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Possible risks of reduced Gleevec dosage?

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#1 BPilgrim


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Posted 21 February 2014 - 08:49 AM

Hello everyone. I am undetectable on 400mg of Gleevec and recently discussed dropping down to 300mg or 200mg with my doctor because of side-effects.  She told me that isn't a good idea because dropping to a lower dosage increases the chance of a relapse.  Her reason had to do with the lower/weaker dosage creating an opportunity for more BCR-ABL fusions to form, and that it only takes one fusion to mutate or be resistant to create major problem. She said the odds are low that could happen since I'm undetectable, but that it is still possible since even undetectable CML patients still have the disease in their body, so why give the disease a chance to strengthen.  Also, I think part of her reason also comes from my having had Gleevec Blood Concentration tests done in the past at both 400mg and 300mg (I tried the lower dosage in the past)...and at 400mg my Gleevec concentration was optimal, but at 300mg it fell by almost 60%, which is not what she expected to happen with only a 25% dosage reduction.

Can somebody with better knowledge than me please comment on this?

I hope everyone is doing well.  I may not comment often, but I read the forum frequently.

Take care.

#2 Trey


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Posted 21 February 2014 - 10:04 AM

I have been on 200mg Gleevec for nearly 5 years after being PCRU for the prior 3 years.  I decided on the dosage reduction, and chose the timing and dosages based on studies showing that some patients who are very responsive to Gleevec have achieved PCRU on as little as 200mg per day.  The theory is that a "speedy responder" should need less drug than a slow responder. 

Your plasma concentration levels may be lower than others.  But then your cellular uptake may be higher.  So plasma concentration alone is not the sole issue involved.  The key is that everyone is different, so you will not know if you can maintain PCRU on low dosage unless you try.  But I would recommend continuous PCRU for at least 2 - 3 years before doing it.  The reason is to get the leukemic count far below PCRU to where they are highly controlled by low dosage.  Even at PCRU there are over a million leukemic cells still in the body. 

Below is a re-posting of previous information I have provided in the past:

I do not personally believe in the "low dosage resistance" theory, which makes no sense to me.  The leukemic cell mutations generally occur when the leukemia is not well controlled, certainly well above CCyR.  A few years ago the leading Oncs were  expressing concern about dosages below 400mg causing drug resistance.   These same Oncs have softened their statements over time.  The NCCN Guidelines recommend dosages below 400mg for low counts and other severe side effects.  Dr Druker has said he is OK with lower dosages for those with low level disease as long as they maintain a  minimum Gleevec plasma drug level of 500 ng/mL.  Quoting Dr Druker:

"Certainly, I would consider lowering the dose for patients who have had a least a 3-log reduction, have a very low risk of relapse, and maintain this for a couple of years.  I would also consider lowering the dose for people with a complete cytogenetic response who have maintained that for at  least 4 years, when I know their risk of relapse is extremely low, and  for anyone for whom imatinib is affecting the quality of their life.  How would I do this?  First of all, I'd look to see what doses did it take to get them to their response. If they needed 800 mg to get to a complete cytogenetic response, I'm not going to be eager to lower their dose. If we started them on 800mg, and they got a very rapid response,  I  might actually think about lowering them. I would absolutely recommend  monitoring plasma levels and not reducing below a drug level of 500 ng/mL"


So Dr Druker obviously believes that 500ng/ml is "safe".  And some can achieve that on lower levels than others -- some maybe on 300mg, and some on 200mg per day.  This is where "your mileage may vary".  Since 400mg will generally provide most patients with 1000 ng/ml or higher, you can do the math.   But recall, the Gleevec absorption rate differs in each person, so Dr  Druker recommends Gleevec plasma level monitoring for lower dosages.  Dr Shah (in a speech in Canada) said that he was rethinking the issue of whether lower dosages could cause resistance, since it now appears that the basis of resistance is probably there from the beginning stages of the CML and not caused by a lower dosage (paraphrasing).  This is shown by the fact that most drug resistance occurs within the first year or two after diagnosis as the low  level resisting cells grow slowly over time to detectable levels while the non-resistant cells are killed off.  That is why the leading Oncs say that if we make it through 2 - 3 years without  drug resistance, then it will not likely occur after that (but there can be rare exceptions).  [NOTE: I am NOT implying that Dr Druker or Dr Shah would agree with my actual dosage reduction.]

There  is another way to look at this issue logically.  The issue of drug resistance is best shown by antibiotic drugs.  Most of us have taken antibiotics, and we were always sternly warned to take all of the pills in the bottle, even if we feel better.  The reason is that the antibiotics kill bacteria, and and if we only partially kill a bacteria (only take partial antibiotic dosage), then that bacteria may just be "stunned" but then survive and grow stronger and learn how to overcome that drug.  That is why antibiotics must constantly be changed and new ones invented, as bacteria becomes resistant to the older antibiotics.  But Gleevec does not work in tha same  way to kill leukemia cells.  Gleevec will simply latch onto a docking  port that the leukemic cell needs to use to proliferate and survive.  By occupying that docking port, the leukemic cell is shut down.  There is no partial shut down.  It is either turned off or it is not.  So logically it does not appear that typical drug resistance is likely to occur for these TKI drugs.  Additionally, because we cannot take enough drug at first to shut down all leukemic cells, one would assume this  would cause resistance in the cells that only saw "partial" dosages, if  the TKI resistance theory were true.  So the issue of resistance does not really fit the TKI drugs (any of them).  But most docs revert to what they have seen drugs do in the past, so they are cautious about this issue until  proven otherwise.  So it seems that the issue of TKI resistance (which has always been unproven) should not be an over-riding concern in the face of bearing long term side effects.  This should allow Oncs the flexibility to use lower dosages of Gleevec, Sprycel, or Tasigna in patients  where it makes sense.

Another issue is relates to leukemic burden.  At diagnosis most of our WBCs are leukemic and there are about 20 - 30 times more than average.  At PCRU very, very few are leukemic and the total number of WBC cells is normal or often less than normal.  So why would it take the same drug dosage to deal with these various levels?

If a person is PCRU for over two years and can decrease to 300mg or even 200mg Gleevec for the long term (or simliar reductions in Sprycel or Tasigna) why make the patient continue to take full dosage forever and suffer with side effects?

#3 BPilgrim


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Posted 21 February 2014 - 12:50 PM

Thanks, Trey.  You're awesome. 

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