18 replies to this topic

[scuba]

Another reference on LSC's, Sonic Hedgehog Pathway inhibition:

https://www.ncbi.nlm...les/PMC2946231/

This was published in 2009, so I assume that no breakthrough was discovered since we don't read much about it since.

[scuba]

This is a Branch discussion from my "Latest PCR Results".

I met with Dr. Cortes today and thought you would like to know his current thinking (in terms of my case).

He told me that I am having an excellent response to 20mg. Sprycel and that I can continue like this indefinitely. He has patients at MMR and better who do just fine. He emphasized that PCR < 0.09 % is "outstanding" and as far as he is concerned is indistinguishable from PCRU - his words. It is a very low residual result with little to zero chance of progression.

However, since I want to go off therapy (some day), he told me that I would have to register PCRU for two years and even then he thinks there is a good chance that I will have to return to therapy. He understands completely why I want to do this - and said he has more and more patients now that are PCRU - no medication and have been disease free (at least according to PCR) for about 3 years now. He has some who have 'relapsed'. The only way to rid of the disease is to eliminate the LSC's. He told me, "we're not sure what an LSC is let alone get rid of it". But he did say they are getting closer.

Targeting the LSC compartment is an area of active research. He told me that BCL inhibitor is not showing promise (answer to Trey). But Jak2 inhibitors are showing promise. He wants to enroll me in a trial in a few months time which combines Sprycel + ruxolitinib. The purpose of the trial is to test for long term progression free. He said that if I am to be progression free with no TKI - they'll need to target as best they can the LSC. He did say, also - that there is a lot more evidence that long term use of a TKI eventually wears out the LSC's and that's why there is an increasing number of patients who can stop long term therapy (those in PCRU) and remain disease free. Targeting the LSC is just a faster approach.

Until he gets permission from the FDA to proceed (with Sprycel + ruxolitinib), he will let me increase my Sprycel dose to 40mg. to test PCRU. I have to return to bi-weekly blood tests to verify my counts don't tank. And if they do, I have to go back on 20mg. right away. He also wants me to monitor closely any change in how I feel.

p.s.

He said that 20mg. would have likely gotten me to PCRU - just take a few more years. Since I am not a patient patient - he agreed to double the dose and hopefully get me there more quickly. We'll see.

Tonight - on to 40mg.

[Tedsey]

Cannot wait to hear when you hit the big zero!

All the best,

Teds

[scuba]

Thanks Teds!

That's my goal!

(actually - my goal is to store the Sprycel in the drawer and never have to take them again)

[LivingWellWithCML]

This is a very helpful read ... Gosh, I almost feel like I met with Cortes myself!  Thanks for sharing all of this!

And it is really great news about your response....hearing that statement about&lt;0.09% should be reassuring to many of us (like me) who are hovering right at that MMR point, but dodging the elusive PCRU.  Having the gift of survival from a TKI must not be taken for granted.

Good stuff ... Very optimistic about the next step in your journey ...

[pamsouth]

I can't believe how much time your doctor spends with you.  I had an appointment with my primary doc last week and she gave me the faxed update from my ncologist.  I noted at the bottome is said "i spent 30 min face to face with this patient"  Now what was the purpose of mentioning that?

I did have some issue I was determined he address. I already with over them with my pharmacist and he help me to word or think of the question.  I said he is not going to like all these questions he is the oncologist.  The pharmacist said doesn't matter make him answer you.  Seems most of his answer were;  not his field, so he tried to point the finger in the other direction.  Next time I am going to tell him.  They all got to work as a teem with me, cause everything effects everything, and everyone is pointing the finger at another doctor and I am one person with one body, soul, spirit!

Pamsouth

[Pin]

I agree with Dan - thanks Scuba, it's so helpful to hear what some of the leading researchers in the field are thinking, especially given how rapidly the research is moving (in some areas anyway).

[Trey]

Interesting that Dr Cortes said "there is a lot more evidence that long term use of a TKI eventually wears out the LSC's".  I postulated this as a "wish-theory" years ago and never heard anyone else say this until now.  My theory was that since leukemic stem cells divide far more often than regular stem cells, and since cells cannot divide indefinitely, the TKI drug may drive the LSCs to burn out by trying to keep up with the drug therapy.  So the cure could be in wearing  out the LSCs until they self-destruct from exhaustion.  This is also why I refuse to stop drug therapy, since the only way to wear out the LSCs is to stay on the drug for a long time, whatever that is.

[scuba]

That is exactly his point. Data is accumulating that LSC's may very well wear out. The "hypothesis" is that LSC progenitor cells (self renewal and differentiating) are constantly attacked and renewal becomes difficult. How long is enough is not known, but is measured in years. They know that after two years (PCRU), 40% do not relapse. After three years?, four years? I didn't ask.

There is also a relationship with speed of PCR decline. Those of us who "bounce" around - well...keep bouncing around. There needs to be a drug level that pushes the progenitor population into oblivion which forces the LSC's out of quiescence. Then they get nailed. Some just don't divide anymore. Those who had a quick drop are likely to have eliminated the progenitor population and the LSC stop dividing and either go dormant permanently or die.

He did mention that some of his colleagues believe that progenitor stem cells (lower level) can revert back to an LSC. But he doesn't subscribe to that and he mentioned no data.

