74 replies to this topic

[scuba]

Absolutely - once a drug goes off Patent protection, it can be manufactured and marketed generically. Gleevec is getting close.

[mikefromillinois]

I have recently enrolled in a 'TKI stop' clinical trial through the University of Chicago Hospital System.  This trial is currently being conducted throughout the US at several different hospitals.  The expected number of enrolled subjects across the US in this trial is 173.  A link to the trial:

 

https://clinicaltria...02269267&rank=1

 

Pursuant to joining the trial I have been provided with detailed "risk" information.  Within this body of Info it is stated that 'to date' there have been a total of 6 TKI stop studies (total of 456 subjects) that have been either published or presented at meetings.  All studies were "non-US" studies.  In these studies it was reported that of the 456 studied subjects, only ONE subject advanced to the blast stage.  Sources for this data were not cited, nor was additional information given about the 6 studies.

 

Me:

 

Diagnosed July 2011

On 100mg Sprycel since August 2011

Went to PCRU within about 9 months, and have remained so ever since (approaching three years)

On Sprycel I have had the usual bouquet of side-effects as many others here have reported.  Some come and go.  Some change in severity for better or worse over time.

 

My onc has had different opinions about stopping meds over the past couple years.  Initially he said he might ok cessation within a clinical trial, then he wavered on the idea, saying that unless my side effects were absolutely unbearable (and they are not) he suggested that we just leave well enough alone since the Sprycel has worked so well against my CML. 

 

I ended up seeking out and joining the current trial on my own, so to speak.  It is a three year study.  There are monthly BCR-ABL tests for the first six months.  For the next 18 months testing is every 60 days.  For the final year of the study testing is every 90 days.

 

I think that adding another 173 studied subjects to the current body of 456 should help shed better light on the viability of removing TKI's from the treatment equation.

 

I'll check in here with developments as time goes by.

[scuba]

I have recently enrolled in a 'TKI stop' clinical trial through the University of Chicago Hospital System.  This trial is currently being conducted throughout the US at several different hospitals.  The expected number of enrolled subjects across the US in this trial is 173.  A link to the trial:

 

https://clinicaltria...02269267&rank=1

 

Pursuant to joining the trial I have been provided with detailed "risk" information.  Within this body of Info it is stated that 'to date' there have been a total of 6 TKI stop studies (total of 456 subjects) that have been either published or presented at meetings.  All studies were "non-US" studies.  In these studies it was reported that of the 456 studied subjects, only ONE subject advanced to the blast stage.  Sources for this data were not cited, nor was additional information given about the 6 studies.

 

Me:

 

Diagnosed July 2011

On 100mg Sprycel since August 2011

Went to PCRU within about 9 months, and have remained so ever since (approaching three years)

On Sprycel I have had the usual bouquet of side-effects as many others here have reported.  Some come and go.  Some change in severity for better or worse over time.

 

My onc has had different opinions about stopping meds over the past couple years.  Initially he said he might ok cessation within a clinical trial, then he wavered on the idea, saying that unless my side effects were absolutely unbearable (and they are not) he suggested that we just leave well enough alone since the Sprycel has worked so well against my CML. 

 

I ended up seeking out and joining the current trial on my own, so to speak.  It is a three year study.  There are monthly BCR-ABL tests for the first six months.  For the next 18 months testing is every 60 days.  For the final year of the study testing is every 90 days.

 

I think that adding another 173 studied subjects to the current body of 456 should help shed better light on the viability of removing TKI's from the treatment equation.

 

I'll check in here with developments as time goes by.

 

This is very interesting. I certainly would welcome learning the details about the "one" patient who advanced to Blast crisis. Everything I have read on these studies did not cite any progression once a patient returned to therapy. Risk is still very low of course - but zero risk is better. Thanks for the update.

[rcase13]

I would be interested as well.
This the first I heard of that. With monthly testing they must have advanced fast! Scary...

[Trey]

One CML patient in a cessation trial lost CMR (PCRU) and restarted Gleevec while still MMR.  He remained MMR for a while but 8.5 months later he lost MMR and went into blast crisis. 

 

This article is the source but it is not open access:

http://jco.ascopubs....8.5797.abstract

[rcase13]

Argh more info would be nice. This scares the hell out of me. No stop trial for me if I ever get to PCRU...

Not a gambling man.

Yellow belly sissy here!

