Still no MMR at 24 months Nilotinib

Hello Alex

Your pcr result is a bit disappointing,but your pcr level didn't increase much that is consoling. As of now I'm taking 800 mg nilotinib.either you should increase to 800 mg nilotinib or after having mutation test you should change to other tki.before changing to other tki,just give a try with 800 mg for at least two months.i hope our veteran members will provide you much insight into the matter.

Thank you so much this is what my consultant said we will try 800 if I have no mutation and failing that switch to another.

Did you notice harsher side effects increasing to 800?

Warm wishes

Alex

I see thank you for letting me know. Let’s hope something will work. Hard not to loose hope at times. So close but so far still.

Karthikeyan, no reply was deleted and in fact looks like it's showed up.

Rt-pcr numbers puzzle me. While trying to make sense of test results I came across documents that analyzed the difference between results that a number of test kits generated (I wonder if people realize that even before IS conversion different test kits can generate massively different results, and yes some are more accurate than others) and others on the variability of results produced in each kit (sample collection, sample processing, etc.).

My conclusions: 3.0 Log/4.0 Log/4.5 Log are all statistical milestones. They exist for the sole purpose of giving medical professionals guidance on the course of the disease. They are not carved in stone and reaching them has no binary impact on CML. If we think for a minute why 0,1%? why not 0,15% or 0,2% or even 0,05%? The disease does not obey to set decimal numbers other than a zero, that’s a multi-decimal zero. Are they relevant? Certainly. Should they be interpreted to the decimal figure, I don’t think so, especially in your case since the number is dancing around the 0,1% mark. Trends are far more important because with time they neutralize the problems above. Unfortunately, trends take time ... months or even years. When do decimals become relevant? when over a long period of time (or short for some people) you are able to reach undetectable and even then one can reach the milestone and it serve no benefit because the likelihood of failing a TFR try is higher than 50%.

Because the long-term prognosis for the disease is generally positive (specially if one has reached CCyR, which by the way that starts at 0,9999%) hitting these becomes more of psychological obsession - I don’t want to fall behind!  But the reassuring part in all of this is MMR does not provide a better long relative survival rate when compared to CCyR, in fact I have seen studies in which it was actually worse.

Hey David,

Yeah that all makes sense. It’s just very frustrating but I must remain grateful for at least making it this far and so far.

Yes it’s IS the PCR is done at the Kings lab. And not on any other medication at all. And take my pills x4 daily at the exact time everyday. I guess maybe Nilotinib isn’t the one to get me there but might prove to be with and increase to 800mg.

Hopefully I’ll have the mutation analysis soon and hope it’s one that’s treatable if I do have one. I would have thought I’d need to see a considerable climb for it to be a bad one?

Many thanks for taking the time to reply to me.

Alex

Hey bud, for one, you look rather young and we tend to be slow meeting the official marks, generally. Secondly, Tasigna seems to produce a prolonged plateau effect for a good portion of patients. You shouldn't worry. From everything I've read, a mutation will show up as a sharp rise, and be confirmed with a second sharp rise in confirmation tests following. Specialists tend not to change treatment unless ccyr is lost >1.0% i.s. Tasigna statistics also produced the most promising results with no patients progressing or transforming while on it (I forget which).

I completely understand, and don't fault you for it. I'm a few years younger, but close enough. Haha. A to another concern you mentioned being that you're at 24 mo. on a 2nd gen, you're actually lower at in your pcr and experiencing smaller fluctuations than I was at 24 mo. on Bosulif by that point- (about .4). My results finally hit the mmr point at about 27 months and have further declined with fluctuations up here and there, since. Currently 3 years later I've consistently stuck around .012%. I wonder what would have happened with out the different med changes, but I've felt the best with Bosulif, regardless. Take good care, friend.

Hi Chris,

I really appreciate your reply. Wow good to know you finally got there. I take my meds strictly at the same time each day at 8am and 8pm. I have an app that reminds me daily. A few times I’ve taken tablets past the 8pm reminder but we are talking 30mins max a handful of times in 2 years so I don’t think my adherence has been an issue.

Yeah what has become clear to me is that we all obsess over these numbers far too much. And I’ve stopped comparing my journey to other people’s response even though trajectories look the same their are so many different factors to consider. I am grateful to be in CCYR and hope that at a minimum I stay their. I also hope my mutation analysis doesn’t throw a massive spanner in the works. One things for sure this disease messes with your head more than anything else.

