Something like "what percent when compared to K562 is considered MMR in this lab?"

Anytime I have asked this type of question to the doctor or the nurse, they just go back to log reduction and take it as number of decimal places I have moved since diagnosis.

[PhilB]

Unfortunately it isn't that rare for doctors to not understand how to interpret the numbers properly.  All you can do is keep asking 'what number would this lab consider to be MMR' until someone give you an answer (or the phone number of someone at the lab who can).  You do have to recognise though that a perfectly valid answer in your case would be 'Why on earth do you want to know?  You are already way beyond that level.'

Phil

[Trey]

Phil the mathemetician wandered home at 3 AM after imbibing heavily with friends.  His wife became very upset, telling him, "You're late! You said you'd be home by 11:45!"  Phil the mathematician replied, "I'm right on time.  I said I'd be home by a quarter of twelve."

[gunner]

Trey, Lucky, and Phil went hunting one day. A suitable target appeared, and Trey fired three feet to the left. Lucky fired three feet to the right. Phil, the statistician, proclaimed "We got it!"

[Trey]

Three mathematicians walk into a bar, with Phil bringing up the rear.   You'd think Phil would have ducked.

[CallMeLucky]

There are three kinds of mathematicians, those who can count, and those who can't.

[HeatherZ]

Thank you Phil for making me smile.  I just got lab work done the other day in prep for my appointment next week.  I am in the panic/worry/anxiety phase of waiting for test results and you definitly brought a huge smile to my face and relieved some of my stress.

[PhilB]

If we're doing old jokes about maths:

Three guys go for a job interview and all get asked the same question: 'What's two plus two?'

• The statistician consults his tables and announces that he's 95% confident that it's somewhare between 3.5 and 4.5
  
• The engineer uses his slide rule (I did say it was an old joke) and finally declares that he makes it 3.98
  
• The accountant looks at the questioner and says 'What do you want it to be?'