[scuba]

One CML patient in a cessation trial lost CMR (PCRU) and restarted Gleevec while still MMR.  He remained MMR for a while but 8.5 months later he lost MMR and went into blast crisis. 

 

This article is the source but it is not open access:

http://jco.ascopubs....8.5797.abstract

 

One CML patient in a cessation trial lost CMR (PCRU) and restarted Gleevec while still MMR.  He remained MMR for a while but 8.5 months later he lost MMR and went into blast crisis. 

 

This article is the source but it is not open access:

http://jco.ascopubs....8.5797.abstract

 

Trey - This doesn't make any sense. From the article you cite:

 

"Conclusion Loss of MMR is a practical and safe criterion for restarting therapy in patients with CML with prolonged CMR."

 

Nothing is mentioned in the abstract about a patient losing MMR and going into Blast crisis while on Gleevec. Where did you read this?

[scuba]

One CML patient in a cessation trial lost CMR (PCRU) and restarted Gleevec while still MMR.  He remained MMR for a while but 8.5 months later he lost MMR and went into blast crisis. 

 

This article is the source but it is not open access:

http://jco.ascopubs....8.5797.abstract

 

Trey - I sent an email to the author of the article you cited above : http://www.bloodjour...so-checked=true

 

and asked for the paper and data on the patient that was MMR for a while but 8.5 months later he lost MMR and went into blast crisis. Hopefully he will reply to my email.

[snowbear]

I think he meant the patient lost MMR and was in CMR when he went into blast crisis.  Still very scary !

 

My doctor has always told me that CMR is not good enough to stop or stay off the TKI's.  You have to be in and maintain MMR. 

[scuba]

I think he meant the patient lost MMR and was in CMR when he went into blast crisis.  Still very scary !

 

My doctor has always told me that CMR is not good enough to stop or stay off the TKI's.  You have to be in and maintain MMR. 

 

Hi Snowbear ... you have it backwards:

 

MMR = Major Molecular Remission

CMR = COMPLETE Molecular Remission

 

MMR is defined as PCR <= 0.1%

CMR is defined as "undetected" meaning it is below ... by another one / two orders of magnitude (i.e. PCR < 0.01%) MMR.

 

CMR is the holy grail.

MMR is very good - and patients achieving MMR do not progress (at least until the article Trey cited for one patient).

 

I find it hard to believe (and I emailed the author of the paper) that a patient went into Blast crisis from MMR. I just don't believe it. So we'll see.

 

(* in fact, patients achievieving CCyr (i.e. complete Cytogenetic Remission where FISH = zero) which is around MMR is more diagnostic of long term remission and progression free survival. It's what they see under the microscope that is most important to long term success - this is a Dr. Cortes quote. PCR is the canary in the mine shaft - it's a warning. But cytogenetics tells them the state of our disease. Getting to FISH = zero is the big achievement.)

[snowbear]

Oops....I got CMR mixed up CCyr.    I was thinking along the lines of the 3 remissions - hematological, cellular, & molecular.

 

Thanks for straightening me out !!  

[Terran]

Scuba, I like the way you think.

[scuba]

Scuba, I like the way you think.

 

Thank you!

[Trey]

There is a .pdf file available which I cannot link to.  But G-search on these terms:

 

Deciding to continue or discontinue tki

 

Click on first item "Deciding to continue or discontinue...." Open PDF slide show, go to slide number 14, look at footnote.

Edited by Trey, 04 May 2015 - 09:12 PM.

[scuba]

There is a .pdf file available which I cannot link to.  But G-search on these terms:

 

Deciding to continue or discontinue tki

 

Click on first item "Deciding to continue or discontinue...." Open PDF slide show, go to slide number 14, look at footnote.

 

Excellent - Trey! Thank you. I have slide 14 open and see the footnote:

 

"One patient diagnosed in 1996 (15 years ago) experienced lymphoid blast crisis 8.5 months after

restarting imatinib while in MMR".

 

I also received an email from Dr. Rousselot (papers primary author) this morning after asking him about this. He replied, "To my opinion, a patient diagnosed with CML a long time before the TKI area and who received several lines of therapies before TKIs is not a good candidate for any attemp of treatment modification or interruption".

 

This was an interesting response.  Patients who received TKI's 'first' have a better chance at cessation, and with relapse 100% return to MMR than those who had other treatments prior to the TKI "era". He noted to me that no patient who stopped TKI therapy (Imatinib) progressed (this study and other studies) after relapse. Every one returned to their prior status.

