17 replies to this topic

[LivingWellWithCML]

Hi everyone,

I hope all of you are having a good early fall season and living well with CML.  I just finished a very frustrating and discouraging 18 month follow-up with my hematologist and would be grateful for advice from you all ... at this point, I'm in a position where I need to find some peace and trust in others who have to deal with this chronic disease, and that would be all of us.  I appreciate folks giving this a read and sharing your thoughts.

Short story:

• BMB/A confirmed CP CML in March 2011
• 18 months since starting Gleevec 400mg (100% peripheral blood draws since diagnosis)
• PB FISH: Reached CCyR in ~ 5 months
• PCR: Undetectable @ 1 year, but 3.37 log reduction (International Standard) at 15 months

For the 18 month follow-up today, I did my blood draw almost 2 weeks in advance to make sure I would have PCR results in hand.  This has never been a problem in the past, but because of red tape and delays, the results were not available at my appointment this morning.  I was very agitated in the appointment, because it's just not that meaningful for me unless I know my PCR result.  After the appointment, I just received a callback from the hematologist saying that it was higher but he wasn't concerned and would check again, but I don't have specifics.  So I'm in a panic that I've lost response to Gleevec (undetectable, then 3.37 log reduction, now something higher maybe (?)).  Within the first two years of treatment, I'm now freaked out.  I couldn't get the specifics on the exact ratio from the test, or the log change from IS baseline.  Is it 3.00 log reduction, which would be within the margin of error for the test?  I don't know - and he wasn't able to share it cause he had to ping the physician who's been sitting on this test for 2 weeks waiting to sign off on it!!  So I just got this big-picture result over the phone and a supposedly settling "I'm not concerned, we'll retest in 3 months." from the hematologist.  I am not settled at all and am looking forward to a completely miserable and anxiety-ridden weekend.

Although I respect the hematologist and appreciate him making a TKI available for me, I am considering making a doc change in order to work with someone who understands that I'm super detail-oriented and want specific numbers on time, and be able to make sound decisions on the direction of my treatment.  I have learned enough from this board to understand the myriad of possible outcomes and I feel informed enough to press for another PCR sooner (6 weeks instead of 3 months), maybe even press for a BMB since I only got one at diagnosis, consider TKI change now or very soon, etc.

In addition, he made it very clear today that he is not interested in PCR test results and is basically only interested in PB FISH test results and maintaining CCyR.  He will use PCR as a guide in order to decide if FISH needs to be run; i.e., if I were to dip back into 2.x log reduction, he would run FISH to see if I'm maintaining CCyR.

Questions/feedback:

* If/when I finally get the specifics back, and I find that it's 3.00 log or worse, what would you do?  PCRU (not IS yet), to -3.36 log (on IS), and now -3.00 log reduction or maybe worse (on IS).  It sure feels like a trend to me, cause the doc said that the sensitivity of their testing machine didn't change when they moved to IS.

* CCyr is what matters, but depth of molecular response is also a factor (I've seen the studies that back it up), and I have been so encouraged to see how much faster folks on Sprycel/Tasigna have responded, so I'm already thinking that I want to make a push toward Sprycel to beat the heck out of this stupid disease.  I'm now starting to regret NOT pushing for it as first-line when I was diagnosed.  Shame on me.

* So far, I have specifically been visiting this cancer center because they run PCR on-premise, but how important is this really?  I mean, don't many thousands of CML patients that have their blood shipped for PCR testing receive results that are meaningful and aren't impacted by blood degredation?

With this situation, would you:

* Just move on with life, stay with the same doc, and wait until your next PCR result in January?

* Switch to one of the renowned, dedicated specialists in the country now (if possible), and get a BMB, etc. to get re-evaluated to see if this is going the right direction, or if there's a problem that needs to be dealt with now?  Believe me, I know that BMBs stink, but it gives a doc a lot of good information to see how things are going.

* Switch to a local/reputable onc who is more into the details, stick w/ Gleevec right now, but push for another PCR test immediately for comparison (I would probably only go to a local onc who only uses a PCR testing center that's on IS).

Wearing my emotions on my sleeve today ... I was an avid runner (even on Gleevec, I was running fabulously and felt fantastic)  but had an injury that forced me to get ankle surgery back in July, so I'm not running or doing any cardio that typically clears my mind and soul.  Not in a good place today.

That said, I feel physically healthy, so there are no physical signs that I can feel that would indicate a major issue.

Thanks in advance to everyone ....

