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Tasigna "Discontinuation Study": Not Sure What Questions to Ask


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#1 bagdaddi

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Posted 30 May 2013 - 10:32 AM

My Onc would like to potentially enroll me in a new Novartis sponsored Tasigna "Discontinuation Study."  The name of the study is ENESTfreedom and involves two randomized groups, both of which will discontinue Tasigna, although the second group will delay an additional year prior to discontinuation.  The criteria of the study and frequency of PCR testing seems consistent with other studies/discussions.  However, in my case, I could end up discontinuing as early as 3 years after diagnosis with only one full year of quarlerly tests >4 log reduction (with the last test prior to discontinuation being >4.5) as defined by the study protocol.  This all seems a little early for me since I am currently only 15 months from diagnosis. 

At this point, I am interested but not sure of the right questions to be asking.  I would appreciate input from the group, especially those that may have already been part of a study.  Aside from the medical aspects, most of my immediate concern centers around not wanting to screw anything up with my insurance, especially if I discontinue and then need to re-initiate Tasigna. 

Thanks in advance for your input. 

ENEST Freedom.jpg



#2 bagdaddi

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Posted 30 May 2013 - 04:55 PM

May be a mute point as I just got my new PCR result, which went up.  @9 months (0.068%), @12 months (0.037%), @15 months (0.096%).  Was hoping to drop to a 4 log reduction, instead increased to just barely a 3 log reduction.  My excitement over a discontinuation study suddenly feels very premature...



#3 Trey

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Posted 30 May 2013 - 05:17 PM

I would ask about probabilities of success if PCRU for a couple years vs PCR positive at the start of the study.  What data exists regarding PCR positive patients discontinuing Tasigna (or any TKI drugs)?  What mechanism of action inside the body would account for maintaining MMR level indefinitely after TKI cessation, and how do they think they know that? 

I personally would not participate in such a discontinuation study unless PCRU for a minimum of 2 years, but more likely 3+ years.  Any discontinuation while still PCR positive would have a high likelihood of failure.  I have chosen to  reduce my Gleevec dosage to 200mg/day since 3 years PCRU with no loss of PCRU status.  I personally believe that is a better approach than cessation until more is known.  So I will be very interested to see the data from this study, I just think the participants should be wary if they have not achieved continuous PCRU status.



#4 GerryL

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Posted 30 May 2013 - 06:05 PM

I'm looking to do a discontinuation in late November. I will have been 2 years PCRU by then. The thing that surprised me about the issue of relapse following discontinuation is that the CML returns at a faster rate. So you need monthly testing to make sure you catch this change early if it occurs. Restarting a TKI should return you to where you were. I wouldn't even attempt it if I hadn't been PCRU for at least two years.



#5 jjg

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Posted 30 May 2013 - 08:30 PM

Hi Gerry, What makes you say "like blast phase". When I stopped treatment my PCR went from < 0.003% to 12% in just over 3 months so the rate of increase was significant but when I resumed TKI treatment, all be it on nilotinib rather than glivec, I responded really well. So for me I don't think that the relapse corresponded to any changes in the structure of the disease just the prevalence. From what I've seen of the data of those who relapse after stopping my experience seems to be common except that most  restart treatment earlier than I did. Were you thinking of the data from the link you posted earlier this week (great info - haven't had time to do more than flick through a few of the pdfs or get the video streams to work on a mac, so I don't know what was said about the data)

http://www.cmladvoca...hes-stop-trials

(slide 11)


Dx Dec 2010 @37

2x IVF egg collection

Glivec 600 & 800mg

PCRU March 2012

Unsuccessful pregnancy attempt - relapsed, 3 months interferon (intron A), bad side effects from interferon

Nilotinib 600mg Oct 2012

PCRU April 2013, 2 years MR4.5 mostly PCRU with a few blips

April 2015 stopped again for pregnancy attempt (donor egg), pregnant first transfer, 0.110 at 10wks, 2.1 at 14wks, 4.2 at 16wks, started interferon, slow dose increase to 25MIU per wk, at full dose PCR< 1 for remainder of pregnancy

Healthy baby girl Jan 2016, breastfed one month

Nilotinib 600mg Feb 2016

MMR May 2016

PCRU Feb 2017


#6 CallMeLucky

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Posted 30 May 2013 - 10:25 PM

"The thing that surprised me about the issue of relapse following discontinuation is that the CML comes back harder and faster then chronic phase, it apparently reacts like blast phase."

I've never heard this before, in fact I have heard the exact opposite.  Do you have any links to any studies that back this up? I would be very interested in seeing them.  My understanding is that in all cases of cessation that resulted in relapse, when rechallenged with TKI drug everyone was able to regain control of disease.  If that is not accurate I think it would make a huge difference to whether or not someone considers cessation.


