18 replies to this topic

[Badger]

Why is a 3-log reduction looked on as such an important milestone as opposed to the overall percent of the Philadelphia chromosome in the blood?  For example, if person one has a baseline of 80% and person two a baseline of 20%, and both reach a 3-log reduction, person one would be at .08% and person two at .02%.  Or is this what the international number represents (I'm only give the log reduction)? 

[Happycat]

Honestly?  I think they talk about log reductions because it can be represented by a whole number (3), versus a fraction like 1/1000th, or vs. a percentage (0.1%).   A whole number is easier to understand for most patients and doctors. 

Traci

[Trey]

Because only BMB and FISH can show the percentage of leukemic WBCs in the blood, and they are not sensitive enough for long term measurement of residual disease.  PCR cannot show the percentage of leukemic WBCs in the blood.  Although a PCR is written as a percentage, it is not a percentage of leukemic WBCs in the blood, but rather a percentage related to a control gene.  So there needs to be some other method of setting a treatment goal, such as log reduction.  The 3 log reduction was picked as a result of early Gleevec trials (IRIS trial) which showed that the 3 log reduction puts the vast majority of patients into a "safe zone" from which they do not normally relapse.  The PCR is mainly a research tool, not primarily a treatment diagnostic tool, so it is not a perfect tool for this purpose.

[Badger]

That's why I'm confused.  Isn't the number that's used as a baseline from the BMB the %BCR-ABL?  And doesn't the PCR also measure the same thing?  I would think that, rather than a 3 log reduction from a baseline %BCR-ABL, the important thing would be the overall percent that one is at.  In my example, wouldn't the guy who started with a baseline of 80% and had a 3 log reduction so he's currently at .08% be worse off than the second guy who started at 20% and is currently at .02%?  Or are these numbers too insignificant to worry about the difference?

[CallMeLucky]

I've grappled with this myself many times using the exact same logic.  Here are my thoughts

1. The 3 log reduction is more a measure for researchers to measure a group than an individual.
2. The 3 log reduction is a prognostic indicator that shows if you can reduce the leukemic burden by such a factor, the likelihood of progression is significantly decreased.  So the actual PCR number is not what is relevant, but rather the fact they were able to diminish the disease by that factor.

It is particularly interesting to me that I recently read a presentation by Dr. Cortes and it explicitly stated that the 3 log reduction was based on a standard baseline and not the individual's decrease.  But it also said that the significance of the individual decrease had not been studied.  So this goes back to my first point, despite this being personalized medicine they cannot run trials and measure everyone individually so they have to come up with a baseline to compare the group against.  The reason they can't or won't say if an individual 3 log reduction is significant is because it has not been studied. 

Frankly I think we are at a disservice when we stay up at night worrying about our PCR and it is clear that these numbers are all statistical gymnastics.  At the end of the day as long as your trend line is going down at a good pace and then stays low, it appears that is what is needed for progression free survival.

[pamsouth]

Trey, I am a little confused as to the language from your regarding;  Quote "it is not a percentage of leukemic WBCs in the blood, but rather a percentage related to a control gene. "  What do you mean Control Gene?

Pam south

[Tedsey]

So it seems to me that the cytogenics are the only reliable thing.  Stay CCR and pray you stay there.  As for Dr Cortez, what standard baseline was he talking about (international scale)?  Do you have a link to this article?  It is unsettling to hear that a personal baseline has not been well researched and may mean nil.  I was dx with what must have been a high PCR (however more or less unquantifiable for 6 months).  At six months and a different lab/onc, my PCR was 13.739% (probably much higher than most lab standards).  At 12mos, I reached CCR with a PCR of 1.334.  My last PCR this Nov. (1 1/2 years later) was .066.  I assume that is close to MMR.  Now, no FISH was ever done (ever), but I came out as 100% cellular on tests.  I can only guess I was in high 90s or 100% if a FISH was done at dx.  I cannot find a percentage or anything reporting a quantifiable karyotype at dx, (only evidence that the fusion protein was found).

And to vent, I still feel very sad and angry that the CML was so bad off when dx (I was told it was not dx early and was on the edge of the next stage).  I had extreme weightloss for 3 years (brushed off totally by docs, but it was a constant struggle that I lost sleep over).  I had seen more than 3 different MDs who looked at my blood.  I had two babies and two surgeries (c-sections).  Eight months before I was dx, I had an absolutely NORMAL CBC.  What happened in that 8 months post CBC?  Why were there no signs of the disease (except weightloss)?  (Ironically, I greatly feared I had stomach cancer--it runs on my mother's side.)  I had beg to get my yearly check up moved up because my abdomen swelled up, SUDDENLY (and not over time that I could ever tell). 

