20 - The CML Testing Eplained

The explanation below is a detailed one and all honors go to Trey, who has posted this on http://ubb-lls.leukemia-lymphoma.org/ubb/Forum17/HTML/001113.html
Thanks Trey for the clear and educational explanation provided below, exactly the way we like it: In Layman’s terms!! (still had to read it twice!!)

-------

This is designed as a general overview to provide a basic layman's understanding of testing and CML. I will avoid the jargon and keep this somewhat short, so this will not cover everything in detail. For more details, Google the phrase and also askyour doctor/Oncologist.

There are tests to diagnose CML, evaluate response to therapy, assess the levels of the remaining disease, and to check for specific problems. Among these are Complete Blood Count (CBC), Bone MarrowBiopsy (BMB), Bone Marrow Aspiration (BMA), Cytogenetics Testing,Fluorescence In Situ Hybridization (FISH) testing, Polymerase ChainReaction (PCR) testing, and some miscellaneous other tests.

When a person is suspected of having CML, testing is done to confirm the diagnosis. A Complete Blood Count (CBC) test will usually show avery high white blood cell (WBC) count, and may also show high platelets (PLT) and other abnormalities. But this does not confirm that a person has CML. The confirmation of CML is usually done by Cytogenetics Testing on cells taken during a Bone Marrow Biopsy (BMB)process. During a BMB, a core sample is taken from the hip bone, and marrow cells are collected that cling to that bone sample. While the hole is open in the hip bone, fluid from the hip marrow is also takenout by a syringe, and this second part is called a Bone MarrowAspiration (BMA). The BMA aspirate or fluid is extracted through thehole created during the BMB. Cytogenetics Testing is done on the core sample and aspirate fluid. The marrow cells are viewed by a labtechnician and/or doctor under a microscope, where the chromosomes are treated with a dye and observed, and the Philadelphia Chromosome (Ph chromosome), which is the indicator of CML, can be seen and a diagnosis made. The core sample is also checked for other abnormalities. So Cytogenetics Testing is done using a BMB core sample and aspirate viewed under a microscope. Cytogenetics Testing is alsoused to check for other chromosome mutations and abnormalities, so aBMB might be done again at six months post-diagnosis, and then every 12-18 months after that, or sooner if other tests show a suspected problem such as loss of response to drug therapy. When therapy reduces the levels of CML disease to where the Cytogenetics Testing can no longer detect any Ph chromosome cells among the approx 20 that are counted, that person has achieved a Complete Cytogenetic Response(CCR).

After diagnosis, it is important to continually monitor response to therapy with regular Complete Blood Count tests. When these CBC tests show that the blood counts have returned to normal levels, and especially the WBC and platelet counts, the person has achieved a Complete Hematological Response (CHR). After that, the CBCs should still be continued, but the frequency is often reduced.

The BMA fluid taken after a BMB core sample procedure can also be used to perform a FISH or PCR test. (FISH is fluorescence in situhybridization and PCR is polymerase chain reaction). Or circulating(peripheral) blood can also be used now adays with nearly equal confidence levels to perform a FISH or PCR. Both FISH and PCR show the levels of CML disease, and are used to monitor progress, or detect setbacks or loss of response to therapy. A FISH test checks approximately 200 - 500 cells, and counts the number of cells that have the Ph chromosome (technically it looks for the BCR-ABL gene in the cells). This is done by a machine which uses a dye process, isolates approx 200 - 500 cells, and counts the leukemic cells. The result is given as a percentage of leukemic cells to good cells, sothe person can say that X% of their cells are leukemic. The limitation of FISH is that it can only count a small sample of cells, so if the level of disease is only a few percent, the FISH report will likely be zero (a zero FISH is also CCR, same as a zero Cytogenetics Test). So FISH is generally not used once the level of leukemia drops below approximately 5%. At that point PCR testing is used to monitor CML patients in this Minimal Residual Disease (MRD) status, since it isfar more sensitive. A trend among Oncologists is to start doing PCRs early instead of FISH, since PCRs are more sensitive and can be used to track log reductions in disease levels, and FISH cannot track log reductions.

