PCR Confusion – A CML Patient’s Perspective

Polymerase Chain Reaction (PCR) testing for BCR-ABL has become the primary method used to monitor leukemia levels in CML patients.  As a CML patient for almost 5 years, and someone who is in regular contact with other CML patients from around the world, I continually see the confusion that surrounds this very important issue. We hang on every PCR test result, since it shows our response to CML drugs or lack of response.  Our progress is tied to PCR numbers and log reductions.  The ultimate goal for us is an undetectable PCR - we live for the results, celebrating if the numbers drop, and becoming discouraged if they increase, no matter how small. Yet, with all the importance tied to the single test, the PCR is also a source of confusion for most CML patients, and it is getting worse, not better.

The confusion regarding the PCR test results stems from several sources.

First, each lab uses slightly different procedures, equipment, and standards, which can affect PCR final results.  So PCR numbers from different labs cannot be directly compared. This is a source of confusion when an oncologist uses different labs, when we change physicians, or when we see a specialist who uses a different lab.  How do we know whether we are progressing or regressing? Sometimes our oncologist does not sufficiently understand this inter-lab variation, and becomes alarmed when the results from one lab show an increase from the previous results from another lab.  This problem has been well documented, and led to the development of the PCR International Scale concept.

The PCR International Scale was supposed to reduce PCR confusion by standardizing PCR results around standard log reduction levels.  But as labs are in the middle of this changeover-and many US labs are not participating-this PCR confusion has been increased by the very method that was supposed to make reporting simpler. 

Recently a CML patient was told she was failing Gleevec therapy because her PCR increase by more than one log.  When the story was sorted out, her PCRs had been done by different labs, and only the more recent PCR result was on the International Scale, and that number was much higher. But the oncologist did not understand this change in PCR methodology and instead of providing a log reduction comparison simply compared the PCR numbers, and assumed she was failing drug therapy.  So the patient was unduly alarmed by the higher number until a fellow CML patient pointed out the misunderstanding through a CML discussion board. 

Another CML patient saw his PCR result increase by more than one log, and his Onc did not initially realize that the lab had changed over to the International Scale, which for this lab increased the PCR numbers significantly.  The International Scale has also introduced interesting factors, including PCRs higher than 100%.  Terrific.

Other sources of PCR confusion continue unabated.  Since a PCR is a sophisticated and complicated estimate, the results can fluctuate. A PCR test could be done twice on the same tube of blood and different results would likely occur.  Some labs say that a PCR is only accurate to within approximately 1/3 log, so although PCR results are out to five significant digits, they are not really that precise. 

There are many variables, the most significant being time from blood draw to actual PCR testing.  If a PCR is done immediately after blood draw it will be higher than if the test is done 24 to 48 hours after the draw.  A false-negative PCR can result from a spoiled sample, and 48 hours is the standard cut-off for many labs, but even then the sample will have degraded by possibly 50%.  I learned the hard way not to have a PCR done late in the week.  Most labs do not work weekends, so the sample could easily spoil before the lab tests it on Monday.

There are still more sources of confusion.  Most PCR reports express the result as a percentage ratio of BCR-ABL to a control gene.  But some report PCR results as non-percentage scientific notation numbers, and others simply report a raw PCR number without reference points. 
The ultimate goal for the CML patient is to reach the PCR undetectable level, whereby the PCR test finds no leukemic cells in the sample.  But not all PCR tests have equivalent sensitivity.  So some patients are PCR undetectable using less sensitive PCR testing, while others with deeper responses remain PCR detectable by more sensitive equipment. 

PCR results are best used when viewed over time.  Longer term trends are more important than an individual PCR result.  But that can be difficult to remember when your PCR result rises.  So the PCR test is both highly important to CML patients and also a source of great confusion.  This is a serious issue since the PCR is a vital tool in determining response to drug therapy, and therefore our treatment options.