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2nd gen TKIs

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#1 jjg


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Posted 25 February 2013 - 10:56 PM

I'm curious about what people think about switching to the 2nd generation TKIs from gleevec.

I should start by saying that I've switched from gleevec to tasigna, mainly for side effects and that switch has been very successful both in terms of side effects and response. I often hear/read talk of resistance and I haven't totally got my head around the difference between resistance say to antibiotics and TKIs. I've also heard people say that with cancer your first strike should be your best effort, which kinda makes sense in my way of thinking - the fewer dodgy cells there are, the smaller the chance of one of them developing a crazy bad mutation. It it that simple?

I was reading this paper: Jorge Cortes and Hagop Kantarjian, How I treat newly diagnosed chronic phase CML, Blood, 2012

http://bloodjournal....9.full.pdf html

Do others have access to this? (I'm inside a university)

I'll try posting a figure from that paper that caught my attention (not sure if it's ok to reproduce the figure, but I hope so...), obviously it is speculative but these authors are well placed to speculate.


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

#2 Trey


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Posted 26 February 2013 - 10:54 AM

Overall, I would expect better from MDA when presenting such important information.  If this chart were the only information about choosing a frontline TKI drug for CML, then one would wrongly conclude that Gleevec is a poor choice, and maybe even a bad choice.  That is because the chart presumably shows that Gleevec "fails" about 4 times as often as 2nd Gen drugs, even considering a 2nd Gen TKI is subsequently used.  This might mislead some to believe that Gleevec somehow lays the foundation for failure that would be avoided if a 2nd Gen TKI were used from the beginning.  But I am sad to say that the data used to develop the chart is disingenuous, and there is no reason I have seen to believe that Gleevec could somehow induce "failure" as long as the patient is properly monitored and drug changes are made when necessary.

There are two faulty methodologies used in the MDA paper which skew this chart: 1) the definitions of "success" and "failure" were re-defined specifically for this chart (which I would say is very poor form), 2) there is no allowance for "Sub-optimal" response, which historically has been shown to work well for the patient  over the long term.  Additionally, there is not enough long term data on the newer TKI drugs, so a single in-house study was used as a data source for the 2nd Gen drugs (the study was done in-house by MDA, who also wrote the paper). 

See page 27 of the paper which discusses how the data was derived.  The definitions of "success" and "failure" as redefined here are not what  have been used historically and universally.  "Success" has been redefined here for this chart as only including what we have previously called "Optimal Success" (i.e., "fast" response).  So "Failure" includes not only true drug failure but also includes suboptimal response (those who are slower responders, yet still steady responders).  To further mislead, the data is skewed by redefining "Success" as CCyR in 6 months rather than the traditional 12 months (NCCN Guidelines, EUTOS, etc).  So if CCyR is not achieved in 6 months is was called "Failure".  That is not a definition used by anyone, except apparently MDA for some odd reason.

Although I have no firm opinion about whether a patient should start with Gleevec or a 2nd Gen TKI, I personally think it does not matter much, unless the patient has a baseline kinase mutation test showing a kinase mutation at diagnosis (not usually done).  If so, only 2nd Gen TKI drugs should be used for those patients.  But I do not believe this paper adds to the frontline TKI drug choice discussion in any meaningful way.  Gleevec has been shown to enable 5+ year survival rates of about 95%, and over the longer term Gleevec response rates are not significantly different than 2nd Gen TKI drugs assuming drug switching is used when required.  It is also apparently true that 2nd Gen drugs have a faster initial response rate in more patients, and if that is deemed important, it is a discriminator.  However, drugs like Sprycel which inhibit additional kinases (SRC) may have downside effects for a number of patients in certain categories.  Since each TKI drug is slightly different in function, there is no other apparent reason to avoid using Gleevec as the starting drug and switching as necessary; but there is also no apparent reason to start with Gleevec as opposed to 2nd Gen TKI drug.  The issue deserves continued debate, but I would hope such debate might be a little more useful from our medical institutions.

#3 Barb@Anderson


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Posted 26 February 2013 - 12:38 PM

Trey, I agree with you.  After reading the article the graph is a poor example to substantiate what the article is trying to convey.  That is if I am reading the article correctly. 

#4 TeddyB


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Posted 26 February 2013 - 02:22 PM

Well, there is a patent going out soon.............

Thanks for that post trey, i remember reading that article aswell, and i didnt like that figure at all, being on Gleevec myself.

#5 CallMeLucky


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Posted 26 February 2013 - 04:55 PM

Also, and maybe I am not clear on what is going on here, but if you compare people who failed Gleevec and then took 2nd Gen drug to people who only took 2nd gen drug you are skewing your numbers with regard to higher risk people (i.e. the ones who failed Gleevec).  It seems to me to make the comparison you need to include people who started on Gleevec and didn't have a problem.  There appears to be a huge assumption here that the people who started with Gleevec and failed would not have failed if they started on something else.  I'm not clear how they can predict that.  To me the only thing this says is if you fail Gleevec, you have a higher chance of failing a second generation TKI.  I don't think that is an unexpected finding.  Obviously if you fail Gleevec your CML is more aggressive and therefore it is reasonable to assume that aggressiveness is more likely to persist even with other treatments.

But what do I know?

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%


#6 Susan61


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Posted 26 February 2013 - 06:03 PM

All I can say is that Everyone is different in how their body handles any TKI.  The Gleevec has worked for me for 12 years.  I did not switch due to some annoying side effects.  I still live with them to this day, but those who really suffered and had no choice but to switch is another story.  I have been able to tolerate all my problems, and actually I think I just made them part of my everyday life as the years went by. Plus I did achieve my PCRU status which kept me going on.

But Thats Just Me!!  I have no idea how things will go as time goes by.  I am just Thankful to still be around 14 years since diagnosis, and I Thank God Everyday for where I am now and not where I used to be.


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