[Sneezy12]

Gt the PCR results! Regards, Frank

[LivingWellWithCML]

Just got them about 30 seconds ago.  Man, would've been nice if I had these results in hand during my appointment this morning, so I could ask the questions I needed to ask.  Ugh!!

PCR trend:

• 4/11/2012: negative (not IS yet)
• 7/11/2012: 0.00043 IS - 3.37 log reduction
• 9/25/2012: 0.00124 IS - 2.91 log reduction

So, negative, not negative, and worse = trend.  Looks like it's time to be an advocate for myself and consider options like: 

• PCR test in 6 weeks instead of
  three months (so, blood draw on Tues Nov 6 with FISH + PCR perhaps), just to
  see if we're bouncing within the margin of error?  This trend is extremely disturbing, and
  wouldn't it be better to know now if I should switch to a different TKI?
• Kinase mutation test (which has a real probability of presenting itself over the first 2 years of treatment).  Is the test sensitive enough to detect mutations with a PCR at this level?
• Switch to Sprycel (more powerful) and expect to trend back down toward PCRU (on International Standard) - unless compassionate Ponatinib is required for T315i (assuming KM test can be run at this stage)
• Increase to Gleevec 600mg for a period of time to see if that makes a difference (I have been tolerating 400mg just fine)

[TeddyB]

Im still new here as you know Dan, but i would get push hard to get the details of your last tests before making any decision, it seems now as if you are in a place where you dont have all the numbers and facts yet, and this is not a good place to be in regards to anxiety.

I would however get another pcr test done sooner than 3 months if i was worried, maybe in 4 or 6 weeks, and i would have another BMB if the next pcr isnt up to par. (Here in Norway we have BMB`s at DX, 3months, 6months and 12months regardless of response, so i know they stink, but ask for a nice chill pill an hour or two before the procedure and it should go a lot smoother, thats what i do and it sure helps a lot) Anyway, my point is, get the results and facts before making any rash decisions, and if your onc wont oblige, then take your results and get a second opinion on them.

So sorry you are having these issues, and i hope some people on this forum can give you some more comfort, unfortunately i dont have a lot of experience in regards to CML yet, but i know i would be a little freaked out too, and id definitely push hard to get the answers i wanted.

Teddy

Edit: I see you have gotten your results now, but can the non IS PCRU test really compare to the two last tests? If not then its only the last two tests that that can be truly comparable and two tests arent really enough to show a trend? Still i think i would ask for a new pcr test a sooner than 3 months if it were me.

[Sneezy12]

The test results are essentialy unchanged. Frank

[Trey]

People will tend to  trust a PCRU and doubt the others.  It is what we want, so we believe it.  But I would doubt the early PCRU unless it is repeated.  PCRU can easily be the result of an over-aged sample.  And your last two results are flat (statistically and methodologically) so they support each other.  Another PCR in 6 weeks would be OK, and so would one in 3 months.  Kinase mutation tests are not very sensitive, so unless a person loses CCyR they are not very accurate.

[scuba]

Dan - Unless you have more than a one log increase - testing in six weeks is not necessary. Your good for 3 months between tests. But if your next test shows an increase again, then you need to move to a six week interval to verify a trend.

PCR is the canary in the mine shaft. It is molecular and reflects very subtle changes. What is important is CCyR - Cytogenetics. Dr. Cortes told me many times that he uses PCR for trend and uses Cytogenetics for prognosis. FISH = zero = you die from something else. PCR rising more than one log over several tests = retest FISH and verify.

PCR testing variation from test to test is about one log (order of magnitude). It just isn't that sensitive except to let you know you still have CML.

Repeated PCR's that are undetected, for many years, that's when the thought of cure is possible. Chris C is testing that idea right now. So far so good. Trey is cured. He just won't admit it to himself. So is Susan61. But that's o.k. I understand. I am eager to get there myself. But again - Dr. Cortes said over and over - it's Cytogenetics that matters. Your FISH is zero. You're gonna live.

p.s. Trey - have you ever considered stopping your 200mg Gleevec and see how you do?  You have been PCRU on 200 mg Gleevec for some time now and that's fantastic. I am just curious if it has crossed your mind to stop taking the drug.

[LivingWellWithCML]

I spoke with an expert in the field late today and he said that PCR spikes up more dramatically if one has mutations, which is not the case here.  Does that sound correct?

Trey, you got to PCRU in less than a year on 400mg, and I assume those PCR results were not ruined by degradation, so I don't think it's unreasonable to have hoped to achieve and maintain a swift molecular response like that.  Man, what I would give to understand the magic potion that made that happen.  Anyway, I specifically go to Emory to --avoid-- degradation or testing issues, since they run the test on-site. And I never do draws on Friday, so I have to assume that they will do their jobs and get the test underway and not let the sample sit. Arrrgh!

