15 replies to this topic

[bluelobster]

Hey People!

I started the PACE ponatinib trial in March after developing resistance to imatinib (6 yrs) and then dasatinib (2 yrs). I don't have T315I. After a month of muscle pain and rashes on 45mg they stopped it for a month and then restarted at same dose. No side effects to speak of and my PCR dropped from 500 to undetectable in under four months. Woo hoo, I feel awesome.

Because of the unquantifiable risk that I might develop resistance to ponatinib as I did to the previous drugs, my oncologist at Johns Hopkins (a true expert in the field) wants me to immediately move to a haplogenic, related-donor BMT. I'm scheduled to be admitted for a transplant Sept 14th, but I'm having second thoughts. I want to wait until we see some indication that the ponatinib response isn't durable.

I'm looking for some opinions on whether to stay the course on ponatinib or go for the BMT. Also, anybody aware of people on ponatinib developing resistance to it?

Mike

[Trey]

There is not enough information available for you to make a decision with absolute certainty.  But here are some thoughts:

Oncs do not know in detail how and why TKI resistance develops.  In fact, some previously held views on the subject are changing.  So they cannot predict resistance for any TKI drug except for those who are diagnosed in Blast Phase.  You are not currently resistant to Ponatinib, and there is no data that would suggest that if a person is resistant to one TKI drug that they will very likely be resistant to another TKI drug.  Look at how many people fail Gleevec but do very well on Tasigna or Sprycel., and maybe even fail two TKI drugs but the third works just fine.  The stats show the opposite of what your Onc has said.  And Ponatinib does not have enough data available to suggest what your Onc has said.  The theory of TKI selection for a patient is currently a "trial and error" approach to try them sequentially until one works, which normally happens.  There are three now, and Bosutinib will likely be approved soon, then Ponatinib, then whatever comes next.

Many Oncs believe that BMT is just another step in a treatment process.  They are not able to put themselves into the postion of the patient.  Because of this, they will jump to conclusions that might seem logical to them, because they view TKI drugs and BMTs as equally useful treatment programs.  But for the patient, there is a big difference, and we look at BMT as a last resort., which I believe is the appropriate point of view.

There is also the issue of defining resistance.  The other two drugs did not work for you, but does anyone know why?  You do not have T315i.  But was it a failure of your hOct1 pump?  Or maybe you overexpress Lyn?  Or maybe you have the wrong angle of dangle?  Who knows?  The issue is that Ponatinib may work differently and overcome the issue, just as the various TKI drugs work differently and overcome different issues.

When you took High School math, did your teacher tell you that any two points will predict that the third will be in a straight line with the other two?  I hope not.  Neither do these drugs work in a straight line prediction model.

Some Oncs have clinical trials for both drugs and BMTs.  I believe your Onc might be in that category.  I would tend to trust such an Onc less, because they do not have a neutral viewpoint.  And even though they lose more patients in their BMT trials, they can rationalize it away easily in their minds.

Some people need to go through the BMT process.  But the decision must be based on more facts than your Onc has used, in my opinion.  If it were me, I would find a way to stick with the Ponatinib.  But the question is, can your Onc throw you out and deny you the drug?

[WoofWoof]

Hey Mike- Three months ago I went to Hopkins to consult with Dr. Doug Smith. At that time my counts on Tasigna were bouncing around. He wanted me to start the BMT process (just in case). His reasoning is that once you show a resistance to one TKI drug, it might mean you won't respond to the entire class. I decided a wait & see attitude that so far has worked out well. The only change that was made was to reduce my Tasigna dosage from 800mg to 600/day. I just had a BCR/ABL draw today so it will be next week until I find out how I'm doing.

Guess there really isn't a good history for any of the meds so we are all constantly learning. I consider my ups & downs as just that-temporary bumps in the road that I can live with. Maybe you could just start the donor search but continue on the ponatinib.

[bluelobster]

Hey Woof - Doug has been my onc from day one nine years ago. He's been great to me and I have a lot of faith in him, but he's really been pushing me in the direction of a BMT.

I already have a ready and willing donor - my sister. She is available at the drop of a hat, so I'm good to go on that front, which seems like all the more reason to wait and see with the ponatinib. Hope you get good results on today's draw!

