14 replies to this topic

[jmoorhou]

I talked to Neal Shah one of the top CML experts on the west coast, he has a Phd in CML, as well as medical degree.  He works at UCSF, a respected cancer clinic it's part of the California UC system.

 

I emailed him and told him about my situation, that I had cut down to 200 mg.  and was a bit anxious.  He said anyone can take 300 Gleevec...which I thought was interesting.....this was after I told him I'd been on full dose for three years, before starting reduction.

 

He also suggested I try cessation instead of reduction.   I didn't get a chance for him to elaborate, but I'm wondering if the body is more apt to kick in with the immune system to fight CML, if you are not taking a TKI.

 

Any ideas anyone?     

 

[Pin]

Not sure about the immune system theory, but I can also say that the specialist I saw in Australia said a similar thing - that perhaps I should aim for cessation first.

I think in your case, it might be worth a shot to see what happens (I'm assuming you told him how good your response has been), if it doesn't work, you can always try again or dose reduce to maintain?

[gerry]

Immune system doesn't kick in because you stop your TKI. It will need to have kicked in prior to stopping.
They've seen more trials for stopping than dose reduction trials. I figure they feel more comfortable with it. Plus here in countries where our meds are subsidised, the preference would be to have us off TKIs as long as it is safe to do so.

[scuba]

Dr. Shah suggested cessation because you are PCRU and have been for several years. You had very quick response on Gleevec.

There is near zero risk to trying cessation first to see if you have a functional cure (i.e. 'treatment free remission'). You would have to have a PCR test taken once a month initially to catch any PCR uptick. If you are to fail cessation, you will likely fail within the first six months. But each month that you continue to be below MMR (i.e. PCR < 0.1%), increases your odds of success.

 

If your PCR does rise above PCRU, you can continue off Gleevec and see if an upward trend develops. Many cessation patients have initial increases above PCRU, but then levels fall back again all the while staying below MMR. If you are comfortable tracking your CML this way, you could go a very long time without any TKI and most important - no more side effects during this time (although withdrawal symptoms are reported). 

 

If your PCR rises and continues to trend upward, you can restart your TKI on a lower dose and continue monitoring. In this way you can find what lowest dose possible is sufficient to maintain response.

 

In my own case - I tested cessation before becoming PCRU. I was at PCR < 0.01% which is technically "detected", but no longer an accurate read (could be false positive). So I tried cessation. I was on 20 mg Sprycel (1/5th normal dose). I was able to stay off Sprycel for nine full months (nine WONDERFUL months). My PCR did go above 0.01% but never went above 0.1%. It was vacillating between 0.01 and 0.08%, but with an overall - very slow trend upward. My doctor wanted me to continue cessation to see if I stay in this range (below MMR). I was tempted, but decided to resume 20mg Sprycel just to prove to myself that I can push my PCR back down and how long that would take. Sure enough, my PCR plummeted within a month on resumed Spyrcel and in two months I was back below 0.01%. Lately, I have even gone "undetected" for the first time (PCRU) - I will test cessation again if I stay PCRU for another PCR test.

 

No one has progressed with advanced disease who tried cessation and lost PCRU. All patients who restarted their TKI regained their prior response quickly. Cessation is safe to try. But there is a psychological barrier that has to be crossed when doing so. Many patients are uncomfortable trying cessation. Near zero risk is not the same as zero risk.

 

Regarding your immune system "kicking in". CML disease - in fact - most cancers occur because our T-cells fail to activate in sufficient numbers to attack cancer cells. As CML cells are part of our  "self", they put out proteins (cytokines) which increases the number of a special T-cell (regulatory T-cell, aka Treg) to shut down other T-cells and not attack (natural killer T-cells). It is a natural mechanism to prevent our own killer T-cells from attacking our healthy cells. Autoimmune diseases are killer T-cells run amok.

 

Cancer is really a problem in bad cell population control. It takes a lot of CML cells to produce enough cytokines to shut down our normal T-cell attack response. There is a theory that when we first developed CML, it was because something triggered a massive stem cell transformation creating the philadelphia chromosome of our normal blood stem cell into leukemic ones - we know radiation does this - exposure to certain chemicals can do this. One spontaneous CML cell creation is not enough. This large population of cells are then able to maintain and expand by shutting down our killer T-cell response. 

