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Optimal (or suboptimal) response timeline

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I was diagnosed with CML in March of 2015 when I was 35 years old (male).  I'm 18 months into treatment and I'm curious to know if where I stand response wise has any effect on my survivability outlook.  I was hoping someone could help outline what the desired timeline is in terms of reaching each of the following responses (or whichever ones have meaningful timelines associated with them) but then also explain how missing those timelines statistically effects one's survival prognosis:

Complete Hematological Response

CyR

MCyR

CCyR

MMR

CMR

 

Thank you!!!

Hi, and welcome!

Without knowing your current PCR figures, we can't really tell you if you've got a optimal response or not.

Below is a guideline from European LeukemiaNet which gives guidelines for optimal responses.

http://www.leukemia-net.org/content/leukemias/cml/recommendations/e8078/...

Given you are 18 moths post-dx, it would be optimal for you to have a PCR result of 0.1% (on the international scale) or lower. Below 1%, but above 0.1% would be a "warning", and above 1% is considered "failure" of your current treatment.

I was in warning, and close to failure for a while - which for me meant changing TKI and then doing really well! So if you don't have an optimal response right now that doesn't mean you won't mean in the new future.

David.

Thank you David.  Here are my PCR results (all on the international scale).

03/19/15: CML Diagnosis - began Nilotinib (Tasigna)

05/21/15: 25.97%

08/13/15: 6.79%

11/16/15: 3.24%

12/30/15: 2.83%

03/09/16: 4.90% - Tasigna deemed a failure. Tested for mutations - none found.

05/12/16: Began Dasatinib (Sprycel) 100MG / Day

06/09/16: 1.49%

08/15/16: 1.70%

What has never made sense to me is that my cytogenetics show that I reached a complete cytogenetic response.  But my PCR tests have never been at or below 1% (close, but never quite there).  I live in the U.S. and I believe our response timeline goals aren't quite as strict as Europe's (which I don't understand - I'd like to hold myself to the stricter standards).  Anyway - I'm not looking for anyone to sugar coat anything.  I know my response to Nilotinib wasn't optimal. And my most recent PCR (which wasn't quite 3 months from the first one while on Sprycel) isn't anything to celebrate either (I really hope I haven't plateaued again, or worse am sliding backwards again).  It's clear to me that the goal would be to at least be below 1% at this point (if not at 0.1%) at 18 months - what isn't clear to me is the why is that significant?  If you're making progress, albeit slow progress, what does it matter that you're not at 0.1% by 18 months?  My only guess right now is that the longer it takes the greater your risk of mutations or resistance...?  All best!

Hi again,

You are right that your response was not optimal, and therefore it was a the right thing to switch to a new TKI.

The thing is with the guidelines is that they don't really take into account what should happen when you switch. You can't expect results instantly, and nor can you really reset the clock so some middle ground interpretation is needed.

From your results, you have gone from 4.9% to 1.7% in a pretty short time - a reduction of around 2/3rds. That's not a bad trend and your next result may be much lower. At one point on dasatnib I went from 3.9% to 0.5% in the space of a month. Progress isn't always linear and in fact rarely is.

Did you have time between nilotinib and dasatinib where you took no TKI? When I switched from imatinib to daastinib I had a couple of weeks treatment-free and my PCR went up a lot in that time.

The 0.1% goal by 12 months is optimal and you, like me, did not achieve that. That doesn't mean you won't ever get a great response (I'm happy where I am, now). I'm not entirely certain how to re-measure what is an optimal / warning once you switch TKIs. Perhaps someone else here has a better idea?

With regard to cytogenetics, as I understand it a complete response is correlated with a BCR-Abl ratio of 1.5% or lower. But this can vary in any one individual.

From the doctors I have spoken to they have stressed that the destination is the important thing, not the journey. If you are a slow responder, but are responding then that really is OK. Some people on this board took years to get to MMR (0.1%) and are doing just fine many years later. I know it's stressful and we all want low results, and we want them yesterday but if I were you I would take comfort that the trend for you is lower results - things are going the right way.

David.