Date  -  Lab  -  Scale  -  Drug  -  Dosage MG  - PCR
2010/Jul -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 1.2%
2010/Oct -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0.25%
2010/Dec -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0.367%
2011/Mar -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0.0081%
2011/Jun -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0%
2011/Sep -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0.00084%
2011/Dec -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0%
2012/Mar -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0.004%
2012/Jun -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0%
2012/Sep -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0%
2012/Dec -  MSKCC  -  Non-IS  -  Sprycel  - 100 - 0%
2013/Jan -  Quest  -  IS  -  Sprycel  -  50-60-70  - 0%
2013/Mar -  Quest  -  IS  -  Sprycel  -  60-70  - 0%
2013/Apr -  CUMC  -  Non-IS  -  Sprycel  - 50 - 0.036%
2013/May -  CUMC  -  Non-IS  -  Sprycel  - 50 - 0.046%
2013/Jun -  Genoptix  -  IS  -  Sprycel  - 50 - 0.0239%
2013/Jul -  Genoptix  -  IS  -  Sprycel  - 70 - 0.0192%
2013/Jul -  Genoptix  -  IS  -  Sprycel  - 70 - 0.0034%
2013/Oct -  Genoptix  -  IS  -  Sprycel  - 70 - 0.0054%
2014/Jan -  Genoptix  -  IS  -  Sprycel  - 70 - 0.0093%
2014/Mar -  Genoptix  -  IS  -  Sprycel  - 100 - 0.013%
2014/Apr -  Genoptix  -  IS  -  Sprycel  - 100 - 0.0048%
2014/Jul -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2014/Nov -  Genoptix  -  IS  -  Sprycel  - 100 - 0.047%
2014/Dec -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2015/Mar -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2015/Jun -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2015/Sep -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2015/Dec -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2016/Mar -  Genoptix  -  IS  -  Sprycel  - 100 - 0.0228%
2016/Jun -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2016/Sep -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2016/Dec -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2017/Mar -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2017/Jun -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2017/Sep -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2017/Dec - Genoptix  -  IS  -  Sprycel  -  100 - 0%
 

 


#7 GerryL

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Posted 30 May 2013 - 11:25 PM

Hi Josie and Lucky,

There seems to be some confusion with what I've written. I didn't say it turned into Blast Phase, Dr Tim Hughes comments were that the CML returned rapidly as fast as blast phase, but once the TKI was restarted it came under control. This is why he recommends monthly testing. It is the speed of the return which interested me, for when I stop my TKI in November.

I've updated my comment above.



#8 GerryL

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Posted 30 May 2013 - 11:28 PM

Link to the site reposted http://www.cmladvoca...cmlhorizons2013

The video is Latest experience from STOP trials (Tim Hughes, Australia)



#9 jjg

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Posted 31 May 2013 - 02:05 AM

I can add a little bit of data to the conversation (n=1=Me). See figure below - the white dots are PCRU, plotted as a 4.5 log reduction (the test sensitivity). To put in context I stopped treatment to try for a pregnancy (not successful). We stopped gleevec much earlier than ideal as we felt we needed to try asap because of my age. We always knew I would relapse.

So the first thing I would say about choosing to go off treatment is the depth of response really counts. Complete molecular response (-4.5 log) corresponds to 1 million cells with CML. At that point it's always coming back. When you look at my PCR up to 12 months it's clear I wasn't heading very far under -4.5 any time soon. We changed to 800mg gleevec at 10 months to try and get a deeper response and to a limited extent it worked - probably gave me an extra week or so. In hindsight I should have switched to tasigna before coming off treatment but my hematologist was worried I would have trouble with startup side effects and that dose interruption would compromise the need for speed.

From what I've heard on these boards it seems common to get close to PCRU and then fluctuate a bit. That is a great place to be for long term prognosis but I'd be guessing not so good for stopping treatment.

image.png

The two points that most are interested in are:

It came back fast

Even though I hung around at the 1 log response level for longer than was comfortable (but less than would have been required if we'd got pregnant) when the TKI (2nd gen) was reintroduced I responded really well and about a month ago I was PCRU :-)

Also of interest:

The interferon worked - my numbers not only stopped increasing, in the end I got a close to 1 log reduction. Interferon was also extremely unpleasant and I don't know how long my body would have coped.

My response to tasigna was faster than for gleevec. It looks as if it has tailed off at the end but hopefully this is just because it has gone undetectable so I've plotted it as -4.5 log. I'm hoping it's headed even further down... don't we all

I never lost hematological response, even at a PCR of 24% my WBC was around 7. Mind you a few weeks after dx and before starting gleevec when my PCR was close to 100% I had one test with normal WBC and the rest were in the teens - so this just could be a n=1 thing.

The one month before starting interferon when my PCR was between 11% and 24% I was slightly unwell just enough for me to recognise - minor bone pain, a few low grade fevers, tired. Other than this the time between stopping gleevec and starting interferon was a very big improvement on gleevec time. Within a week of stopping gleevec I was BACK, although it did take longer to fully recover from the high dose gleevec.


Dx Dec 2010 @37

2x IVF egg collection

Glivec 600 & 800mg

PCRU March 2012

Unsuccessful pregnancy attempt - relapsed, 3 months interferon (intron A), bad side effects from interferon

Nilotinib 600mg Oct 2012

PCRU April 2013, 2 years MR4.5 mostly PCRU with a few blips

April 2015 stopped again for pregnancy attempt (donor egg), pregnant first transfer, 0.110 at 10wks, 2.1 at 14wks, 4.2 at 16wks, started interferon, slow dose increase to 25MIU per wk, at full dose PCR< 1 for remainder of pregnancy

Healthy baby girl Jan 2016, breastfed one month

Nilotinib 600mg Feb 2016

MMR May 2016

PCRU Feb 2017





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