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When does a blip become a trend?

  • November 2012: Diagnosed at 320%
  • ...
  • July: Lowest ever PCR at 0.33% (8 months post diagnosis)
  • August: 0.49%. No panic, just a blip. These things happen and I can't expect a drop every single time I'm tested.
  • September: 1.04%. Hmm. That's double the previous month. Will probably start to get worried if the next one is upwards again.

When, for you, does a blip become a trend? And if the trend is upwards a few months in a row, what is there to do? Dose increase? Switch TKI? (I'm on dasatinib after having a hard time in imatinib).

Trying to stay rational, but got to admit to being a bit disappointed with the result that came through the letterbox today.

David.

Hi David,

well, in my own experience a trend is when you have 3 consecutive results showing a rise (or fall) in BCR-ABL1 transcripts. It might also depends on the sample taken- by which I mean whether it was a 'good' sample with at least 10,000 ABL1 control genes (or other control gene depending on the lab) - If the control gene is not at the above level that the result will not be reliable.

I understand why you are disappointed but try not to panic - easy to say I know- but if your July result was 0.33% and August was 0.49% then I would say that was not a significant difference. It might be that Septembers result was from a less good sample (control gene etc.) so that might well be a blip.

Try to find out if for the last test, the control gene used was at a good level. Your doctor should be able to tell you this.

If the sample was good then you would need to hold your patience a little longer and see what the next result is - which I assume is on the way?

2 results (from samples with an adequate control/normal gene level- i.e contains at least 10,000 ABL1 gene) should indicate in which direction your BCR-ABL1 levels are going. Static, rising or reducing.

If the next one shows a rise then you would need a 3rd to confirm and you might then ask your doctor to test for:
a)your plasma level - the drug should be at or over 1000 ng per ml
b)and/or a mutation test.

Next steps: If your plasma levels are below optimal you could try raising the dose (depends on the dose you are already taking)
If the plasma level is optimal the a change in TKI... in your case nilotinib, or bosutinib (which is available through the CDF and looks pretty effective).

Talk to your doctor about the last samples control gene and ask for the level it contained.

Hope this helps,

Sandy

Thanks Sandy. I've dropped my consultant an email suggesting another PCR around now ... that way, there'd be another data point for my next clinic appointment.

Hi David.

Sandys advice is sound as always, and I'm sure this will give you some comfort.

I am still fairly new to all this and am no way fully schooled in CML. However, I would speak to your medical team and explain your concerns and hopefully they will continue your monthly PCR texting cycle until you are comfortable..

When I spoke to my team regarding how quick my PCR should be falling, they were positive about slight fluctuations due to labs and samples, and said they would need 'at least 3 or 4' PCR results showing an increase or static results, to even begin to discuss trends. They kept drumming home we are all different and definitely not to panic due to numerous factors.

I think if this is something that is even starting to worry you, I would contact your consultant, or a team member for a chat to discuss your concerns, especially if your next appt is a good few weeks away.

Please keep us informed of how things go with your latest results.

Take care!

John

Sometimes they are just blips, and get us worried for nothing.

Just got my latest PCR and down below 0.2% from 1.04%.

What was I worrying about?! Phew. :-) Onwards and downwards.

I am glad this subject has come up. I have been taking imatinib for CML for since I was diagnosed in 2004. PCR tests showed a gradual reduction to 0%, but my last test came back as 1.006%.
The silly thing was that I had been noticing a few symptoms of CML: blood blisters, tiredness, unexplained bruising. I put a lot of it down to the worsening of my heart conditions (left ventricular malfunction caused by 4 heart attacks, and re-stenosis of stented native arteries), especially the tiredness, and I'd been having the blood blisters since I'd been first diagnosed.
I have since had another blood test, and I am awaiting the result. I hope the imatinib is still going to work, as most of the alternatives are contra-indicated with the drugs I need to take to control angina.
Must finish this before I fall asleep!
Happy Christmas and a Healthy New Year to all.