I got the doc to agree to another PCR at the 6 week point in early November.  He won't endorse any dosage or TKI changes, but it is tempting to start scoring to 600mg, cause I gotta beat this thing down.

M3.5 or M4.0 would be better for me to swallow, but flattening or losing IS MMR is extremely unsettling.

Appreciate everyone's input ... Thanks y'all ...

[LivingWellWithCML]

Thanks Michael.  Yup, that all makes sense.  And although none of this information is new to me, it's more difficult to accept when it impacts my own case.  I guess Cortes would say the same thing that my doc said -- stay on G 400mg, PCR is low enough to assume CCyR (cause they haven't run FISH in 6 months), and wait for the next test.  Anyway, I pressed for a 6-week PCR, and they are going to do it, so I'm cool with that.

Regardless, if you were in my shoes, wouldn't you feel compelled to request a transition off G and move to Sprycel (50 - 70 mg?) anyway?  Smaller levels of residual disease certainly reduce the odds of a progression scenario, and given that I appear to be flattening out already on G at 18 months (or getting worse, who knows), I have to think that it'd be best to take action now and move to a more potent TKI now rather than later, or consider a G dosage increase (600 or 800 mg).  What if there are pathway communication issues taking place in my body right this moment (on G) that could be shut down with Sprycel now?  Of course, there's the side effects risk - I've been virtually side effect-free on G, so a dosage increase could be tolerable and effective, but I don't know what Sprycel would bring in addition to a couple of weeks of headaches.

I have much admiration for those of you (Michael, you included!) who have endured challenging roads in chronic phase, but kept such a positive and hopeful attitude.  This is my first potential setback, and I can't go for a good 5 mile run to clear my head .....

[Marnie]

I agree with the others on your test results.  The changes seem small and probably are statistically insignificant.  Your issues with your doc, however, are not small.  I think it's important to have a doc that you trust, and who meets your needs.  I'm on my 4th oncologist (one was due to insurance switch, but two of them just didn't work for me. . . .communication style).

With your current numbers, it doesn't look like you need one of the national experts. . .but you do need someone that you are comfortable working with.

Marnie

[Pin]

Hey Dan,

This sucks - I'm sorry that the new testing is clouding things up for you especially when we live by these numbers (I know I shouldn't but I do)

International scale seems to do some weird things to people's results - I know the doctor said that they are comparable, but I don't feel convinced that they are for some reason. I guess in this case, undetectable should be undetectable no matter what (if the sensitivity is the same) - it's definitely not unreasonable to have hoped for or achieved a PCRU within that timeframe, I think what Trey is emphasising is that if the PCRU was inaccurate, then you are not necessarily trending up, just flat.  I totally understand your stress about this - I think you definitely need that third test though to make sure that there is actually a trend upwards, rather than a flattening. It may be that for you, flat isn't good enough especially if it is hanging around MMR. I have all my fingers crossed that the next one is much better. I am due for my test next week, and I know how I feel around PCR time...

Pin xxx.

[GerryL]

Hi Pin,

I've got my fingers crossed for you for this test, all along your results have been similar to mine. How are the side effects going?

[Pin]

Thanks Gerry, getting nervous about this one already, think I have been for about a month - side effects are ok at the moment, manageable I guess you would call it. I still have a whole range of them, and they come and go as they please though Hope I end up where you are soon!

[CallMeLucky]

Dan,

I understand your feelings and your anxiety, I think in similar ways.  There are a couple of things to try to keep in mind although, reason is difficult when going through this.  The first is that you have a switch to IS which throws everything off.  There is no trend anymore.  They tells us not to change labs for PCR testing because you cannot compare the results.  You might as well have changed labs because from what I understand the conversion factor can throw off individual test results.  What might be interesting is to see your pre-conversion results, if the lab stored those.  Either way, I think Trey is on the right track with the PCRU either not being true undetectable or similar to my situation over the past year where I would bounce in and out of detectable.  I went from something like .0008 to undetectable to .004, freaked out, then next test was undetectable again.  You are dealing with the accuracy of a grenade.  If the PCRU was you hovering around detectable limit, then they switched conversion and made your numbers report higher, the last two are basically flat.  I would bet your next PCR goes down or stays flat, which is essentially MMR.  Could you switch and get a deeper response?  Sure and maybe you should switch just for the mental side of it, but the reality is that you are probably fine.  If you had a mutation it is likely it would have shown up before this - when they say within first two years you would really be pushing the outlier to get such a deep response and then start to have a climb back up.  More than likely this is statistical noise in an imperfect test.  On the chance you are becoming resistant to Gleevec, then the rise in PCR will likely be gradual and you can switch after the next test.  You have done well on Gleevec so if possible you should try to ride it out.  I have had good response on Gleevec but the side effects are getting to be too much so i am going to change, and nervous about new side effects.  It is normal to react and want to make a change quick but you have to get it straight with yourself that you would be acting on incomplete information.  You can make the change but you don't know why you are making the change and for me that is what would hold me back until I had more information.

