33 replies to this topic

[MJB]

Even three years in to this diagnosis I find that I still have questions! So, here goes..

In Feb. my PCR was .02, pretty sure that Memorial Sloan does not use the international scale. In Feb., I hit my limit andI was fed up with taking 600 mg of tasigna and it's irritating side effects. So, I decided to play with my dose and take only 300 mg once a day. I know..I know! Anyways my May PCR was great! .0048! Since it went down I assumed that the low dose would be fine, told my onc. Needless to say she is not happy and sent a message to me to go back to 600 cause it would be dangerous to take so low a dose. Gleevec quit working for me at the 1 year mark and I have the 35ins splice variant but why would it be dangerous when I am MMR, three years post diagnosis and had a reduction in PCR on the lower dose?

Thanks for your help!

iForget

[Trey]

At first, some suggested that low dose TKI drugs might cause kinase mutations.  That belief has pretty much been abandoned by most leading Oncs.  Now most believe that kinase mutations occur because the mutations or predisposition was there early on, but only appeared after the TKI drug killed off the non-mutated leukemic cells.  This is why the incidence of kinase mutations is highest during the first couple years, then declines rapidly to a very low level after that.  So there is no evidence that variation of drug levels can cause drug resistance.  Our drugs are not like antibiotics and bacteria, whereby low dosage can cause mutations if the bacteria are only halfway killed and then get rejuvenated.  Our CML drugs either shut down a BCR-ABL or they do not.  There is no "halfway killing" process with our CML drugs.  So the issue of low dose resistance is an outdated concept.

[GerryL]

Hi Trey,

I had a similar discussion with my Hematologist yesterday - I've managed to get him to let me try 300mg Gleevec, but when I mentioned moving to 200mg in a year or two (providing I keep my PCRU) he was pretty adamant that he didn't like it and mentioned mutations to me. When I said didn't mutation come out within the first two years he agreed that this was so, but still insisted that they can appear later on, if you're not on enough dosage. I'm hoping that by the time I look to moving to a lower dosage there is more data on the subject.

[pamsouth]

Trey,  I also posted just posted this on TKI cessestion.

I confused on this mutation, as my  new onc nurse just mentioned that the doctor said lower my dose could cause mutations.  So I don't know if I this will make an sense.  I am trying to wrap my brain around this.  So here goes;

I have a chart i am look at that has the Long term cell at the top , then another stem cells that has two daughters then the myeloid side and lymphoid side.

What level do mutations start at, the top of the Long Term Stem Cell Genealogy, does this stem cell creates a different transcript, I mean before it even turns into the Myeloid level, or in the middle where the myeloid starts, or at the bottom where you have the white cell granulytes,  or anywhere.  Is it after the Long term stem cells when it becomes nucleus, or are they always nucleus even at the top of the chain?  Are we talking mutations of the BCR/ABL or mutations of other chromosomes, there are 23 pairs?  Again could this be mutations that are started by the very Long Term Stem Cell that has changed the transcript, before it even becomes BCR/ABL. Perhaps we are talking mutations of the BCR/ABL where they create a different protein?

I mean even if you stay on 400 mg and your PCRU runs just below the radar and say you still have a million BCR/ABl residual can't they mutate.  What is the big deal with lowering your dose and being more concerned with mutations, in another words can't you have mutations regardless of your dose and regardless of your response to TKI.

Confused!

PamSouth

[Lori's okay]

My onc put me on 300mg Tasigna (150 mg twice a day) for several weeks when my blood counts were getting too low.  We increased to 450 a day as soon as the counts went back up a little.  I'm responding very well.  The officially recognized reduced dose for Tasigna in the medication insert is 400mg given as 200 twice a day.  My side effects on 300 were so good I called it the 'heavenly half dose'.  Sides are totally tolerable on 450 for me. 

(I am very early in this:  on meds only 5 months.)

Seems you could try going back to 600.  Sometimes after a break the higher dose is not as bad as it was before the break. 

Or another onc might be willing to work with you more on this. 