Mike

[bluelobster]

Trey,

Thanks for the thoughtful response. I am right in line with your reasoning and it is good to hear it from someone else. I have been concerned about my onc being biased toward the BMT - I just so happen to have a half-match sister available and Hopkins is running a haplo BMT trial. Good if I need it, but not a reason to rush in to it. Fortunately the ponatinib trial I'm in is not at Hopkins, so there is no conflict of interest there. I can stick with the ponatinib indefinately and am leaning heavily in that direction. It is good to hear someone else say they would do the same thing. Thanks so much!

Mike

[Trey]

From what you had said, I knew it was Dr Smith.  And unfortunately I have previously heard of him pushing patients into his various clinical trials.  Sorry to have to say that.  If it were me, I would not trust him to be neutral on this issue.

Haplo BMT is still experimental.  There has been misinformation about it not having GVHD issues when in fact it can be a very serious issue.  And graft rejection is not a trivial issue.  If it was your only choice, then the decision would be made for you.  But giving up a deep response to TKIs for a BMT is STUPID*.  Sorry for yelling.  I'm OK now.....  Think placid thoughts.... On the beach.....  There's no place like home....There's no place like home....Toto is here....Kansas.....Definitely Kansas....

* Submitted for possible inclusion in the DTIEHAOS** Hall of Fame

** DTIEHAOS: Dumbest Things I Ever Heard An Onc Say

[WoofWoof]

Trey- I also had a feeling it was Dr. Smith, that's why I mentioned his name.

Don't go getting too peaceful on us Trey, that's when the sharts strike!

[HPL]

Trey - I am kind of shocked that you show such restraint in sharing your feelings, tell us how you really! feel

Mike - I am also in the Ponatinib trial, for almost 2 years now. (Phase 1). I am like you, only a transplant is my option if I shoud fail Ponatinib. I have had 4 'weak positives' in a row at OHSU, so I seem to have hit a solid stable level. But as all of us, we're only as good as our last test. I have often asked my doctors about what they know about other patients, since when you're in phase 1, there isn't a lot of other data to compare against, but from what I hear, getting a good response on Ponatinib is as good if not better than same response from earlier TKI's. I have no large scientific sample to base it on, but that seems to be the opinion of those experts I have asked. My advice would be to get a second opinion as well around the Ponatinib trial, can't hurt to ask. I know there were some that lost their response early on, but they were on something like 2 and 4 mg dosages, way below therapeutic values.

As for the BMT, I had (operative word had) my best friend go through a haplo BMT, his father was his donor. Unfortunately that didn't work, and by the time he did get into Ariad trial, I believe it was too late for him, and he passed away in January. So I unfortunately have way too much emotions around the haplo procedure. He always told me that he felt that his doctor pushed him in that direction too... But like you, I have my sister lined up and if my next tests show that I am losing response, then we pull the trigger then. But at this time, my doctor sees no reason to persue the, BMT path. But I do have the T315I, but I know of many others who do not in the trial who have had gret success and maintained it.

There is no great answer, but definately reach out, talk to those who are truely experts, while at the same time understand their motivation.

Wishing you continued success on Ponatinib !

Hans

Zavie's Number #1303

[CallMeLucky]

I have a very good doctor, who is a CML specialist and I trust very much.  However, I have already decided that if she ever tells me I need a transplant I will get a second opinion from another CML specialist at another facility.  It is nothing personal, but I think before I make an irreversible decision, I want another pair of fresh eyes looking at it and weighing in.

You do not mention if you have ever been in Accelerated Phase or Blast crisis, assuming you have always stayed in Chronic Phase, I would also be reluctant to rush into the transplant.  I'm not qualified to tell you what to do, just sharing my feelings if it were me.  You also haven't mentioned your age, which is another big factor in transplant.

Best of luck on your decision, sorry you have to stress over this - but as I mentioned above, I would get another opinion before I made my final decision.

[bluelobster]

Wow, this is all really helpful! Trey, Woof, Hans, and Lucky - thank you all!

I did get a second opinion from the director of the transplant unit at UMD where I am in the ponatinib trial. He agreed that I needed a transplant and did a search of the donor database to see if there were any potential full-match donors (I was suspicious of Hopkins decision to not do high-resolution typing on several 6/6 matches). He came back and said there weren't any full matches. He recommeded that I proceed with the haplo BMT at Hopkins.

Trey & Woof - I am glad to hear others have had the same experience with my oncologist. He really made me feel like I was risking my life if I didn't get the BMT now. I was feeling like it would be irresponsible of me as a father and husband to not get the BMT.

