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Question for the Brainiacs about cessation vs. reduction


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#1 jmoorhou

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Posted 06 July 2017 - 02:04 AM

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?     

 

:wub: :P :lol: :(


Diagnosed 3/2014 WBC 28 Non detectable within 3 monthsGleevec 400 mg 5/2014 one hour after dinner really improves nausea300 mg 12/15/2016200 mg and 300 mg Gleevec 2/25/2017 (after 3 years on Gleevec) For last four months taking 300 mg per day. Last CMC showed liver enzymes elevated, went to a good Naturopath and he recommended 4 Tumeric, 10,000 mg Vitamen D, and 3 milk thistle (silymarin) daily. Also use One<p>Day Detox Dandeloin tea, and Nettle Tea and a slice of ginger every day...in two months liver tests were below normal.Janis

#2 Pin

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Posted 06 July 2017 - 06:51 AM

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?

Diagnosed 9 June 2011, Glivec 400mg June 2011-July 2017, Tasigna 600mg July 2017-present (switched due to intolerable side effects, and desire for future cessation attempt).

Commenced monthly testing when MR4.0 lost during 2012.

 

2017: <0.01, <0.01, 0.005 (200mg Glivec, Adelaide) <0.01, 0.001 (new test sensitivity)

2016: <0.01, <0.01, PCRU, 0.002 (Adelaide)

2015: <0.01, <0.01, <0.01, 0.013

2014: PCRU, <0.01, <0.01, <0.01, <0.01

2013: 0.01, 0.014, 0.016, 0.026, 0.041, <0.01, <0.01 

2012: <0.01, <0.01, 0.013, 0.032, 0.021

2011: 38.00, 12.00, 0.14


#3 gerry

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Posted 06 July 2017 - 07:04 AM

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.

#4 scuba

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Posted 06 July 2017 - 10:10 AM

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


Diagnosed 11 May 2011 (100% FiSH, 155% PCR)

with b2a2 BCR-ABL fusion transcript coding for the 210kDa BCR-ABL protein

 

Sprycel: 20 mg per day - taken at lights out with Quercetin and/or Magnesium Taurate

6-8 grams Curcumin C3 complex.

 

2015 PCR: < 0.01% (M.D. Anderson scale)

2016 PCR: < 0.01% (M.D. Anderson scale) 

March        2017 PCR:     0.01% (M.D. Anderson scale)

June          2017 PCR:     "undetected"

September 2017 PCR:     "undetected"


#5 jmoorhou

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Posted 06 July 2017 - 11:05 AM

Great answer, thanks Scuba.


Diagnosed 3/2014 WBC 28 Non detectable within 3 monthsGleevec 400 mg 5/2014 one hour after dinner really improves nausea300 mg 12/15/2016200 mg and 300 mg Gleevec 2/25/2017 (after 3 years on Gleevec) For last four months taking 300 mg per day. Last CMC showed liver enzymes elevated, went to a good Naturopath and he recommended 4 Tumeric, 10,000 mg Vitamen D, and 3 milk thistle (silymarin) daily. Also use One<p>Day Detox Dandeloin tea, and Nettle Tea and a slice of ginger every day...in two months liver tests were below normal.Janis

#6 kat73

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Posted 06 July 2017 - 12:14 PM

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?


Dx July 2009 on routine physical.  WBC 94.  Started Gleevec 400 mg Sept 2009.  MMR at 2yrs.  Side effects (malaise, depression/anxiety, fatigue, nausea, periorbital edema) never improved.  Kidney issues developed because of Gleevec.  Switched to Sprycel 70 mg in Aug 2011.  Above side effects disappeared or improved.  Have been MR3.5 - 4.5 ever since.  Two untreated pleural effusions followed by one treated by stopping Sprycel Jan 2017.  After 9 weeks, PCR showed loss of MMR; re-started Sprycel at 50 mg and in 3 months was back to <0.01% IS.  Pleural effusion returned within a couple of months, same as before (moderate, left side only).  Stopped Sprycel 50 mg for 12 weeks; pleural effusion resolved.  At about a monthoff the drug, PCR was 0.03; at 11 weeks it was 2.06 - lost CCyR? Have returned to 50 mg Sprycel for 3 weeks, intending to reduce to 20 mg going forward.


#7 scuba

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Posted 06 July 2017 - 01:04 PM

"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. 


Diagnosed 11 May 2011 (100% FiSH, 155% PCR)

with b2a2 BCR-ABL fusion transcript coding for the 210kDa BCR-ABL protein

 

Sprycel: 20 mg per day - taken at lights out with Quercetin and/or Magnesium Taurate

6-8 grams Curcumin C3 complex.

 

2015 PCR: < 0.01% (M.D. Anderson scale)

2016 PCR: < 0.01% (M.D. Anderson scale) 

March        2017 PCR:     0.01% (M.D. Anderson scale)

June          2017 PCR:     "undetected"

September 2017 PCR:     "undetected"


#8 cmljax

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Posted 06 July 2017 - 01:09 PM

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.