There is also a link on this site to a study presented at the last ASH meeting that described very good results from reduced dosages on Tasigna and Sprycel.  Would your onc listen if you bring in studies?

http://ash.confex.co...Paper44523.html

Good luck.  Sorry to ramble.

Lori

[Judy2]

Hi Trey or Anyone Else Who Can Answer This,

Trey, you said that most think that the mutations or predisposition was there early on but only appeared after the TKI killed off the non-mutated leukemic cells. So, if the mutation is there all along, even if it hasn't come to the forefront and you have mutation testing done and it is negative does that mean that you are in the clear for having a mutation? Would the testing pick it up even if it hadn't appeared? In that scenario would you have to have mutation testing done only once? Or if there is a predisposition to a mutation and you are on a low dose of a TKI would this possibly allow the predisposition to come out and therefore would staying on a full dose keep the predispositioin "in check"? Would a low dose make you susceptible to having your predisposition become a reality?

Judy

[mariebow]

I have been taking Tasigna for about 3 months early on about a week into my Tasigna 300mg twice a day I was having pain in bone and muscles, my onc took me off a week then put me back on a half a dose.  My wbc is normal and tests looked good.  I have wondered about continuing on the low dosage and askd my onc was he going to keep me on the  half dose and for now he is happy with my results.  He said that there was studies that show that others were doing good on the half dosages,  I am not educated on all the info like you all are, but I am gradually learning.  My nurse did call me and said that I was not at the 0% mark or whatever yet, but it had gone down about half.  But still concerne because I hear comments about lot of doctors would not lower dosages.  any comments appreciated

[djm]

I'm curious about this too.  I was diagnosed at the beginning of the month (May 5).  How do these mutations affect the effectiveness of Gleevec?  I'm currently taking 600mg and am not having much trouble with the side effects.  At the time of dx, I was at 300k WBC, and as of two days ago I'm down to 13k.  I hope that that is a good indication that I am responding well to Gleevec.  My doc mentioned that depending on next weeks blood work, she may reduce my dosage to 400mg.  At first I thought that is excellent, but after reading about this mutation stuff in this thread, I'm having second thoughts.

BTW, this forum has been nothing but a huge help.  I've been reading it everyday since my dx.

[Happycat]

MJB,

Solid tumors are genetically unstable and find other signaling pathways to grow and spread to other organs.  This occurs via genetic mutations.  The average solid tumor has about a dozen different mutations.  It seems liquid tumors (boy, that sounds weird to me) are more stable than solid tumors, and don't undergo as many mutations. Perhaps this makes sense since liquid tumors are already in a mobile medium (blood) - hence, they can pretty much go where they please.

There are two reasons I can think of about why doctors don't sanction lower doses.

1). Minimum effective dose - clinical trials seek to determine the minimal effective dose (I think that's phase I or phase ii typically).  Thus, to most doctors, the lower doses have already been tried in the clinical trials, and found to not be effective.

2). ADMET properties - The effective dose is determined by many factors, but things like absorption, distribution, metabolism, excretion and toxicity come into play.  Your doctor is likely concerned that a dose that is too low means you will not absorb enough, or it will metabolize too quickly and you will "run out" of active drug metabolites to keep the CML under control in between doses.

Doctors don't want to take a lot of risks on doses, because of malpractice suits, etc.  Thus, they prefer to see clinical studies before giving it their blessing.

Keep in mind that the effective doses are determined in clinical trials with pretty sick patients. In order to determine if lower doses are effective for patients in MMR or CCyR, they would have to do another clinical trial. To pharma, this means spending money to show that patients can take LESS of a drug, which in the long run means less money in the corporate coffers. Not a whole lot of incentive there. The only time I see pharma doing low dose studies is when the drug is too toxic at higher doses, or has intolerable side effects, or is so ungodly expensive that insurance companies won't pay for it. All of these scenarios would mean keeping customers, and thus keeping more, albeit somewhat less, money.

