16 replies to this topic

[scuba]

I received my latest 3 month PCR test result:

No change from 3 months ago ... bcr-able is the same as before...bummer.

I was hoping for a renewed trend downward. I'm still MMR so Dr. Cortes response was - you can stay the course - you're fine. However ...

I take 20mg. Sprycel + 8grams Curcumin. I believe the Curcumin is helping me get this low detectable result on only 20mg Sprycel, but it seems in order for me to get CML to resume a decrease, I have to do something else.

Here's the good news that I think will have interest on this forum. Dr. Cortes wants to put me into a trial to test eradication of the CML stem cell (LSC). This would be done in addition to taking Sprycel (and the Curcumin). He says there is evidence they may have a combo medication that works with the TKI (in my case Sprycel) to attack both the progenitor cells and the LSC compartment. The two work together. I would be tracked  (with PCR tests). I meet next week with him to arrange.

I could also increase my Sprycel dose (he relented and will let me try that if I want) - but thinks that this new approach is worth a try. The benefit of the two drug approach is that if it works, I will see an immediate drop in residual PCR from where it is now. It is anticipated I would go PCRU fast. Once that happens, I would be taken off all drugs to test for relapse. The goal is that if the LSC's are gone I would have no relapse. This is called cure.

[CallMeLucky]

Did he say what the drug is?

Hedgehog inhibitor or something else?

Curious if it is a new drug in development or an existing drug that they think might work.

[scuba]

No he did not. I will learn all of that when we meet in person. I have no idea on what it could be? Open to speculation.

My only concern will be side affects and dose. I don't know what trial level it is (Phase I or II). I could be the guinea pig for dosing (i.e. at what point would it kill me, etc.). And I have a concern on how often they would want to see me. The upside of course is LSC eradication if it works, in which case, I would put up with just about any side affects since they would be "temporary".

Here is some research I came across that may be what Dr. Cortes is thinking about: http://www.cirm.ca.g...ell-eradication

Another approach: http://www.nature.co...310-237_F1.html

The last link refers to an article from 2010. Since we haven't heard much since, no idea if this approach has merit. The good news is that the researchers are looking specifically at LSC eradication. That's our goal.

[CallMeLucky]

I would find it odd if they took someone with stable chronic disease and put them in a phase I trial.  I suppose it does happen, but I think they have to be really careful with this.  It is one thing to say a patient has a poor prognosis and therefore we can "experiment".  It is another to look at someone like you, who based on where you are today, conceivably you will live your normal life span.  to give you an experimental drug that could harm you would seem terribly risky.  That is why I was wondering if it was a drug that already existed.  If it is an experimental drug then I would expect that they initially trialed it on patients with advanced disease, in which case it would be very interesting to hear how it worked for them. 

[Trey]

Probably a BCL inhibitor. 

This article describes some aspects (not all) of the current thinking about LSC eradication:

http://www.ncbi.nlm....les/PMC3342507/

I would be careful to assess the hazards of inadvertently inhibiting good hematopoietic stem cells along with the leukemic ones.  Such things can happen in clinical trials.  You did not have a large pool of good hematopoeitic stem cells (very low blood counts), so may not be able to afford the loss of any significant numbers of them. 

[pamsouth]

That is what I am looking for a cure!!!  Recently went to another doc for another opinion all he said is you will be on these TKI'S  for the rest of your life.  I said we are far from a cure and he said maybe in 50 years.

Anyhow, Next Friday 6/28, I am Starting on Sprycel 50 mg, for at least two - three months.  If I have a good response and tolerate it I will stay at 50 mg, if not I have agreed to go as high as 70 mg, but no higher and that is only if I can tolerate them.  It was not an easy task to get the oncology to agree, he like to go by standard protocol.  I begged him to meet me 1/2 way and so that is the agreement.  Now let's see how that pans out.  But what I didn't mention to him, but I will, is that I will also be taking the Curcumin, starting out at low dose.  I tried it curcumin last year, while on Gleevec, and had a bleed.  I go next Tuesday for my Colonoscopy, so hopefully that will be fine.  Just want to make sure before I start on sprycel that everything checks out OK.  I asked onc for and ekg an an x-ray before starting Sprycel, the nurse said he would order it, but they usually only order EKG & X-Rays for Tasingana and she didn't know if insurance would pay for it, so I told her I would call the billing manager and ask her.  I am a little surprised as the warning on Sprycel are high for PE, etc.