Dx 9/26/16 WBC 28800; platelets 749; FISH 97% PCR 43%

Tasigna 600MG per day

October 2016                     PCR 22% IS

November 2016                 PCR 5.8% IS

December 2016                 PCR 0.1% IS  MMR!!

March 10, 2017                 PCR 0.006% IS  MR 4.22

Tasigna 450MG per day

April 5, 2017                      PCR <.003% IS

June 5, 2017                     PCR <.003% IS (dose reduction validated!!!)

Tasigna 300MG per day starting June 15, 2017

6-day drug break starting June 20, 2017 due to multiple AE's

July 24, 2017                     PCR <.003% IS

September 18, 2017          Negative, AKA PCRU

Tasigna 150mg per day starting 9/18/17

October 30, 2017               Negative

December 11, 2017           Negative


#9 Jan0080

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Posted 06 July 2017 - 01:13 PM

Neal Shah is the expert that my Oncologist confers with. 


Diagnosed Dec 27, 2016 started Sprycel 100 mg Jan 7, 2017. Initial PCR 77.9 after 30 days 28.4, day 79 1.4 and day 115 0.1%. That is a 99.9% reduction! Sprycel 100 mg for 3 months, 80 mg for 1 month and now at 50 mg. Hooray for Sprycel!!! PCR June 5, 2017 0.04! Dose reduction to 40 mg 6/15/2017 due to shortness of breath. 20 mg as of June 29th. PCR .02 9/11/2017. PCR .015 IS as of 12/11/2017. Lungs substantially better. Low dose Sprycel works!

Adverse Effect - At about week 6 of Sprycel sharp muscle pain that would start at 2 AM and last for about 4 hours. This lasted about 4 weeks and went away, thank goodness.

#10 jmoorhou

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Posted 06 July 2017 - 02:51 PM

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.
Diagnosed 3/2014 WBC 28 Non detectable within 3 monthsGleevec 400 mg 5/2014 one hour after dinner really improves nausea300 mg 12/15/2016200 mg and 300 mg Gleevec 2/25/2017 (after 3 years on Gleevec) For last four months taking 300 mg per day. Last CMC showed liver enzymes elevated, went to a good Naturopath and he recommended 4 Tumeric, 10,000 mg Vitamen D, and 3 milk thistle (silymarin) daily. Also use One<p>Day Detox Dandeloin tea, and Nettle Tea and a slice of ginger every day...in two months liver tests were below normal.Janis

#11 gerry

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Posted 06 July 2017 - 05:07 PM

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.

#12 stpaddy

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Posted 11 July 2017 - 07:17 PM

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


Husband dx March 2016; 400mg Gleevec started April 2016;

July 2016 PCR 3.06% 

Oct 2016 PCR 0.002%

Jan 2017 PCR 0.004%

April 4, 2017 PCR 0.001%

Reduced to 300mg Gleevec at end of April 2017 due to fatigue   

July 2017 PCR 0.001%

Oct 3, 2017 PCR 0.001%

Oct 18, 2017 PCR 0.003%

Dec 19, 2017 PCR 0.001%


#13 jmoorhou

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Posted 11 July 2017 - 08:27 PM

Not sure what he meant, but maybe anyone can cut down to 300 mg without becoming detectable very quickly.
Diagnosed 3/2014 WBC 28 Non detectable within 3 monthsGleevec 400 mg 5/2014 one hour after dinner really improves nausea300 mg 12/15/2016200 mg and 300 mg Gleevec 2/25/2017 (after 3 years on Gleevec) For last four months taking 300 mg per day. Last CMC showed liver enzymes elevated, went to a good Naturopath and he recommended 4 Tumeric, 10,000 mg Vitamen D, and 3 milk thistle (silymarin) daily. Also use One<p>Day Detox Dandeloin tea, and Nettle Tea and a slice of ginger every day...in two months liver tests were below normal.Janis

#14 Trey

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Posted 13 July 2017 - 07:21 PM

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.



#15 jmoorhou

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Posted 16 July 2017 - 12:06 AM

Interesting.
Diagnosed 3/2014 WBC 28 Non detectable within 3 monthsGleevec 400 mg 5/2014 one hour after dinner really improves nausea300 mg 12/15/2016200 mg and 300 mg Gleevec 2/25/2017 (after 3 years on Gleevec) For last four months taking 300 mg per day. Last CMC showed liver enzymes elevated, went to a good Naturopath and he recommended 4 Tumeric, 10,000 mg Vitamen D, and 3 milk thistle (silymarin) daily. Also use One<p>Day Detox Dandeloin tea, and Nettle Tea and a slice of ginger every day...in two months liver tests were below normal.Janis




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