My two (cynical) cents,

Traci

[Trey]

Dear Confused, Curious, and Cynical Readers,

Most Oncs do not know much about CML.  That's OK for most people, since the drugs do the real work.  But if you ask the Onc about low dosage TKI they will reply like a robot that it could cause mutations.  But what proof of this exists, Gentle Reader????  None.  So how does any urban myth begin?  Who knows, but repetition does not turn sharts into ice cream.  Believe me, I have tried.  I have even taken a pilgrimage to Brenham.  No luck.

http://en.wikipedia....Bell_Creameries

Cell hierarchy charts will not reveal any clues into this issue.  And since Kinase Mutation Tests cannot detect mutated leukemic cells below roughly CCyR levels, the test is often inaccurate unless the mutated cells are the primary leukemic cell type, which often only happens at a sudden 1 log increase plus loss of CCyR.  Miss Cynic has provided a good explanation of the other factors involved, so I shall not repeat the psychology into why Oncs do what they do.

I present the following factoids for your consideration:

1) The NCCN CML Treatment Guidelines authorize low dosage TKI drug dosages. 

2) Leading CML Oncs regularly authorize reduced TKI drug dosages (Dr Cortes at MDA has patients such as our Michael on 15% dosage -- is he trying to induce mutations to perform some evil experiment?  If so, can we watch?)

3) Dr Druker has changed from worrying about low dosage TKI drugs a few years ago to authorizing low dose Gleevec for long term "maintenance therapy" after several years PCRU, as reported by one of our members here.

4) Most kinase mutations occur while patients are taking full dosage TKI drugs (from what I have observed on this L&L website).

5) There are over 100 known kinase mutations, and most do not prevent the TKI drug from working, although they can sometimes reduce effectiveness, and only a very few can prevent the TKI drug from working.

6) Our TKI blood level concentrations change all day long.  Peak concentration occurs a couple hours after taking the drug, then it declines continually until the next dose.  So aren't we all on "half dose" or less most of the day and night?  Why isn't that a problem if the theory of low dosage mutation applies? 

If your Onc remains unconvinced, ask him to explain why TKI drugs and antibiotics act the same way to cause "mutations" (hint -- they don't, and "mutations" are not all the same).

[pamsouth]

Traci, 

I think your >""My two (cynical) cents""<< is probably 99.9 % on the money!!

PamSouth

[pamsouth]

Thanks Trey,

Great explanation, simplified, for even my small brain.  Puts my mind at ease.

Sometimes we don't even have to be a scientist to understand it.

Our favorite is Blue Bell.

PamSouth

[pammartin]

Factoids noted and appreciated, between Ms.Cynic and Mr. Knowledgeable I believe I finally have begun to comprehend the mutation concept.  Now if I could just figure out why my WBC & RBC are within range, but absolute neuts are .76 and my BUN & creatinin are low but LDH is fairly high, I might just feel like cooking a meal or two this weekend.  Thanks everyone, I have been wondering about these mutations for 6 months, the water has cleared considerably after reading your responses. My journey continues to find a oncologist that will show up for appointments and is willing to consider reducing my Sprycel to 70 mg so I feel better and hopefully maintain response.

[MJB]

Thank you everyone for your replies and information. I really think you are right Traci about the costs driving the dosage! great points Trey about levels in between doses. So, if you were me, would you go back to 600 as the doctor orders or stay at 300 based on The last PCR results?

IForget

[Headi]