Hi,

"........What has never made sense to me is that my cytogenetics show that I reached a complete cytogenetic response.  But my PCR tests have never been at or below 1% (close, but never quite there).  I live in the U.S. and I believe our response timeline goals aren't quite as strict as Europe's (which I don't understand - I'd like to hold myself to the stricter standards)...... "

The issue with comparing cytogenetics with quantitative PCR testing is that one tests 20 cells and the other tests upwards of 10,000 cells (the most sensitive can test 100,000 cells). So you can see why testing a sample of 20 cells may well put you at CCyR given that you have responded - even though not optimally- to TKI therapy. Since you changed to dasatinib you have had a  further response which is a good sign, however you should not worry too much about another plateau just yet. As David has said, it may be that your next PCR test will show a further drop. You need to look at a trend of at least 3 consecutive results before you can be sure of your response. 

It is also important that the sample taken contained at least 10,000 transcripts with a normal gene (usually ABL or BCR or GUSB) that your lab uses to compare the number of abnormal (BCR-ABL1) transcripts and thus give you a percentage ratio.

It may help if you read our Q-PCR Primer for Patients which you can download from our site. It gives a background to CML and chromosomes plus explains the different tests like cytogenetics and FISH - and how they differ from Q-PCR testing.

Regarding ELNet Recommendations, they are more or less in tandem with the booklet published by NCCN.org NCCN Guidelines for CML Patients  which you may find helpful.

Please keep us updated on your next result - Oh and welcome to this forum ;o)

Sandy

 

Hi

Sorry for the late reply to this post, but I wanted to add my views.  I am also concerned about the "suboptimal" timeline for responses as it is amazing how much importance the clinicians and researchers place on what, in my view, are somewhat arbitrary time points such as 3, 6, 12 and 18 months.  There is an analogy about how, if 100 swimmers are placed in a pool and sharks chase them, it doesn't matter how fast they swim as long as they manage to get to the other side before the sharks get them.  So, if CCyR or MMR are considered "safe" zones, what does it really matter how long it takes us to get there?

I think that the "typical" patient is supposed to have a reduction in BCR-ABL that proceeds at a certain rate.  Since CCyR is a good place to be, every day we spend out of CCyR or MMR means that the probability of ever reaching that milestone is reduced and the probability of progression is increased.  At least, that's how I understand it.  But every person is different and I don't know whether the guidelines apply to everyone - my doctor doesn't seem to be in the least concerned by my lack of reaching the magic, optimal 1% at 6 months (I'm at 1.4%) and the possibility of changing medications has not even been discussed.  

Another point: I think we have to bear in mind that the "guidelines" are as a result of statistical analysis of various responses over a number of studies.  Often, the probability of overall survival is calculated by considering death from ANY cause; that means that the patients who don't survive until the end of the study may have died as a result of something entirely different.  So I cling on to these types of considerations when I become down and worried about my response. 

I am also quite interested in another question: does the level of response correlate with the side effects that people experience?  I haven't found an answer to this question - I have a comparatively slow response and virtually no side effects, while others respond extremely well clinically but sometimes have to stop treatment due to intolerance.

Good luck to everyone with their ongoing treatment!

Martin

Hi Sandy and David (and anyone else),

It's been a while and wanted to share my scores again.  While I feel fine - I continue to worry that I'm in some sort of "at risk" zone. From what I read in the NCCN Guidelines about milestones I've gone beyond the point where they suggest switching TKI again or looking into transplant.  Good or bad news, It helps me to hear from people that know more about this than the average joe.  I switched to Dasatinib in May of 2016 (about 17 months ago) and I've yet to reach PCR <0.1%.  Here are my PCR results since then:

6/9/16: 1.49%

8/15/16: 1.78%

11/23/16: 0.82%

2/15/17: 1.41%

4/19/17: 1.45%

5/22/17: 0.51%

7/26/17: 0.8%

11/1/17: 0.57%

My family is exctatic about last week's results - and I'm pretending to be on the outside for them - but internally I can't stop worrying that I should be pushing for better results.  At this rate, .001 seems so far away.  If I were 80 I wound't be worrying about this - but I'm 38 now, have a 5 month and 3.5 year old sons.  I sure would like to be around for 40 more years. Can anyone explain to me why the NCCN Guidelines would suggest looking into switching TKI or considering transplant if secondary drug hasn't gotten me below 0.1% in 12 months?  There has to be some significance that otherwise they wouldn't just publish something out of thin air right?