Very reassuring to hear your story and wish you continued health and success.

All the best

Alex

Absolutely mate it would be good to hear from other slow responders especially those on a 2nd gen drug as it does seem we are few and in between. But as you say “we’re all right jack” no need visit the forum I guess. Did your doc perform a mutation analysis? I am awaiting my next gen sequencing result but my doc just said it takes ages to receive them here in the UK it’s been 6 weeks here so far. To add insult to injury things seem to take soooo long here it drives me crazy. But I have to be grateful we get treatment for free here and access to any drug. Very lucky considering.

Take care

Alex

Blimey yes mine were sent to Kings also. I think a lot of COVID samples are sent to kings and PCR tested also. Maybe that’s effecting timescales! Either way it’s a hideous amount of time to wait and of course worry!

Yeah that’s what I was hoping for but you never know with this stuff. Good luck on the 19th keep us posted.

Alex

Thanks Chris!

Yes it’s a marathon and not a sprint but it is a race I’d like to remain in haha. It is disheartening to see things going slowly or not budging as quickly as we’d like but I’ve now learned not to compare my journey to others. It’ll happen when it happens or it won’t. So close so I’ll be grateful for that for now.

Alex

Thanks mate that’s encouraging to hear and fantastic news for you. I hope to one day have those numbers. My doctor doesn’t even consider this an uptick but effectively the same result as my previous. Luckily for me he is always super relaxed. I am hoping it’s a plateau that’s going to give in sometime. Annoying it descided to be a plateau right on the line. So typically me! Does make you wonder what actually goes on in the body to cause the plateau, I almost visualise it like constantly placing weights on a surface and when the weight is heavy enough it punches through. It’s reassuring that my uptick is hopefully that and not the beginning of something else. You are absolutely right this disease for me is more of psychological burden.

I take no herbal supplements. Take my meds exactly as prescribed. The only difference in the last 6 months is I gave up red meat, ate more fruit (not grapefruit or pomegranate), x4 Brazil nuts a day (gave them up since my last result as made me paranoid that was interfering) and have a daily Actimel probiotic (still take) and exercised way more.

Thanks again for your encouragement.

Alex

Blimey I didn’t now that. For a long time I was having a morning shake consisting of, blueberries, raspberries, spinach, actimel, alpro almond milk, banana and peanut butter. Tasted amazing: did this most mornings for a good 4-5 months in the last 6 months and wonder if that has effected absorption. And exercise effecting BCRABL??? OMG now I can’t even exercise 🤦‍♂️. Well I have ditched my shakes now haven’t had one actually for a couple of months - the disease is an absolute head f@&k...

Links to early research verifying CCyR as a significant milestone

• https://ashpublications.org/blood/article/118/21/745/83181/Clinical-Sign...

Time to achieving CCyR and MMR with frontline TKI's in CML-CP, reflects similar prognostic implications regardless of the modality of frontline therapy used to achieve it. However, earlier achievement of CCyR with nilotinib or dasatinib results in a higher percentage of patients obtaining the long-term benefit associated with early responses.

This paper is from 2011, subsequent work has validated this result. Complete cytogenetic response is the single most important indicator of progression free survival in CML.

Cheers Scuba. I wonder why when we reach CCYR it isn’t celebrated as much as MMR. My doc a while back said we tend not to get too excited when people reach CCYR which is odd if it’s the most important milestone - I am grateful I am here at the moment and hope one day permitting I’ll get lower numbers into MMR. Frustrating to be on the line of this clearly physiological obsession of being in MMR when most people are by this time.

Need to relax on this one. Exercise is great for you and helps your TKI do its job.

I'll explain.

Often scientists look at data in isolation from a cause and effect point of view.. We vary one parameter and then measure a result for a system response. Then we draw conclusions. These conclusions can often be wrong, but are a starting point. In reality, biology is more of "circuit" with interconnected parts engaged in hysteresis feedback loops. Change one thing and many things can change often affecting the original interpretation of the data. This is why no one experiment is definitive and more study is often needed so that a true "cause" and "effect" can be determined.

In the paper you link above (from 2011), they report bcr-abl increases following exercise. By itself, one would worry. But think about what is happening and was revealed in other research.