There are two types of PCR tests. One is called a Qualitative PCR,which is a simple "yes/no" test that says it either detected BCR-ABL(leukemic cells) or did not detect them, but no number - this is generally only useful to help diagnose CML since it helps distinguish between CML and other types of leukemia. The other type of PCR, the Quantitative PCR, counts the number of BCR-ABL (Ph chromosome cells)and reports it, so this is the type of PCR that is useful to track treatment progress, especially in Minimal Residual Disease (MRD)status where the levels of Ph chromosome cells are low and harder to detect. Some Oncologists will do a baseline Quantitative PCR at or near diagnosis to establish a baseline from which to evaluate progress, especially toward a 3 log reduction in disease levels.

PCR tests a sample of blood or marrow fluid, and can detect approximately 1 leukemic cell out of 1 million cells in the sample. As such, it is the most sensitive testing available at this time. PCR testing can be done with relatively equivalent results from either blood or BMA fluid. During a PCR test, the BCR-ABL in leukemic cells is counted and the result of the test is given as a percentage ratio of BCR-ABL (leukemic cells) to another gene in the cells (called a control gene). So PCR results are not a ratio of leukemic cells to good cells as we might think, which technically means that a PCR result is not actually a total percentage of leukemic cells in thebody. This is one reason why PCR results from one person to another,and one lab to another, are not equivalent, due to lack of standardization among labs regarding equipment and which control genes are used (there are several different control genes used for CML PCRs). That is a reason for sticking with the same lab, so the results will be directly comparable for each PCR done, and trends can be watched. It is important when switching labs that the first PCR from the new lab be used to set a new baseline, and not be directly compared to the previous PCR from the other lab.

PCR results are very useful for showing trends, whether progress or retrogression. The hope for PCR results is to see progress toward a 3 logarithmic (3 log) reduction from the level of disease that existed at the time of diagnosis. This 3 log reduction is called a Major Molecular Response (MMR). A recent advance in PCR testing is that many (but not all) labs now give the log reduction along with the percentage number. So if your lab provides the log number, then use that. But if the lab does not provide this information, it makes the 3 log reduction goal more difficult to track, since many do not knowwhere they started at diagnosis. Because drugs like Gleevec and Sprycel can rapidly reduce the levels of leukemic cells, if the first PCR is not done before starting drug therapy, the baseline forcalculating a 3 log reduction will not be very accurate. If someonehas a baseline PCR value done at diagnosis, the 3 log goal can be calculated by taking the baseline PCR number and moving the decimal point 3 places to the left. For example, if the PCR at diagnosis was10.0%, then moving the decimal point one place to the left is 1.0% (1log), two decimal places is .1% (2 log), and three decimal places is .01%, which is a 3 log reduction. So 3 log/MMR for that person at that lab would be .01%. If someone does not have a baseline PCR, and thelab does not provide log reduction numbers, some literature suggeststhat .01% should be the 3 log estimated goal, which assumes a starting value of 10.0.
If a 3 log reduction is achieved, the next goal becomes maintaining the 3 log reduction or even continued reduction toward PCRundetectable (PCRU), where the PCR is not sensitive enough to detectany leukemic cells in the sample. This PCRU is called CompleteMolecular Response (CMR), which is the deepest level of responsecurrently measurable. In PCRU status, the leukemic cells are mostlikely still there, although fewer than 1 in a million. There is notest to determine if a person with CML is actually cured (usuallyassociated with a stem cell/marrow transplant). The current indicatoris 5 years without therapy coupled with continuous PCRU.
FISH numbers do not correlate to log reductions, so PCR must be usedfor log reduction measurements. Also, FISH percentages do not relateto PCR percentage numbers. For instance, at diagnosis I had both a FISH and PCR done. The FISH was 100% and the PCR was 7%. That isbecause FISH is a percentage of leukemic cells to good cells, but PCR is not (see explanation in earlier paragraph). Beyond that, the FISH has an error rate of approx 5%, so your FISH could read 5% but actually be zero. When the FISH result gets below approx 10%, you should rely on PCRs from then on. A recent trend is to only perform PCRs from the start and not use FISH.

There are other tests that are used for monitoring CML patients, suchas a Liver Function Test to make sure the liver is not adversely affected by CML drugs; a Basic Metabolic Profile (or Panel test) which checks both mineral levels and kidney function; heart function tests(a disputed issue among researchers); CAT Scans or physical checks forenlarged spleen, checks for enlarged lymph nodes; and complete orpartial physical exams. There are also other lab tests to check forspecific problems when suspected.

------

Thanks again Trey, Very Helpful!!