I had a nurse pick up on my anxiety not too long ago and she said that lots of people live a nice long life with PCR levels in my range. Thats great if true - can someone point towards those studies so I can stop worrying?

Best,

Brown

Try community.alls.org in the states. I am from Colorado and frequently visit that site also. Many topics on your subject.

Thanks. That url is dead or broken. Typo?

Sorry, community.lls.org

also google, treys cml blog, a good read.

 

Hi Brown,

You're about two and a half years since diagnosis, right? In that case, on a strict reading of NCCN guidelines (or ELNet ones) you're right, there is an argument to be made about switching TKI or investigating transplant options (e.g. checking any sibling matches).

However, the trend of your results is downwards and that's a really good thing. 0.001% might seem like a long way away - but it's not always a realistic goal for everyone or even most people. If you manage to get to MMR and continue to feel fine then that would be a fantastic result.

I was at a conference a while back, and one of the clinicians there (a leader in CML treatment) was discussing the "magic" 0.1% goal and his thoughts that it was a rather arbitrary number and people even up to 1% and stable do just fine in the long run. You won't find that written down in any literature, but it's worth a thought. Sometimes we can get fixated with particular numbers.

So long as the trend of your results to continue downwards and creep to MMR or lower, I'd be inclined to stick with things as they are - especially if you are tolerating dasatinib well. But perhaps it's worth chatting through the scenarios with your doctor ... at least that way you might have some thresholds agreed to stick / switch etc. For example, you could agree that so long as the trend of results is downwards you stick with things, but if you see three substantial rises in a row then that triggers some action. You might get more certainty that way and feel more in control.

Also, and please excuse me if this doesn't apply to you, but are you certain you are fully compliant with your meds? Taken at the same time, and every single day? I met someone recently that felt they were fully compliant but when diarised things found she was vomited relatively frequently within an hour or two of taking their TKI ... and of course expelling some of it in the process.

David.

 

There is a nice video on this site that clearly states that sub optimal response has no noticeable effect on survival.

:) I checked when I was sub optimal. It does affect your ability to come off tki's eventually but even that's not definite

Thank you David for the response. And any question is fair game - but yes, I take my meds like clock work.

 

Best,

Brown

Evah,

Could you tell me the title of the video?  I scrolled through them all but none of them jumped out at me as the one you mentioned.

 

Best,

Brown

https://www.cmlsupport.org.uk/videos/how-should-cp-phase-cml-management-...

Definitely not the most obvious of titles!!

BDmemphis can you provide any updates? I'm curious because I also have not seen 0.1. Had 0.111 from bmb at 16 months (no mutations) but actually went up at 18 months rather than dropping that extra 0.011. I feel fine and my results are not alarming but I am trying to see if others are in this weird zone where we are responding but not "ideally".

Hi David/sandy,

Pulling back an old post for reference.

I am just trying to understand why the pcr does not hit optimal response for few.

Considering efficasy and potent nature of nilotnib. It should help reach optimal response(with no additional mutation).

My question - why nilotnib doesnt work or bring bcr abl within optimal normal range when there are no additional mutation and meds taken deligently without missing.

I have my first RT PCR in 2 weeks. I am tensed now:-(

Kindly share your thoughts

Hi,

 

Speed of response is very variable; this forum has referred to tortoises and hares on many occasions. There are people who get to MMR in 3-6 months (hares), and some who take several years to get there, or perhaps don't even get there (tortoises). I am coming up to 12 years since dx; I took 18 months to get to MMR (0.1%), but as my results were always generally trending down we stuck to it. The guidelines which say optimal response is 0.1% at 12 months had not been written then so I couldn't get stressed about it. I was also told at that time I would be on a TKI for life. I stayed on 400mg imatinib for 10.5 years, then reduced to 200mg for a year, and am now 4 month into trying TFR.      

For those worried about BDMemphis and others in similar slow responses I can confirm that BD is doing well with his treatment as of July 2022.  I sometimes worry when people drop off of the forum (especially if they have similar slow responses) but thankfully he is well.