Richard

Hi Richard,
I am sure this will turn out to be a 'blip'. The advice is always to look for a trend from at least 2-3 PCR results and as you have obviously had stable results this is most likely to be from a sample that just didn't shape up-!

The CML symptoms you mention could very well be from the other causes you mention as it is unlikely that at such low levels of BCR/ABL you would have any symptoms at all.

Should it turn out that you need a change of TKI, then there is one that is probably suitable given your cardiovascular problems, and that is bosutinib (I know someone else who has a similar profile to you and is responding very well to this TKI) it is available through the CDF in England ... so don't worry about alternatives to imatinib.

Hope this is reassuring enough for you to enjoy christmas/New Year celebrations.

Sandy

Hello Richard,

I was going through your post on increasing pcr after a long period of PCRU. How are you doing now ?

Thomas

Hi

How are you doing now? What is your latest pcr result ?

Regards

Thomas

I'm at around 0.4% now ... but I'm a slightly strange case insofar that I wasn't able to make full use of the TKI due to another drug interacting with it. I underwent an operation to surgically correct the problem the drug (omeprazole) that was causing the problem (see the thread about Nissen Fundoplication for the gory details!), so hoping the next PCR will be lower!

0.4% is still a good bit better than above 1% !

My haematologist says there is nothing to worry about, as, having a low, but stable, PCR is indicative of the need to stay on Imatinib.

What is now rearing its ugly head is an inability to metabolise Vitamin B12, in other words, pernicious anaemia. Apparently, some of the symptoms are similar to CML (in fact, before the cause was discovered, it was linked in the same group of illnesses as leukaemia), so this is probably what has been causing my "discomfort", as it increases the incidence of angina (due to red blood cells being mal-formed, and compromised in carrying oxygen).

Maybe there is light at the end of the tunnel, and not just the tax-man with a torch!

Thanks for all your prayers and support on this forum. I really do appreciate it.

Happy Easter

Richard

Dear Richard,

You must be relieved that the cause of your recent problems has been identified...i.e lack of B12, which of course is not something that you would welcome under normal circumstances. However, in this case at least you can now take steps to increase your levels and I assume that you are receiving B12 injections on a regular basis? I hope so.

I wonder if this is something that may be a consequence of long term therapy? I know a few people on longer term therapy who suffer from a lack of B12, but having said that it might well be that there are many different causes and they would have developed low B112 levels anyway.

As for low and stable PCR results, yes your doctor is right of course, but I have just been to a meeting in Milan regarding how long term deep molecular responses indicate not only that you have a good response to therapy, but also that you may be in the select few that can stop therapy and live in treatment free remission.

TFR will not be achievable for the majority, but studies are showing that for the lucky few who reach MR3 (0.1% BCR-ABL) very quickly, at least within 3-6 months, and go on to achieve deeper stable MRs (preferably more than 3 years) down towards MR4.5 MR5 etc. are the people who have the best chance of stopping and living in TFR for the long term.

The thinking is that although a small number of people do achieve fast and deep MRs on imatinib in first line, there is an increase in the number of people on 2nd gen TKIs in first line who reach deeper MRs at a faster rate. 2Gen TKIs undoubtedly have a more profound effect on the BCR-ABL gene and consequently get it down to deeper molecular levels (like MR4 etc) in less time, but they also have potentially more grade 3 and 4 side effects than imatinib (particularly cardiac effects in those who may have existing or unidentified conditions) so there is a trade off that we should be aware of. There is always risk, no matter what.

Of course, not everyone has the goal to stop therapy and a lot of people are content to stay on therapy as long as quality of life is not an issue. But for younger people, say under 45, as well as those who may be older but continue to work or lead active lives etc. TFR might well be a reasonable goal for them.