Just got back my FISH AND PCR on Gleevec and both were at 3 %.  It jumps around between 1% to as high as 13 %.  I hasn't been down to 3 % for sometimes now, just as I am getting ready to switch from Gleevec to Sprycel.  Then I begun to wonder if I should make the switch.  Been worried about my kidneys, my GFR is at stage 3 CKD and I didn't know if that is from Gleevec been on since 2005, or the diuertic been on since 1997 or age or all of the above.   Anyhow I used to take diurectic daily for swelling and blood pressure but only take it once a week now and a switching to a different diurectic without the blood pressure med in it.  I have lost 35 ? 40 lbs, so I have had to change some of my med's and bought a whole lot of clothes and doing some shoping with friends, actually was a lot of fun, shopping and mixi/match, summer sales on now. 

So Scuba here I go after 8 years of Gleevec and am 65 years of age into new territory, starting on Sprycel at 50 mg and hoping to stay at that dose.

PamSouth

[scuba]

Trey - They are considering these drugs in addition to Dasatinib (Sprycel):

azacitidine and ruxolitinib

I don't know if one or both will be used in addition to Sprycel and at what dose. Both drugs are used in other blood disorders (notable MDS) and have shown incomplete affect on LSC's (obviously or there would be front page news). Perhaps in combination with Sprycel they anticipate a burden reduction of LSC's sufficient to resume the downward trend in PCR and enable eradication through population reduction. I am speculating on the last part. I'll learn more on their thinking when I meet with Cortes.

[Trey]

Azacitidine is Vidaza, a harsh chemotherapy drug.  Sounds like a dumb option.  If it were me, I would not allow anyone to put that stuff in me.  Are you sure Dr Cortes isn't trying to treat the trisomy 8 issue instead of looking for stem cell eradication? 

Ruxolitinib makes more sense.  It is a JAK/STAT pathway inhibitor which has been shown to make leukemic (BCR-ABL) cells more sensitive to TKI drugs (only tested with Gleevec as far as I know).  But beware the effects on blood counts which could be significant.  This is what I mentioned earlier that such drugs may not suit your situation and could put you off all drugs for a significant timeframe if your counts get screwed up badly. 

http://bloodjournal....19/20/4614.full

Ask Dr Cortes why he wouldn't consider a BCL inhibitor instead. 

[scuba]

I'll find out next week. I haven't had a bone marrow examination in a very long while. At that time PCR was greater than zero and I was positive FISH as well as myelosuppressed. Since then PCR has plummeted to a low, but continued detectable, Fish = zero and blood counts have rebounded to normal in most cases. Platelets are lower range normal.

I may just ask him to increase dose of Sprycel and see what that does first. Or maybe I should have another bone marrow in order to rule out Trisomy 8. Cortes did say that when blood counts come back to near normal and PCR < 0.1%;Fish=0, he sees Trisomy 8 disappear. But we won't know until we look.

The other alternative is to just leave it alone (which he did suggest). Steady state low PCR (<0.1% IS) has outstanding results (long term survival).

[LivingWellWithCML]

"Stay the course" sounds like an excellent option given how well you're doing, eh?  You could blaze the trail on a combo-therapy trial and seek eradication, but it just seems risky since you have achieved an excellent response and are stable.  Thanks for sharing and will be very curious to hear more after your consultation with Cortes .....

[scuba]

Thanks Dan ... I may just ask for an increase in dose (to 40mg) or ... I am seriously thinking of stopping Sprycel altogether and see what happens over the next three months. CML is a slow disease - there is a chance that since it has been beaten back to very low levels that the 20mg. Sprycel isn't really doing much anyway. I want to test that my taking Curcumin alone can keep me at this low residual level. And I would take it one month at a time. Worse case - my PCR goes up 1/2 to one log. I'm still in the safe zone.

When I see Dr. Cortes I will ask him if he will monitor to me doing this - which means six week PCR checks to verify if my PCR is climbing or staying the same. If it climbs, then I go on 40mg. if it doesn't - then I go another six weeks TKI free.

Just a thought.

(Trey - I will also ask about BCL inhibitors. Makes a lot of sense from what I read.)

[Trey]

Stopping Sprycel at this point makes no sense.  Think about it.  If you have continuous detectable leukemic cells, they are churning away making new ones, so your body has not found a way to deal with them on its own (such as theories of T-cells learning how to recognize the leukemic cells and killing them off).  I know you would like to think it might, but it has not.

[scuba]

Trey - I don't disagree - but there are many examples in the discontinuation trials where low level detectable disease (<0.1% IS scale) stayed at that level even though TKI was stopped. That is why I thought it might be worth a try. The key is to monitor closely for any signs of growth.