In exercise, overall white cell count goes up - particularly T-cells (which fight cancer) as well as neutrophils. These cells are stored in the spleen ready to be deployed quickly (as opposed to being "made" in the bone marrow). Upon exercise these neutrophils are released straight away into the blood and are now circulating for a time. They get picked up by the nurse's syringe when the blood is sampled. This is why bcr-abl goes up. The reverse would be true if you donated a pint of blood and then had a PCR test done. You'd think you were cured!

• https://www.webmd.com/cold-and-flu/qa/how-does-exercise-affect-white-blo...

This is why bcr-abl on its own must be interpreted in context over time. Over the course of a day, bcr-abl is probably varying a few fold (as your article pointed out) but mostly within the PCR error test range. Any increase or decrease should be examined over several tests measured weeks to months apart. What the paper doesn't reveal is what happens to bcr-abl after exercise stops for an extended time. During this phase, white cells are scavenged back into the spleen or recycled.

A true worrying bcr-abl increase would be if the cells are being generated in the bone marrow as part of a leukemia stem cell expasion. That would be a concern. The only way to know if that's the case would be to have a bone marrow test (aspiration). Not worth the pain or cost if PCR is not trending up over a longer period of time having nothing to do with exercise. Different biological systems at work (spleen release vs bone marrow) measuring the same parameter (bcr-abl).

Also - it depends on type of exercise and perhaps gender.

In women, aerobic exercise has been shown to decrease WBC count

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281960/

All this means is biology is complex (especially at the gene level). But, I would still avoid a PCR test right after a one hour hard workout! Why get all worked up with a higher bcr-abl number you did not expect!

(side note: I had a PCR and CBC taken right after a 3 day fast and before eating. They though my WBC's crashed and I needed urgent medical care. I told them I had not eaten in a few days  - no worries. Next test a few months later, WBC's were normal. Since I was undetected before and after the fast, I have no direct data on fasting impact on bcr-abl although there was this paper: https://www.researchgate.net/publication/337253299_Effects_of_Ramadan_Fa...)

Thanks for the very detailed explanation Scuba. You’re always a great source of encouragement and source of material. I suffer unfortunately with Anxiety have done for years so for me having something like this can trigger a barrage of worry for every little thing. I am mostly doing well but I have times when maybe I look into things too deeply and over worry. I exercise for my mental state as well as looking and feeling good for myself. I am learning to relax more I just didn’t want to do anything that jeopardises my ongoing response.

PS I didn’t workout before my PCR test, but I was working out with weights (pretty heavy to build muscle) and cardio X3 times a week. I did also increase my protein intake ie Tuna, Chicken breast etc...

Thanks as always.

Alex

I thought I would post this article (I'm sure it has been posted previously but I have not seen it).  It is very interesting in that, if I understood it right, most all TKI's have similar outcomes in the long term and CCyR is highly predictive of OS (similar to MMR).

"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854752/

"Furthermore, CCyR at 6, 12 and 18 months also significantly predicted for longer EFS, independently of the TKI modality. Furthermore, achievement of CCyR at 12 months was significantly predictive for FFS, TFS and OS irrespective of TKI modality."

"We also compared EFS according to the type of response achieved at 12 months i.e MMR alone vs CCyR with no MMR vs no MMR, no CCyR. As expected, patients who achieved 12 months MMR or CCyR without MMR had better EFS as compared with patients who did not achieve MMR or CCyR (P<0.0001) (Supplemental Figure 4)."

""The kinetics of the response to imatinib 800 and 2nd generation TKI show that there is a higher rate of the deepest responses (e.g., MR4.5). Although the rates of MMR reach similar levels by 60 months of therapy, the rates of MR4.5 remain higher with imatinib 800 and 2nd generation TKI than with imatinib 400."

The one above caught my attention in that Imatinib 400mg reaches MMR similar to the others at 60 months.  Of course 60 months is way past 12 months so I think reading between the lines will help us to not worry as much, or as often as we do about MMR NOW!

"These deeper responses do not seem to offer a benefit in the risk of transformation or death, but are important if one is to consider treatment discontinuation which is currently only considered for patients with sustained undetectable transcripts."

The one above pretty much states my feeling exactly.  Deep response is awesome but mostly only significant if TFR is the ultimate goal (Not overall survival).  Of course I would love TFR, but OS is much more valuable to me with three kids at home.  