Dr. Cortes subscribes to your thinking on Leukemic cells - that if there is one (LSC), then they can expand. A cure lies in eradication or immune response fix. He said that transcription errors (including bcr-abl) happen all of the time naturally - it's just that we who have CML are unable to fix it for whatever reason. And since we can't fix it yet - then one cell is one cell too many. I personally don't believe that as you well know and it was a fun conversation with him. Of course I have CML and he doesn't.

Personally I believe you and Susan are cured - You had fast precipitous drops in PCR once therapy was started that went below detection quickly and continues unabated there for years. In Susan's case, she had Interferon prior to therapy which there is evidence her T-cell population was primed (that would be the fix). Susan will never have CML again.

You, however, could very well be cured, but a new transcription error could restart the disease since there is no check on it. And so taking a TKI may need to be lifelong anyway. Eradicating LSCs may not be enough - since a normal HSC can divide into an LSC and start the disease all over. But that would take years and years - so having precious years TKI free is worth it to me. Keep in mind that, we, who have CML and those who are off therapy (Chris C) - still get monitored regularly. CML will never rear it's head again like those who have it, don't know it and the clone keeps expanding until the Spleen, blood counts and other symptoms are felt.

(I had a reaction to the increased dose overnight. Severe headache and chest cavity pain around my heart. Maybe going to 40mg was not smart since 20mg was working so well. And now I have to be under close surveillance for blood count tanking. Of course - if I get through this - it just might be what was needed to get me out of this steady PCR state I have been in and resume a more precipitous PCR decline.)

[mdszj]

Maybe you can alternate 20 and 40 for a week or so to help you ease into the higher dose.  I did that with 50 and 100 for 2 weeks when I went back up from 50 to 100.

[scuba]

That's a great idea ... I may do that. I'm just now feeling back to normal and it's almost "pill" time.

[scuba]

I decided to not take the 40mg last night and instead opted for my usual 20mg. Sleep was normal and I feel great - was able to go on my morning run.

Tonight I will try 40mg. and see if the heart/headache issue returns. If it does, I'll alternate. If it doesn't - then I should be able to stay on 40mg until next PCR (or myelosuppression sets in again which I doubt will happen).

I have decided that if I get a one log drop or even PCRU while under 40mg., I'll go back to 20mg. and see if it holds. Sprycel is toxic - it certainly isn't doing my heart any good.

[pamsouth]

Scuba,  I was just wondering what doses does Sprycel come in.  Do you split pills or do they mome in like 20 mg, 40 mg, 100mg.  and do they all split?  Just wondering.

PamSouth

[pamsouth]

Another thought, without reading thru the whole thread and all your post.  Sorry my memory is a bit short these days.  But did you or have you ever had PE in lungs or cardio, or any swelling while on Sprycel and if so what dose were you on?

Thanks PamSouth

[scuba]

I have never had any issues with Sprycel even at 70mg which I took for a week or two. But after taking 20mg. for a long time - it does seem that a sudden change in dose caused a reaction (the headache was the surprise, but maybe it was a bad glass of wine). I'll go back to 40mg tonight. I think I may be looking for an excuse to go back to 20mg!

Sprycel comes in 20mg. increments. So instead of taking one pill, I take two. Dr. Cortes wants me to take both at the same time in order to have a higher initial blood level. One can also get single pill dose at 50mg, 70mg and 100 mg.

My exercising I suspect minimizes the chance of pleural effusion. I get good respiration (very elastic lungs - never smoked except recreationally) with deep gas exchange. And I scuba dive with enriched air (more O2) which is a form of barometric treatment.

This whole dose increase is to see if I can get to PCRU like Tedsey has done. I don't want to be all alone here. I want to join the PCRU club.

[pamsouth]

So does the 50mg, 70mg, 100mg have a score across it to split dosage if you need too.

PamSouth

[mdszj]

Scuba - that is a good interesting post.  I have been wondering if exercise could help prevent pleural effusions.  I figure it cant hurt anything but I would like to know more about this issue and was wondering if Cortes (or any other docs) may have said anything about it.  thx for any info on this.

Mike

[scuba]

Mike -

http://www.livestron...eural-effusion/

When I run - I run until my breathing is pretty maxed out - meaning I can barely get enough breath to keep going. Lungs are surging, chest is expanding deeply. Breathing is a full as I can tolerate. When I was younger I could do a mile in under five minutes. Now I do a mile in less than nine. If feels the same - I'm just slower now, but breathing is at max. Welcome to older age.

Pleural effusion happens in part because the chest is not expanding allowing fluid to accumulate. Moving your body in any and all directions is the single most important thing you can do for yourself. Tai Chi, stretching, chasing the dog - anything that lends you to move your body will increase your lifespan. It really is that simple. I choose to run because it's releases a lot of feel good hormones. But anything that gets your heart rate up and keeps it there for a few minutes will help your lungs.

Walking for 30 minutes is way to start. No one should be a couch potato and expect to stay healthy. A minimum - absolute minimum is 30 minutes a day.

Cortes just told me that my college days are gone and so are the 5 minute miles. He said nothing about Pleural effusion because I didn't ask. He is very good at answering questions without offering commentary.

[CallMeLucky]

Pam - Sprycel pills cannot be split.  I've heard of one or two people who did it but it clearly states on the product label that the pills are not be to split, crushed, or chewed.