19 - The First PCR Results

So, here's the PCR test damage with history:

12/3/2007 2.2X10-1 (.22 if I remember my high-school math correctly)
12/24/2007 8.5x10-5 (.000085)
03/07/2008 1.1x10-2 (.011)

So the middle result is obviously a little off and the doc ordered another PCR test for 3 weeks from now to get a better idea on the trend. As I started typing this Blog entry, I had a little lighbulb glow above my head with an idea on why the result on 12/24 seems so far off. I work with numbers a lot and have it happen quite often that when manually balancing figures on a 10-key I'm off by 3 (due to striking a wrong key; 6 instead of 9; 1 instead of 4 etc.). I wonder if this isn't just a simple input error where the 5 was hit rather than the 2, which would have put the results more in line with expectations. Either way the trend seems to be going into the right direction and I guess we'll find out a little more the next test around. BTW this means I have a 1 log reduction. The log bit means the decimal has moved over to the left one spot.

Example:
Base = 1
1 log reduction = .1
2 log reduction = .01 etc.

For those interested in the various stages of remission, here's a little summary:

Basically there are three stages or remission

1. Complete hematological remission (CHR)- This is when the blood shows no sign of leukemia, the white count and platelets are within normal range. This usually occurs within a month of taking Gleevec and is the first stage of remission. Goal Attained!!
2. Complete cytogenetic response- This is called CCR and occurs when out of 20-50 marrow cells, no cell with a Philadelphia chromosome was detected. - For this we do the Bone marrow at 6 months (now is too early yet according to my onc.)
3. Finally we have molecular remission (MR) where out of upto 1 million cells, no BCR-ABL transcripts are detected. there are two stages of molecular response.

• Major molecular response (MMR) which is when there has been a 3 log or more reduction in BCR-ABL transcripts from PCR compared to diagnosis values (1000-fold reduction). So a 1 log reduction after 3 months seems like a move in the right direction and I guess my goal figure here is .00022.
• Complete molecular response is when no BCR-ABL transcripts are detected by PCR. Goal Figure 0.00000, You are now PCRU (PCRundetectable), The ultimate goal!!

PS: Doc liked the Shitty Chromosome Shirt, and called me a nerd for wearing it!! - Hey, at least he has a sense of humor!!

18 - The Crossed Fingers

Keep 'em crossed. We will find out the PCR results @ 4:30 PM..................... I'll keep you posted!

PS: I'm wearing my Shitty Chromosomes shirt, we'll see if the doc will be "havin' a laugh".

17 - The New Arrival

Well it’s exactly 3 weeks from now that there will a third female in the household (excluding dog), that is if the due date is a tad more accurate this time around (Ella was induced after being 2 weeks overdue, I know Jill hopes not to have to go through that again). All secret hopes for a boy have disappeared since the last ultrasound a week or so ago, but naturally I’m just as happy. I think the pregnancy has been fairly easy so far for Jill, or at least she hasn’t said much to the contrary. A little sleep deprived as of late due to uncomfortable sleeping positions, but overall it hasn’t been too bad, but who am I to say, I’m not carrying her around am I.

In general this pregnancy has been less filled with anticipation than the first time around (though we’re of course very excited, don’t get me wrong). Partially, probably, due to the fact that we’ve been through it before with Ella AND we know the sleepless nights that lay ahead. For another part it was a little overshadowed by the Leukemia diagnosis half way through, which then made us think of things like: should we sign up with a cord blood bank and store the cord blood, rather than, say, what color to paint the nursery.

All in all it’s hard to imagine there will be another little one in your life that you’ll love as much as you do the one that already is a part of your life, and who you know so well. But I’m sure that will be instant upon birth, as it was with Ella.

We’ve been asked if we would be trying for a third, you know the “give it a once more for a boy” pregnancy. We haven’t seriously discussed it too much, I think we both want to see where we’ll be at a year or so from now and then see. So for now, the answer is no, but we’re leaving the option open. Also, at this point I’m not even sure what effects the Gleevec might have in this regard if the man is taking it. I know it’s possible in the woman’s case, Like Erin Zammett did (though she quit taking Gleevec during the pregnancy all together, can’t have been an easy choice either) and according to Rob over in England it might not be an issue anymore, though nothing’s for certain. I guess I’ll have to ask the Doc.

Speaking of the Doc. I’ll be seeing him tomorrow and find out about my first PCR test results, which should hopefully give an indication if the Gleevec is doing it’s thing. A little anxious as you might imagine so: Keep your fingers crossed for me please!!