Just thought I would post for those in CCyR who are worried about not reaching MMR quickly.  Keep getting your labs every three months and monitoring that you stay under 1.0 and are either going down or on a plateau and I think things look promising.

I am pleased to announce that for the first time I have reached MMR!  Not by a lot and honestly could go slightly up or down on the next one but I thank God as it is a result I am always looking for and had never reached.  0.084% IS down from 0.16%.  It has been 33 months so sloth mode but it is a marathon.  Trending slowly down.

0.36%, 0.34%, 0.12%, 0.16%,....0.084%

I have been taking D3, K2, and (Calcium/Magnesium/Zinc) for a while now and the only change I have made is being very strict on the time (exactly 12 hours apart) that I am taking the medicine.  

I hope I don't get a slight rise as I did in the previous two results as I am right on the edge of MMR but honestly it is not clinically significant for overall survival.  Still feels good though.

ColoradoGuy, That is great news! I'm really happy to hear you got under that ever elusive MMR goal. I know it has been quite the journey for you to get there. I held off on responding to your post since I was waiting to get my 30 month results. I was hoping to celebrate with you, but alas my numbers went from 0.106 (24 month) to 0.147 (27 month) to now 0.297 (30 month). I'm incredibly disheartened with these results. My oncologist says that the difference is "noise of the test" and my results are relatively flat. I asked about switching medications, and they do not want to switch medications with these results. I know the test can give up to half a log error, but I have a hard time seeing this as flat; I see it more as consecutively increasing. I am trying to remain optimistic that I have been under 1% for 24 months now, but can't seem to convince myself this is good. I'm struggling with these results. I wonder what the group would suggest if they were in my shoes? Remain on medication as suggested by my oncologist or push harder for a switch? Thank you. 

I do believe that CCyR is great and had found comfort in research that it is no difference in overall survival once you have been there for a couple of years.  I don't see why switching should be such a big deal if you clearly have responded to Sprycel and can always go back to it.  Other than the headache of providing doctor authorizations and coordinating with insurance I would say this could be done in less than 7-10 days.  I also see why they don't want to mess with it though.  Keep in mind they see a lot of people with a lot worse side effects and probably worse numbers too.  I do miss taking one pill and not worrying about fasting.  I have three alarms set up for daily nilotinib (two to take it and one to let me know not to eat anything for the next three hours in the afternoon).  I have also heard that Bosutinib can cause blow ups...yes that kind which I would not want.  The NCCN guidelines changed the chart to make under 1.0 as target reached for a reason.  Hang in there and I hope you get going the other direction and closer to and under 0.1 soon.  

I hear you too mate! It is worrying when our numbers seem “stuck” even if that means a slight increase in our cases. Maybe we focus too much on the numbers and not our overall health too much. It becomes an obsession of not being left behind when so many others seem to do so much “better”... and so much quicker. Not everyone reaches MMR and that’s something some of us have to accept. As others have pointed out clinically it offers no advantage over MMR other than doing TFR which for me I am not interested in. One day I may be but the worry of having no treatment would be a physiological nightmare if this is what life is like on treatment that is working. Give me a 100% cure and all be all over it. Has your doctor not ordered mutation analysis too? I wonder why my doc did when I am very close to MMR maybe just procedure but does this mean I could have a mutation even if the numbers haven’t shot up or are plateaued. Doesn’t seem to be a consistency between patients and doctors. Who knows.

I guess the take home is we may never hit MMR or we may hit it one day. I read a post on here where a lady had only just started reaching numbers lower than 0.2 and she’s had CML for 9 years. As NCCN has done anything under 1% is where you need to be and if you go lower all the better but it really offers no benefit. Of course I’d like to be MMR (for a kind of closure point of view, but anyone can loose MMR) but I won’t crave it like I used to and I won’t live my life revolved around a decimal point... everyone’s days are numbered and I don’t want to waste what time I have left however long that is obsessing over it. As long as we are less than 1% and stable we have to learn to accept that might be a place we stay. And a good place as far as I have seen. What we all really want is some kind of certificate to say “you’re gonna live buddy” and MMR is kind of that. But it should be CCYR that gives us that “closure certificate” not MMR.