Hello Trey,  Thanks for your list of factoids.  I have a question on factoid #6 which you may or may not have an opinion on.  My NEW onc. has prescribed Tasigna for me after I got bilateral pleural efflusions from Sprycel. I was happy with Sprycel up til then and it also got me into PCRU with minimal side effects. Back to Tasigna, though. I asked him if I could do half the dose as I am a small person, 115 lbs., shouldn't it be titated as to size? Why should I take as much as someone twice my size? He surprised me by having no problem with my doing that. I then asked him about mutations if I did that.  He basically said mutations have nothing to do with the amount of TKI a  person is taking confirming your former post. Now my opinion question, finally! Do you, or anyone else on this medication have an opinion as to whether I would be better protected by taking the 150 mg dose in half, 75mg in the morning and the other 75mg 12 hrs later.  I know the main advantage of taking half the dose is not to have to do it 2 times a day with the food restrictiions, but am a little worried about how many hours are not covered with a TKI. I think my dr. said that Taigna has a 17 hr half life. I'm not sure what that means and if it has any signfigance with regard to how often a dose is taken. My onc is pretty much going to let me do what I want as long as I keep an accurate daily log for him. I feel like if I start with a lower dose than is called for I may be able to deal better with any side effects, since now I'm down to the 3rd and last TKI I know of for treating CML.

[Headi]

Hi Pam,

I am so happy with my new onc. He is everything you're looking for. I'm so sorry you're not closer, I would share him in a minute. My son works part time at a local hospital and in discussing my situation with the hospital techs he got a recommendation for 2 oncs that they all had had positive dealings with. This was a really good group of people to get dr info from as they deal with most of the local drs and usually know who the good ones are and since, as the saying goes, "they don't have a dog in the race" they don't mind being candid. I then asked my GP and he chose the one he liked and was most familiar with. So if you have some way of getting information from a medically knowlledgable independant source you might find the right person. Try the radiology, ultrasound departments if you can find a way.  By the way if you do get to do the low Sprycel dose, let me know how you make out with the PE's. I'm going to be starting on Tasigna, but not sure about it yet. Sprycel worked so well for me I would go back to it if I could avoid the PE at a lower dose. My onc said I could stay on it at a lower dose if I wanted, but doubted that it would prevent the PE and felt I would have to take steroids & diuretic along with it. So I chose Tasigna.

My best wishes for finding a caring communicative dr.

Headi

[NotJack?]

Half dose is 1 pill(150mg) in the morning, and 1 pill in the afternoon.  You need to take Tasigna twice a day based on the 1/2 life of the drug.  (Not before 8 hours after taking a dose, and not after 14 hours, if memory serves.  This came from Dr Druker.

[Trey]

Headi,

Most Oncs do not believe size of the person should drive drug dosage.  They are probably correct in most cases, but some Japanese size studies suggest a possible relationship.  But there are small people who need max dosage, which demonstrates that factors other than size are likely more important.

If you have remained PCRU, I think you could either take the 150mg once per day or split the low dosage.  I would probably split dosage for side effects reduction purposes, and [CAUTION: ONLY WHAT I WOULD DO] would ignore food restrictions due to the low dosage.  Most Oncs would not ignore the Tasigna instructions in this regard, but I would, if it were me. 

[Headi]

Trey,

Thank you for yur response to my question. It is very helpful. My onc didn't say that he agreed with my rational of size related dosage, just that he agreed that I should be able to take a smaller dose than recommended. I like the idea of dividing the 150 into twice a day. I don't fully understand the food restriction, but since I did have a small q-t prolongation recently I will probably adhere to those critera. (except for my morning coffe w/cream & sugar, thats not food is it?) My cardiologist said there is nothing wrong with my heart, he said problem was related to low potassium. I did a weeks worth of supplements and the q-t was gone on my next EKG, so the onc gave OK for tasigna as long as we watch the labs. I completely understand your "CAUTION". All of us have to weigh the odds with what ever information we can gleen from others on this site and then make up our own minds on how to proceed. BUT, I have read your posts for over 2 years now and can easily tell that you have educted yourself well beyond most oncs and probably have an better handle on this disease than most of them, so your opinion carries a lot of weight probably for most of us here. Thank you again. 

Headi

[Headi]

Hi Jack,

I hope your memory serves right, it would give me a 2 hour leeway on the night time dose.  I would like that. I still don't understand what half life means. Is that how long it is active or alive in the body? I believe my onc said tasigna had a 17 hour half life.  Does that mean it lasts 17 hrs. in your body or only half of 17 hrs.?

Headi