So it is clear to me, physicians must look at people on the cellular & molecular level first  But real personalized medicine seems like such a pipe dream.  But with the success of TKIs with CML, it appears to be gaining more interest, if only it can become affordable (outward symptoms will be thrown to the wayside---so very unreliable... "Oh doc, I have a pain in my #!$*#...").  I still have yet to experience the famous night sweats (and my WBC was 180,000 at dx).  Guess I will have to wait 'til menopause, if I get there.  Then, I will freak out the CML is getting worse...  Oh wait! I already do that.  Oh well...

I am so ready to spit in a cup and send it off to that Google founder's wife.  I don't care what they do with it (hold the research ransom for $$$$--or whatever).  It is hard to live with my CML story or to think that the "excellent" MDs I saw at a renown medical institution were just plain bad at what they did for a living.  But I guess no one looks for or wants to believe it is cancer in someone my age (I had one doc tell me that she would not check my heart, when I asked,  because I was too young to have heart problems!  I am also adopted (at the time I didn't have any medical info)!!!!  People of all ages have heart problems!  Yes, it is mostly older people you see on the billboards for cancer centers (and mostly the elderly that I see at my cancer center), but people of all ages get cancer.  That's enough for me.  If caught early enough, many will live at least an avg. lifespan. 

Sorry, I needed to vent again,

Teds

[scuba]

Teds - have you had bone marrow work done?  I don't recall in the forum discussions ...

[CallMeLucky]

http://www.wherearey...orge Cortes.pdf

Check out the slide on Molecular Response in CML

"3 log reduction (from standardized baseline).  Using reduction from individual baseline not validated."

[scuba]

Gary, This was very good.  It really helps me get insight to Dr. Cortes' thinking.

Note that the date was 2009.  A lot has changed since then with the success of Dasatinib (Sprycel) and Nilotinib (Tasigna).  Dr. Cortes no longer prescribes Gleevec (Imatinib) for first line therapy.  And he prefers cytogenetics every six months to monitor BOTH Ph+ and Ph- cells along with PCR.  He also said that cytogenetics is a very good prognosticator for success or failure.  And he is doing a lot of work on dose.

[pamsouth]

SCUBA,

Did you not receive an email or letter from Novartis, they were to shut off co-pays for Gleeven Dec 2010 but extended it to the end of 2011.  Now Novartis will only give co-pays for Tasigna.  There is a big push for the newer patents.  Gleevec set to expire in 2015 and when it becomes generic will be very affordable. I read somewhere it drop to $5.00 to $10.00 a pill.  Tasigna and Spyrcel are more expensive and newer patents. 

I truly believe after reading some report that many people are still doing well on Gleevec and Gleevec should still be a first line of defense.

I think a lot of the push is to get the newer patents out there as money will be desperately need for research.

I not saying if you sincerely need to switch drugs not to switch.  But newer doesn't necessarily mean better.

When I went to IU Cancer center of Indiana for a 2nd opinion.  The doctor said most patients just want the newest, latest, or even the one on trial. Not necessarily because they need to switch they just think it is better.  But you are the opposite.  You want to stay on your Gleevec.   All these TKI have side effects so I think sometimes you just exchange one problem for another.  But them I am would think if you really wanted to know which drug you should be on would be to know which mutation you have and which drug was designed for that particular mutation.

So many things to consider, and it is not a one size fits all.

I really got tired of thinking about cancer and wanted my life back until my ONC suggested, no pushed, to switch to Tasigna, so I was forced to go back and do some research.  Now it is the Holidays and I have made my decision to switch Onc and to stay on Gleevec.  But am still keeping one eye on the discussion  board.

The other thing I like about Gleevec, the longer it is around the more data we have.

I have been on Gleevec since 2005 and hope to STAY on it for the remainder of my life.

We have Blue Cross Michigan UAW Retiree.  Received our insurance plan for next year.  Cobra, out of pocket and deductible up again!!

Also received 11 page letter from UAW RETIREE Medical Benefits Trust that holds and invest our health insurance. There was little good news to report in terms of the broad economic trends.  These economic developments are having a negative impact on the value of the UAW medical trust or funds for our insurance.  unless our world economic quickly recovers (health care) these broad trends will put further pressure on our financial health.  In another words our health trust funds must live with in its means.  1. Investment earnings. 2. Health care inflation. 3. Health care utilization of the retiree population ages. 4. Changes in Medicare legislation. 5. Changes in health behaviors. 5. Life expectancy.

The above was taken from UAW RETIREE MEDIAL BENEFIT TRUST REPORT RECEIVED DECEMBER 8, 2011.

[scuba]

Pam,

I absolutely understand and empathize on the financial benefit of Gleevec.  Once it goes off patent, CML treatment could be no different in cost than a couple hundred dollars a month if not less.  And - if Gleevec works for someone with minimal side affects, they made it.  They have what will become a low cost solution.

However, the CML game is one of population dynamics.  You want to get the population of CML cells down relatively quickly for effective management.  In that regard, Spyrcel and Tasigna (and some of the other drugs coming) are extremely effective more than Gleevec in reducing tumor burden. 