Push for a repeat in 6 weeks if it really bothers you.  Try to find peace in this very disruptive and sometimes inconsistent thing we have in our lives.

[LivingWellWithCML]

Thanks Gary - much appreciated.  Yup, I'm getting a 6-week test in early November, so we'll see what that says.  But I really wish my ankle could heal a bit faster, cause I've lost a critical outlet that clears my mind.  It's a rough stretch, but I know this wonderful group has been through these type of challenges (and worse).  Time to move on with life until I get these results in mid November ...

[scuba]

I sometimes wonder if PCRU alone is sufficient to believe that we could be on our way to becoming disease "free".

[PDF]

Detection of BCR-ABL positive cells in an asymptomatic patient: A

http://www.google.co...vPFThGydQuRo9Vw

In this article (PDF download), the researchers describe a patient that had initial elevated WBC's (like most of us) and was found to have positive BCR-ABL in many cells (FISH) and also positive PCR.

What was interesting is that the patient normalized on his own (WBC's returned to normal) but still had elevated FISH and PCR. Over 50% of his bone marrow cells were positive for the Philadelphia Chromosome. Instead of treatment (since the patient was not symptomatic), the patient was observed every 3 months (like we are) and tested for FISH/PCR. He is still positive for the fusion gene, but symptom free for over a year (at the time of the article).

This begs the question in my mind of whether we need to be PCRU before we can discontinue treatment. Obviously, something exists in the patient described above's body that keeps the fusion gene in check (T-cells?). Rather than subject the patient to nasty TKI's they simply watch under a surveillance protocol.

Is it possible (and I am conjecturing here), that all we needed to have done was get our CML under control (become asymptomatic) with greatly reduced PCR to MMR levels. And then stop treatment and watch.  See if the disease reappears - and if it does, we just go back on our drugs. Is it possible that all CML treatment needed was to help our body's get over the burden so that it can take care of itself? How many in the general population are walking around with positive PCR for years and years and are healthy - their immune system manages low fusion gene disease just fine.

Some of us believe that if there is even one cell that has the fusion gene (bcr-abl) that CML is inevitable and the person has CML or will eventually develop CML. But is it inevitable?

I pose this question not to suggest that those of us who have low residual disease might stop taking a TKI - but to wonder what would really happen?

I have argued in this forum that having Ph+ chromosome alone does not necessarily mean disease. That something else we don't understand happened in our body's that enabled the fusion gene to run rampant. Lord knows we probably have many other abnormal chromosomes that we don't know about and the body seems able to handle it. Is there any data at all that shows whether CML absolutely re-emerges when a patient stops taking a TKI? Or is that PCR merely becomes positive again and panic sets in and patients go back to taking a TKI (IRIS study).

In my case - I am at MMR (positive PCR) and it seems to be steady, and I do admit I won't try and stop taking Sprycel at this point. I will try only after I reach  PCRU and stay there for a period of time. I do need to see all zero's (0.000) first. But I just wonder...do I really need to have all zero's?

Should minimal residual Ph+ PCR be the goal and not necessarily PCRU before someone tries and gets off the drug(s)? I wish I had the guts to try!

[Trey]

That article makes the same mistake seen in many similar articles.  It confuses "asymptomatic and healthy" with not having CML.  The article discusses someone with CML, and who is still FISH and PCR detectable.  How is that "disease free"?  Many people diagnosed with CML were asymptomatic and otherwise "healthy".  Almost all of these cases are just early stage CML where the blood counts are variable, and this early stage CML can last for years in some patients.  Even if there .01% of people who have a "spontaneous remission" because of some medical anomaly that means nothing to the other 99.99%.

[scuba]

I don't disagree ... I am just wondering if it might be possible to remain "asymptomatic" for many many years without having to take a TKI (after having taken one to become MMR). I wonder if it is possible for many patients (not just the very few anomalous) to not progress to accelerated/blast phase, maintain low level PCR and do so for years.

A side question in my mind - is accelerated/blast phase always associated with symptoms? or can someone get into Blast phase and not know it?