Yes. I want that 100% cure too. TFR is for me also very good, but I do not want to gamble with my body. Who can guarantee that I will reach DMR and that I can discontinue treatment and that it will not come back ? Maybe it will come back and then I suffer from pleural effusions from dasatinib ...

Everywehere, I read that people are looking for a 'true' cure by eliminating the stem cell pool. There is a lot of reasearch that gives hope.

That "noise of the test" I can believe.

I reached CCyR at 9 months (0,57% IS). 3 months after it was 0,84 %IS. So they measured again 1 month after, and it was 0,74% IS again. (all with Imatinib 400).

Exactly that. My family always say to me worry when your doctor worries and he’s never worried yet. Rather than focus on the magic numbers I will focus my energy on that for the time being. Yes 40 was diagnosed like you @38. A day we all will never forget unfortunately. But apparently it’s the one C you want to get if you ever get one. Aren’t we lucky 🤣

Me too 2 months before my 38th!

Yes we are still young and it does make sense for those with many years ahead.

Wow that is extremely reassuring and I wonder why that person never switched or increased dosage. I guess being this close to MMR isn’t a concern. If you start rising above 0.5% maybe that raises some alarms. Thanks for that info it does make you have hope hearing these stories and their aren’t enough of them on this site. Only those in MMR. Would be good to hear from some other CCYR hoverers. We are a select bunch it seems.

Who knows mate. I know younger people seem to take longer maybe our bodies defences allow a certain amount of the drug through or when CML has a blip in production some more of the drug slips through and attacks. From a science point of view I guess it’s comparable to being in MMR 3 but not MMR4 or MMR5. Takes a while to drill down or maybe the profile of our current drug blocks enough but doesn’t block as effectively as another shaped molecule ie drug.

Yeah I suffer from anxiety too and mental OCD traits so I have to understand everything and fix everything and if I can’t I am hopeless.

Lets hope that either A we get lower numbers or B have stable numbers where we are. And no progression!

All the best stay in touch!

Thank you, I will see about 3 months at the next check up. What is the risk about PAH ? 

If you have MR4 for more then 5 years, are you not in TFR yet ?

Does somebody have experience with Bosutinib ? Seems that should be safer.

Well today my husband saw his consultant & after 5 yrs he has reached MMR. Hovered at between 0.7 & 0.2 for yrs on Nilotinib since dx with WBC at456
Was on 600mg switched to 800mg 18 mths ago. Had a negative mutation test some time ago. His path has been a bit up & then down, very slow,but last 3 pcrs have been 0.097,0.07 & 0.063.

Oh wowzers that is fantastic news I am so pleased for you both and this has given me yet more hope. For the time being I’ll learn to live on the edge of MMR until that does happen. I really really appreciate you taking the time to reply to this channel. As coloradoguy said we are sloths not turtles haha. Still no update on my mutation report it’s been 3 months and I was told it was slow. My blood is surely out of date by now even if on ice🤣. I guess those who start from a higher point takes longer in my case wbc of 330 and platelets of 900 at diagnosis also. I was in a bad way.

Ill have a drink for you both. Wonderful news.

Alex

Gosh still no news for you too!! I do think COVID is playing a part as they use PCR testing for that analysis as my friend works for a supplier of PCR machines to labs. I guess no news is good news. At least I am holding onto that. We’ll see.

Did you get your NGS result? I got mine after some pressing. It just came back as "zero mutations". 

Thank you, Alex.

My consultant did explain that PCR laboratory findings do vary from day-to-day and that the variation in my result from the last to the present is statistically insignificant. Therefore, I appear to be stuck around about MMR with zero mutations on the next-generation sequencing investigation. My consultant assures me that this is quite satisfactory and I need not be concerned.

Indeed, it is disconcerting when posters (who are super-responders) are alarmed that their PCR has increased from 0.0001% to 0.0002%. You are quite correct that we should not be comparing our personal result with others.

I have been told that the next generation sequencing tests for mutations are giving results, for the main part, identical to the standard local laboratory tests. 

Let us know how you get on.

Alex, good to hear this. I plateaued (there are too many consecutive vowels in that word) around 0.5% from 9 months in to 18 months, and then went down to around 0.05% (The number is on a post from around 2007 but can't find it.)

Best wishes

Alastair

Alex Congratulations!!So happy for you!!

Faidra