Cheers,
Rob

16 - The Shitty Chromosomes

Love these in your face T-Shirts from Mike (Jill shook her head when I held my fashion show, meaning she thinks Mike is nuts!!). So if you want to wear something unusual to your next oncologist visit, order the CML Shirt from Mike's store. Can't wait to see his face next week!

www.cafepress.com/8232

Thanks Mike!!

PS: For those of you wondering about the significance of Philadelphia, it's the Philadelphia Chromosome that's responsible for someone joining the CML Club.

15 - The Statistics

Found these statistics of CML on the website of the American Cancer Society, thought they were kind of interesting.

The American Cancer Society estimates that 4,830 new cases of chronic myeloid leukemia (CML) will be diagnosed in the United States during 2008 (that's 13.2 people per day, or a little more than one person every 2 hours). About 450 people in the United States will die of CML during 2008.

Based on my quick calculation you have an annual chance of 1 in 62,864 to get CML which is about on par with the chances of striking it rich on Antiques road show (1 in 60,000 per http://www.funny2.com/odds.htm). Guess I'd better bring my Jackalope next time they're in town!

CML accounts for about 10% to 15% of all leukemias. The average person's lifetime risk of getting CML is less than 1/5 of 1% (less than 1 in 500). The risk is slightly higher in men than in women.
The average age at the time of diagnosis is around 67 years (Cut that in half for me) . Chronic myeloid leukemias affect mostly adults, and are only rarely seen in children.
Because of dramatic progress in treatment over the past few years, most people with CML are now surviving at least 5 years after diagnosis (That's a comfort........., I Guess.........). But because the highly effective drugs are still fairly new, the average survival of people now being diagnosed with CML is not known. (We'll hope for the best!)

14 - The Bad Week

The day before Valentine’s (Yes, that totally commercialized day in February) my wife and daughter got sideswiped by a driver who must have been blind. Trying to make a left turn across 2 lanes of traffic without seeing my wife in the middle lane and banging right into her!! All seems to be well at this point, though the car was a total loss. Unfortunately Jill had to spend 24 hours in the hospital for observation (well observation of the baby really), she was starting to have small contractions. Ella was given a once over but the headbang against the window did not seem to have fazed her (tough Dutch scull).

The next day Jill came home from the Hospital and I found out from Kaiser that my sister was not a Bone Marrow match to me (but in my heart I already knew that, due to my superior prettiness genes). A bit of a bummer, but I’m glad I found out after my sister’s visit.

Then Friday rolled around and my wife was told they wouldn’t be renewing her shared teaching contract for the upcoming school year. Which means she will either have to teach full-time or if we decide to do so quit all together (not a great option since we have Kaiser’s insurance through her work, and Gleevec costs around $110 per day). The shared contract has really worked out nice for us, since it means that Ella does not have to go to a babysitter too often (no grandparents around to do that dirty work for us). I usually work Tues-Sat and Jill works Mon-Tue/Wed, which makes our weekends together kind of short but it does give us the opportunity to raise our child and only have her go 1-2 days per week to the sitter. I guess we’ll have to come up with some new master plan……

I think that was bad news in triplicate, so I’m assuming we’ll be good for a while.

13 - The Next Visitors

It’s been a bit since the last entry, somehow I never quite got around to sitting down and typing my story over the past month, even though I have quite a few things running through my head. First thing first: my sister’s visit (and my beloved brother-in-law as well of course - this is the one who still hasn't cracked a joke about my c'cision (I'm still amazed))! As expected we had a wonderful time, they arrived Friday and left Monday before heading off to Costa Rica for a week. Must be nice getting all those vacation days in Holland, need to move back soon!!! It was great to see her/them in person for the first time since the whole Leukemia thing broke. It felt good to give her a big hug and sniff and snotter for a few minutes. I think it helped to see that I still looked the same and can still be the same pain in the rear as I always have been. The next couple of days we spent playing golf (where my BinL broke another driver of mine, that’s 2 clubs in the past 2 games), wining, dining, and visiting Knott’s Berry Farm.

We took the Blacksmith Picture at Knott’s, reminded us both of our grandpa who was a blacksmith in Holland. The smell was exactly what his shop used to smell like, funny how the nose triggers memories. Anyway, all in all we couldn’t have had a better visit and were a little sad to see them leave so soon!

Next posting will hopefully be a tad quicker!
Cheers,Rob