 

The reverse may be true. By reducing this damaged population using TKI's - enough CML cells are destroyed that those remaining are unable to put out enough cytokines to shut down our normal killer T-cell response. Our bodies are able once again to defend against CML without a TKI. It's just a theory. But - those patients who have successfully tried cessation and succeeded - they no longer show CML. Something is protecting them without a TKI present. We simply don't know if it takes the eradication of every single CML cell. My own opinion is that eradication is not required give what we now know about T-cells and how they work. Regaining an immune response is what is required.

 

http://www.nature.co...cr2016151a.html

[jmoorhou]

Great answer, thanks Scuba.

[kat73]

It still begs the question concerning development of resistance.  WHY are so many oncs reluctant about decreasing dosage, especially when cessation studies have documented that, so far, all patients who relapse are able to regain control after restarting TKIs?  They never say WHY.  "No data" is only part of the explanation.  My onc, for instance, believes underdosing will eventually cause resistance and the drug will stop working.  He is a CML expert and he believes this.  He will never prescribe 20 mg Sprycel - never.  I wish the oncs would all come out of the closet on this question and say where they stand, once and for all.  Is developing resistance the fear that they have in lowering dosages to 1/2 or 1/4 recommended?  Is that why they'd prefer a trial of cessation to lowering the dose?

[scuba]

"My onc, for instance, believes underdosing will eventually cause resistance and the drug will stop working.  He is a CML expert and he believes this.  He will never prescribe 20 mg Sprycel - never."

 

You have had P.E. - and are currently below 0.01% PCR on 50mg sprycel. You likely will maintain this response even on 20mg sprycel and further decrease your risk of another P.E. Your doctor is mistaken on 20mg sprycel leading to resistance.

 

Unfortunately - the practice of medicine is as much art as it is science. Clinical drug testing is a statistical exercise with no one correct answer. Each of us is unique in the proteins that our cells make and so one size does not fit all in terms of drug response. Sprycel is a very potent drug with a half life of only 5 hours in the body. In those five hours, a lot of damage to CML cells occurs - but also a lot of damage to normal cells can occur as well for which during the next 19 hours repair is done. This is why sprycel was recommenced to be given once per day instead of divided into smaller doses twice per day). Pleural effusions were much more common on the twice per day regimen even though each dose was smaller. 

[cmljax]

Kat:

My onc is the same as yours. I have only gotten dose reductions because of serious AE's - first reduction was due to multiple squamous cell skin cancers and even more multiple precancerous lesions; second reduction was multiple additional AE's - fatigue, swollen salivary glands, recurring mouth ulcers. Absent these side effects, my onc would not permit any dose reduction.  The AE's give the oncs "legal cover" because the established protocols permit dose reductions and even dose interruptions as an acceptable way to manage AE's.

 

My onc also is willing to monitor me in cessation but only after 3 years of therapy (I have 9 months under my belt) and 2 years of consecutive MR 4.5 or better (Assuming I am still there, I have 3 months under my belt).  I get the impression that he would not let me dose reduce any further on my way to cessation as he has said that DESTINY trials do not have enough years of data yet to convince him.

 

In the end, I think it is a potential legal issue for many oncs like yours and mine.  There is only downside for them to stray from accepted protocols.  I do not believe that reducing dose causes resistance unless the reduced dose is less than therapeutic and maybe not even then.  And therein lies the problem: the minimum therapeutic dose varies by person so the only way to find out your minimal level is to experiment.  The good news is that more and more oncs are beginning to experiment with dose reduction and that number should only continue to increase.

[Jan0080]

Neal Shah is the expert that my Oncologist confers with. 

[jmoorhou]

My regular Onc always brings up mutations also....there must be something to it...where did they get that idea. The latest trials don't seem to point to this.

[gerry]

I have to wonder how many different types of mutations they've found. Are there any new ones they are seeing. Were the mutations there from the start and are there any showing up after a number of years into treatment.

[stpaddy]

Just reading this thread and not sure I understand what Dr. Shah meant by saying anyone can take 300mg Gleevec?  Just wondering...thx.

[jmoorhou]

Not sure what he meant, but maybe anyone can cut down to 300 mg without becoming detectable very quickly.

[Trey]

Dr Shah and Dr Druker both started out believing that low dosage TKI treatment could lead to kinase mutations.  I asked both of them about that in approx 2009.  Now both reject that theory and regularly prescribe low dosage TKI drugs for patients.

[jmoorhou]

Interesting.