Lucky - I briefly progressed to blast crisis at the beginning of this year before starting the ponatinib.

Hans - when you say your best friend's transplant "didn't work," what happened? Did the graft not take, the leukemia come back, ....?  I'm so glad to hear that you have had success with ponatinib.

You might be interested in the following: I emailed Dr. Jorge Cortes at MD Anderson, one of the principal investigators on the Phase I trial, to ask if there have there been any patients taking ponatinib who achieved a complete response and subsequently developed resistance to it. He replied this morning:

We have seen occasional patients lose their response to ponatinib. The risks appear to be higher for patients treated in the more advanced stages of the disease.

One question for all of you: how frequently are you / would you recommend having PCR tested to catch any resistance before the disease develops to the point of jeopardizing a BMT? Quarterly seems too infrequent to me. Monthly?

Mike

[CallMeLucky]

Mike,

Everything I have read suggests that if you entered a more advanced stage, particularly Blast Crisis, that you will require a transplant.  The fact ponatinib has brougt you back to CP is very good and gives you the best chances during the transplant.  Given this additional information, if it were me, I would be preparing myself for the transplant.  Of course I am not a doctor or an expert, but as a patient, if I were in your situation, I would be planning for that next step.  It sounds like you already got your second opinion and you have concensus.  The question I would still be asking is to move forward with the type of transplant they want to do, or wait and try to find a better match.  Unfortunately there is no right or wrong answer that can be known ahead of time.  Whatever you decide, give it a fair amount of thought, make up your mind, and then once you do, move forward and don't look back.  You will gain nothing by second guessing yourself down the road, commit to your decision and then give it your best.

Best of luck Mike with whatever decision you come to, I'm wishing the best for you......

[HPL]

MIke,

My friend had his father as his donor, he didn't have any matches on the registry. They said his father was a slightly better match then his mother. At his one year mark after the transplant, they found that his CML was back with a 2/20 on the cytogenetics. They tried a DLI, but that didn't work. He did experience some graft vs. host, I don't know enough to put a severity on it, but it did impact his quality of life. Although for the record, he had an eye infection and couldn't see that well, but he still beat me in golf....He went back into blast crises eventually, and while initially ponatinib did get him back to Chronic, that didn't last. His Cytogenetics were quite complex (Trey helped me analyse them one), with multiple abnormalities in the CML cells. I wonder how much that had a play in it. I have been meaning to see if his wife could go back and see if they were always there, or if that was as a result of the transplant. Unfortunately after failing Ponatinib, he went into blast crises quickly and no oppertunity to even try a 2nd transplant. He passed away in January of this year.

I hope that you know that all of us have an individual journey, and what works and doesn't work is one person's story. There are plenty of success stories out there, unfortunately we always tend to hear and at least remember the negative ones.

Best wishes !

Hans

[Rissa]

I'm glad I saw this thread.  I saw my onc the week before last and he recommended I call Dr. Smith from Johns Hopkins and talk to him about joining his clinical trial.  I thought it was strange.  Why would I want to be in a clinical trial if I'm doing so well on gleevec?  It just doesn't make any sense.  I haven't called yet.

[CallMeLucky]

Rissa - they may want to include you in the trial as part of a control group to compare other patients against.  It may be worth checking out.  Low participation in clinical trials stalls progress for new treatment.  Obviously if you are doing well they shouldn't want to switch your treatment.  But if they just want to keep track of you so they can compare how you are doing against people who taking a trial drug or something like that, it can be a real benefit to everyone.

[Rissa]

I guess it wouldn't hurt to call and at least get information on it.

[Trey]

Mike,

What were the signs of your "brief" Blast Phase?  It can be very different from being diagnosed in Blast Phase, so a transplant is not as clear in that case.  Oncs are not very good at diagnosing the advanced phases, and there is disagreement about them.  So they often throw more people into the latter stages than belong there.

BMT docs are also quick to recommend a BMT.  That is what they do for a living.  Of course they believe people should have them.  None of them have gone through it.

I just know that if it were me with a deep response, I would ride the TKI train to the end until it threw me off, not get off at an unknown whistle stop along the way because someone didn't know whether I might keep a lifelong response to that TKI.  I believe there will be more drugs, and more ways to treat the CML as time goes by.  Ponatinib will not be the last train out of town.

I suppose you have read my Transplant posting:

http://community.lls.../message/101600