 

What is it about prior treatment (1995 time frame) that affects the bone marrow in this way? We're just guinea pigs with these chemicals.

 

So for me - an N=1 - personal cessation trial, my risk of blast crisis progression is miniscule. And since I never had any treatment other than a TKI, according to the notes above and Dr. Rousselot's reply, my personal risk of progression is still zero. And since I believe that vitamin D helps leukemic blasts to differentiate (go ahead and smile), I have a bit of insurance.

 

One more point on this "one" patient from 1996 vs today. It is interesting that this patient regained MMR after resuming Imatinib, but still went into a lymphoid blast crisis - not a Myeloid blast crisis. This patients' PCR was still MMR (i.e. imatinib was working) when the blast crisis occurred !!. This patients blast crisis was not of CML origin. BCR-ABL was not causing the blast crisis. What this tells me - or better- reminds me is that CML is but ONE leukemia. Leukemia is not just about bcr-abl.

[scuba]

There is a .pdf file available which I cannot link to.  But G-search on these terms:

 

Deciding to continue or discontinue tki

 

Click on first item "Deciding to continue or discontinue...." Open PDF slide show, go to slide number 14, look at footnote.

 

Trey - take a look at slides 32 - 39. I recall our conversations where you felt that eradication of "all" Leukemic stem cells is required for "cure". And I did not feel that way since I believe our bodies translocate DNA (including bcr-abl) all of the time as part of living and exposure to stuff. A good shot of ionizing radiation probably produces a lot of LSC's - and therein lies the difference. It's about population control. High population, for whatever reason, overwhelms the immune system. 

 

The theory on cessation success is summarized very well in slide 39. Take a close look at that diagram. It seems the LIC's (leukemic initiating cell) is what leads to disease and of course the dreaded blast crisis (blast crisis is what kills) because of their faster growth rate. Dasatinib kills these higher order cells to a greater degree than Imatinib. Successful TKI treatment and subsequent cessation must eliminate all of these cells. It is the pool of unkilled LIC's that leads to rapid re-start and loss of MMR (hence the need for monthly testing). It does seem that because LSC's are slow and are not active much in the bone marrow niche, disease re-start may take years (your theory on outlasting the stem cell) or not at all. 

 

My take away is that I have Leukemic stem cells. The fact that I have not "relapsed" since stopping Sprycel suggests I may have eliminated all of the LIC's - won't know for another 8 - 24 months - but so far so good. The question to is whether the remaining LSC's are sufficient in number to re-start CML sometime down the road. My own guess is that it will. So I am just buying some treatment free time to enjoy no drug and no anemia. But if the population of LSC's is small, and the subsequent production of LIC's is killed - then maybe?

 

Or - my new Curcumin and vitamin D nutrition program may just be able to keep the LSC's at bay since my immune system is strengthened (my own personal view -not scientific). It is the immune system that checks these things. And unless my immune system is damaged beyond repair, I would have no hope of ever succeeding with cessation. But then other cancers are going to get me since we don't have drugs for all of them.

 

*(note that the motivation for cessation in Europe, in particular, is cost. Even repeated attempts at cessation is being tried after initial cessation fails. It is driven by cost. If cost is no object and side effects are minimal - then staying on a low dose drug is a very good insurance policy. But at least it is your choice. In the U.S., we may come to a time when a patient does not have that choice - they may be forced to drop TKI treatment if they reach CMR or MMR at a sustained level for two years. In your case - you would have been forced to stop taking Gleevec and monitored monthly since that would be cheaper. Perhaps when Gleevec goes off patent, cost of PCR testing will be greater. Europe is preparing to force patients off their TKI's once long term CMR/MMR is achieved.)

[snowbear]

Scuba - are you worried about your doctor dropping you as a patient since you stopped your TKI on your own?

[scuba]

Scuba - are you worried about your doctor dropping you as a patient since you stopped your TKI on your own?

 

Not at all. I have a very good rapport with him - more of a collaboration. He knows I understand the risks and the science and is willing to work with me in a watchful role. He participates in writing the NCCN guidelines that non-specialist Oncologist use to treat their CML patients. He appreciates my reasons. He says I have a 50-50 shot! That's up from zero in February.

[snowbear]

That's great that your doctor is willing to work with you.

[scuba]

That's great that your doctor is willing to work with you.

 

He's been great to work with me on this adventure.