I understand you believe that only 'one' leukemic cell is enough to re-grow a tumor, but that is not the case. It's population dynamics and disease 'burden'. The body may very well have this disease under control when the population is low enough.

Nevertheless your point is taken. I feel I have room to experiment since I know what to test in order to verify. I have a strong suspicion, however, that Dr. Cortes will say No - so this may be moot. But I think about it - a lot.

[TeddyB]

I wish you the best of luck Scuba, whatever you decide.

Please keep us posted.

Teddy

[ChrisC]

Hey,

Quick question: those folks in the trials you refer to, whose tests showed a return to measurable-but-low BCR-ABL and were still allowed to continue without restarting their TKI, as long as the measure remained low: didn't they first have to meet the study's criteria of having been uninterruptedly PCRU for at least two years prior to stopping their TKI?

You might want to look into that, since as Trey points out, there are still functioning bad guys working in your blood.

Why stop being vigilant at this point, since you've come so far towards your goal?

All the best,

ChrisC

[CallMeLucky]

I generally accept most of your theories, even if I don't fully agree with them.  Completely ignoring the issue I am currently going through, I have to say that I think for you to stop is a mistake.  Certainly your right to experiment as you see fit but I believe, as I think most would, that you are almost guaranteed to see your numbers go up.  I would bet they go up in short time, but even if they take a few months it would be practically inevitable.  I caution because we do not fully understand the mechanisms of resistance and mutation, and we also cannot guarantee the trajectory of clonal evolution.  Yes CML moves slow - until it doesn't and then it moves quite quickly.  Do not take for granted that things will go the way you plan in the event you stop treatment, at the end of the day this is still cancer and it can be unpredictable.  You have had two compounding factors with myelosuppression and trisomy 8.  Please proceed with caution.  I only say this because I care.  I would go to 40mg and see how it goes.  You are doing well, continue to drive it down, see if you can get to PCRu, sustain it for a couple of years, then think about cessation, by then maybe there will a trial that is worth while or maybe you will be able to extinguish everything.  At this time it is clear you have not extinguished the stem cells, the idea that your body is going to keep this under control for the rest of your life is not backed up by the science. 

Of course the decision is yours and you would certainly have our moral support in any course you choose.  Best of luck.......

[scuba]

I will be seeing Dr. Cortes in a few hours. It will be the first time I will have seen him in more than a year (maybe two). We work through email. It's been great this way since he has confidence in my understanding the science behind the disease and the drugs used to treat it so he doesn't require Clinic visits. It's just labs ... they take blood, report results, We converse by email. It's been an easy process since my "experiments" revolved around Curcumin and otherwise very low PCR numbers. But now my PCR numbers are not trending downward - and nothing I have done lately has affected that (Curcumin notwithstanding). They do believe that the Curcumin is augmenting the Sprycel so I can get away with less Sprycel dose than normal and still have a great response. But I seek cure. And that requires an in person visit - including discussion about stopping Sprycel to see if my counts stay the same, doubling the dose, and/or trying new drugs in combination with Dasatinib.

I asked about BCL inhibitors and Dr. Cortes says there is not much data on their effectiveness (LSC's) in comparison with the other drugs he wants me to consider. I suspect getting LSC's to exit quiescence and divide is where the answer lies. It is during division that they are most susceptible to TKI drugs. I will ask him about the biochemistry of action of these drugs and what he expects they can do. Maybe a good 'ol fashion blood letting (which does induce Stem cell division) would help!?

The good news in all of this is that I am going after the LSC's and not too concerned about disease relapse. The LSC's are where the problem is located. I feel the progenitor cells are under control - and it is the LSC compartment that continues to re-populate them and maintain disease. My feeling is that if I am going to have to take drugs - then I want to do so in a way that gets at the root of the problem not just maintains me where I am. And maybe that will help others if my experimenting with these new drugs can work.

This is the area I am actively researching regarding LSC's: https://www.scienced...0808002572?np=y

The Sonic Hedgehog pathway seems to show great promise in reducing (or eliminating) the LSC compartment. Curcumin, by the way, also downregulates the sHh pathway: http://cancerres.aac.../70/8/3382.long I suspect that is why I am able to get a great response on only 20mg. Sprycel. I do believe my LSC's have been reduced (hence my recovery from myelosuppression) - it's just not good enough. Some other drug that is more potent might be able to do the trick. Of course one does need the sHh pathway for life. It just doesn't need it up-regulated the way CML induces.