Long term low grade side effects and maybe for some, coupled with additional treatments for co-morbidities can put a bit of a strain on quality of life. In my opinion, if stable deeper MRs are there then it can do no harm to at least discuss with doctors the pros and cons of joining one of the stopping studies, of which there are many currently recruiting in Europe, including the UK (DESTINY).

Of course TFR, as I said, will only be achievable for between 9-15% of first line imatinib users, but with 2nd gen TKIs now being used as first line therapy, we may see an increase in that percentage in the future.

Having been TKI free since a year after my SCT in 2003, I can see both sides of the issue of to stop or not to stop, especially as my PCRs have now been at a low positive for around 18 months and are consistently at MR5 (0.001%). It seems that my immune system is perfectly capable of controlling the BCR-ABL gene and although it is there if you look hard enough, it is unlikely to cause me any problem in future, so I am comfortable in my TFR.
Someone at the meeting I attended mentioned that if you tested the whole population of any country, you would be likely to find some level of BCR-ABL in 70%, but for some unknown reason this abnormality does not go on to develop into CML. Curious but fascinating.

Good luck with getting your B12 up to normal levels.

Sandy

Hi!

 

I am resurrecting this topic. I just received my 11 month PCR result and it has gone up to 1,8 % from 1,07 % at 9 months. I've read that the error margin is about half log so according to my estimation it is borderline.

 

I've had quite a up-and-down path so far with my 4,5 month result being 11 %, 6 month 18%, 7,5 month 1,5 %, 9 month 1,07% and now 11 months 1,8%. It seems that it is quite difficult for me to get below or at 1 % in less than 12 months. I am currently on 800 mg of nilotinib. Should I consider this more of an uptick or start looking for a drug switch?

 

Timo

Holy moly, this is an old one!

But I do remember how worried I was when I got those results. And looking back, it really was just a blip and not a trend. It did take me another year to get to MMR, and now I hover around MR4.5 on low dose dasatinib

This is much easier said than done, but I would try not to worry. You may find that your next result is much lower. In general, you would need to see 3 significant rises in a row before you would consider switching (obviously there are exceptions to this “rule”) but your trend is downwards. You would probably be really happy if at 7 months you were 5%, 9 months 3%, and now 1.8%. 

So many of us didn’t hit the “optimal” treatment guidelines but still do great in the long run. I’m definitely one of them.

David.

Hi David

Yes, it's an old one but I figured it reflected my situation quite well. :)

I know the trend is downwards. In my case, it seems it is moving in a sort of a wave pattern down, not linear plummeting as my consultant expects. The last time my boat was rocked was when PCR went from 11 % to 18%. Now it is basically from 1,1% to 1,8%. What are the coincidences? I hope the next fall would then come in the same manner as it was last time (from 18% to 1,5%).

Anyhow, goes to show that people overanalyze the results. I am not even worried about MMR - it comes when it comes. I am worried that I will not  reach CcyR in the necessary timeline, although I believe I already may be in CcyR since my FISH a month 6 was 16 %. I've also read that some residual cells may have an higher BCR-ABL expression which may put the PCR to jump around for a while.

Thanks for the reply, David

 

Timo

Hi Timo,

I would just add that a PCR result does depend on the sample taken, and that can vary. You need to have at least 10,000 transcripts of the normal gene -termed the housekeeping gene - used by the lab so they can assess the ratio (%) between the normal gene (for example ABL) and the abnormal fusion gene - BCR/ABL, present in any given blood sample. If for some reason there is not an adequate number of normal gene transcripts it will affect the PCR result.

 

Sandy

Hi Sandy

Yes, I have understood the same that sample quality is crucial. Unfortunately detailed data on my analysis is not available to me, although the operating procedure at the lab stipulates 10000 control genes as an absolute minimum. I´d figure they would not publish the result if the amount of control gene is not sufficient? Anyhow, hopefully the next one is lower. If not, then most likely dasatinib will be my future poison

Timo