Perhaps a patient can use Sprycel to get to MMR or better and then switch to Gleevec for maintenance?  That might work.   The key is still to get the tumor burden down.  And for that, I am thankful there is Sprycel.  Gleevec did not work for me.  So I have no choice.

[Tedsey]

Michael,

Sorry to answer so late.  I have been off the boards a bit, but lurking when I can.  I get a BMB every six months.  Since I am not yet MMR after 2 years, my next one will be due sometime this February.  After my last experience, I am going to take the nurse up on the "little margarita with my Lidocaine" she offered last time.  I should have had one!

Last one showed increased blasts, (don't forget I had been pancytopenic), and improved anemia.  Otherwise, nothing alarming.

Take care,

Teds

[Tedsey]

Thanks Luck.  I just couldn't read through it all.  It was getting rather depressing.  I cannot get to MMR after being on the strongest CML drug (Sprycel) heading on 16 months (but I think I must be close---OK, OK, standard deviation, standard deviation...).  Of course, I have not read the particulars of the study to see how many of the population started out above, below or near the lab standard.  Clearly there are those who start with a greater leukemic burdon than others overall.  That must have some impact on numbers (despite stage of the disease).  Since Dr. C. says that a standard PCR has more clout than an individual's number from dx, again, without reading the particulars of how the study was created, it is hard to digest not knowing if a starting PCR was controlled for.  But I guess it is all about how fast you reach the lab standard and go from there.  But there seems to be some pieces missing without seeing all the particulars of the study.  So, I will not let it depress me.  It is just one study.  There are those on the far left and those on the far right.  It is possible to be on either side even with the best and worst predictors of survival.  And it is very possible Dr Cortez is wrong.  In my heart of hearts, there is more to predicting progression than looking at how fast patients get to MMR in a certain time period against a lab standard.  There must be other predictors at the cellular and molecular level (even epigenetic events, including environmental) that must be considered per individual.  Medicine is not there yet, so we still rely on methods as a Sokol and a study such as this, thus, things that only look at the surface.  My instincts tell me this particular info. is likely irrelevant (or happens for a completely different reason---and we cannot rule out chance or construction of a possibly flawed study).  I know I am not in a position to seriously critique Dr.C. and his colleagues.  But I have a wee-bit of an informed opinion.  I guess, all in all, I refuse to have someone tell me when I am going to die.  I prefer studies that support what seems to stop the progression of leukemia in some people and why.  Regarding this study, why do we have to know all this?  But if it is to push people to develop even better drugs (because, even with Imatinib, people still die from CML), then I am all for it.  Guess I am just talking outta my butt again.  Ahhhh!  That was a relief.

All the best and thanks for posting the slide show.

Teds

[scuba]

Hi Teds,

When did you start taking Sprycel and what was the PCR level at that time. 

Dr. Cortes told me that he does not tie the start date of treatment on other drugs to the current drug. He looks for response rate with the new drug in comparison and that becomes the start date.  So for me, I started Sprycel 20mg. in May 2011 with near 100% Ph+ in my bone marrow and 55% PCR. By November, Ph+ dropped to zero and PCR fell to 0.12%.  Cortes said this is response in 7 months that he is happy about and gives me a good prognosis.  He's thrilled that I did this on 20mg. I am curious what your response rate has turned out to be since you began Sprycel only.  That would be the comparison for Sprycel effectiveness. I am "myelosuppressed" still, but mildly so.  I don't like it and wonder why my body can't make more cells to compensate.  But that's the way it goes. I want a zero in the PCR number and I want the Monosomy 7 that appeared to go away by next bone marrow.  Cortes told me that he "likes" bone marrows.  Joy and rapture on that.

Merry Christmas!

[Tedsey]

Thanks for the info.  I started Sprycel Aug 30, 2010 (PCR 4.921%).  I was CCR 12/10 (PCR 1.334%).  And at about six months after Sprycel, PCR was .684%  My last PCR was .066% on 11/11.  The PCR is done by LabCorp.  They are not on the international scale.  I never went to an onc who believed in FISH, but I am probably too far along in treatment for that.  My last karyotyping was done 12/10. 

He "likes" bone marrows!?!?!  I would like to hear him say that after he gets one.  It should be the law that eveyone who orders one must undergo one himself AND only with lidocaine.  For the record, I don't like bone marrows.  I am still very angry with mine for turning on me.

All the best and a Merry Christmas to you too!

[Tedsey]

Oh, and lots of zeros your way!

[scuba]

I love zero's.  Nothing but zero.  I like "undetected" even better.

[scuba]

So in 3 1/2 months you went from Ph+ to CCyR (Ph+ = zero).  And your bcr-abl transcript level (what the Ph+ makes) keeps dropping so that it is below 0.0 _.  This is a very good response in the time since you started Sprycel.

Looks to me like it's working.