16 replies to this topic

[gerry]

http://www.medscape....56201?src=stfb 

Jerald P. Radich, MD video - you need to log in to watch

 

One of the biggest concerns for community physicians these days, and one that patients are going to bring up to you, is the idea of discontinuation. After you have had a good response on imatinib or one of the second-generation drugs, can you actually get off these drugs successfully?

Historically, we thought that people would be on tyrosine kinase inhibitors for life, because in the lab, you can actually take putative CML [chronic myeloid leukemia] stem cells, add tyrosine kinase [inhibitors], and the cells do not die. Essentially, we thought that if that's true, there will always be a reservoir of stem cells, and once you discontinue therapy, patients will just relapse.

Like many things in medicine, we have been proven wrong. There have been a remarkable number of studies now, and it's unique, because there are very few places in medicine where different studies in different centers have yielded almost exactly the same response. What is comforting now, at this ASH [American Society of Hematology meeting], is that almost a dozen studies—either as follow-up of older studies or new studies—have shown the same results.

In summary, those results are that among patients who have been on tyrosine kinase [inhibitor]s for at least 3 years and have had essentially undetectable or very low levels of disease burden by BCR-ABL measurement for at least 2 years, about 40%-60% of those patients can discontinue drug and their disease will not come back. And now that has been followed in some of the larger studies, such as the study out of France, for up to 5 years.^[1] If relapses come, most—about 80%—come within the first 3 months; there is only a little nibbling of relapses that occur after a year and a half. Generally, if patients are going to relapse, they are going to relapse early.

A few things are unresolved. One interesting thing is that although the second-generation drugs will get you to a low level [of disease] more than the first-generation drugs, once you are there, it does not seem to make much difference on who relapses or not. This is another indication where if you have a younger person for whom you think that getting them off drug is a goal, these are patients who probably should go on a second-generation drug early on. Older patients who might be suffering some of the cardiovascular side effects of the second-generation drugs and who you really do not want to get off drug for 30 or 40 years because they're starting their diagnosis at age 65 will probably do fine just on imatinib. That is one point.

The other point is that although it appears there are ways to tweak agents, such as adding interferon and the like, to get people into deeper response early on, [in] some studies that have looked at patients who have a suboptimal response and then added another agent to get them into a deeper response, it looks like we don't push that many more patients into that deeper response. And there is always a cost to that, with the added therapy.

Moreover, we do not know whether those patients whom we actually have to push to get a deeper response, if we are able to [then] discontinue them, that this will actually let them have a long period of time without disease like the people who naively go into deep responses. If you have a patient in that line who wants to add other drugs to get into a deeper response, you should really do that on a clinical trial.

It's reassuring that there has only been one case so far among people who have discontinued drug that has gone on to accelerated phase or blast crisis. That is the worry we all had.

After relapse, almost everyone responds after rechallenge very quickly, although often not to the exact same levels of deep response. One has to remember that if unopposed BCR-ABL activity is associated with progression, there may be clones hidden for years that may eventually go to relapse.

 

This is not completely without risk, and if you have patients who want to discontinue therapy because of a variety of reasons—side effects, pregnancy, and the like—you have to realize that there is a small but probably real risk involved.

Those are the types of issues that we hopefully will be able to resolve as years go on. We are trying to do biological studies now to try to determine up front which patients will be able to successfully discontinue and which patients will not. Right now, none of those are really ready for the clinic.

[r06ue1]

Interesting that he said stem cells are not affected by TKI's in a lab.  I was always under the impression from other posts on these boards that if they came out of hiding, they could be killed.  If they have the stem cells in the lab, are they working on drugs that can kill them?  

 

This is always what I worry about when it comes to profit margins and bottom lines, that companies just aren't too thrilled with the idea of creating cures when there is so much more profit in treatments.  Hope I am wrong about that.

[scuba]

As stated above, the author of the article is not correct about stem cells not being killed in the lab by TKI's. Non-dividing stem cells are not killed, but dividing stem cells are in fact killed. In fact - any non-dividing cml cell regardless of type is not killed. This is a critical point.

 

Cml cells are killed only when they go into cell division particularly during transition from the G1 to S phase of the cell cycle. During this phase ATP utilization is dramatic and required (ATP is energy for the cell). TKI's block ATP from binding to the bcr-abl pocket site disrupting this process. The cell can't divide and that inability triggers a cascade of events that ultimately destroys the cell. The cell goes into apoptosis and dies. When a cell is not dividing it does not require ATP at the bcr-abl binding site and TKI has no effect.

 

CML stem cells also die when they divide. They die when exposed to TKI's during cell division. What makes stem cells 'resistant' to TKI's vs the daughter cells (neutrophils and the like) is that they have the ability to enter quiescence for a long time (non-division for years) whereas the daughter cells do not - they are always dividing until told not. And then they die normally to reduce numbers.

 

The reason why upwards of 50% of patients who stop taking TKI's and succeed in treatment free remission is that their Leukemic stem cell population has been greatly reduced if not outright eliminated. This elimination is due to the stem cells slowly getting killed off as they enter cell division. Some people have a rapid turnover of their stem cells and lucky for them, the TKI's do the work. For those who have a much slower turnover of stem cells, a significant portion of their leukemic stem cells are able to stick around post TKI to re-start the disease.

 

Trey has a theory to which I subscribe that over long enough time, leukemic stem cells burn themselves out. Two years may not be enough time, but maybe 4 years? or 8 or longer. We don't know. This burnout is due to the fact that when LSC's come out of quiescence and do divide, a TKI is available to kill them.

 

If this were not the case, then restoration of the bone marrow would not be possible let alone functional cure for 50% of us who try cessation and succeed. Eliminating leukemic stem cells with healthy normal stem cells has to occur in order for normal bone marrow function to be restored.

[r06ue1]

Thanks for the info Scuba.  I did read on some other page that scientists believed stem cells might not die for many decades (normal cell division death, once it has been exhausted), if true, some of those going off their TKI's may in fact have their CML come back if they haven't caught every single one of them as they divide.  

 

Perhaps in the future with newer technology, we will be able to get the counts on leukemic stem cells in our systems, then doctors would truly be able to tell us we are cancer free.

[scuba]

Thanks for the info Scuba.  I did read on some other page that scientists believed stem cells might not die for many decades (normal cell division death, once it has been exhausted), if true, some of those going off their TKI's may in fact have their CML come back if they haven't caught every single one of them as they divide.  

 

Perhaps in the future with newer technology, we will be able to get the counts on leukemic stem cells in our systems, then doctors would truly be able to tell us we are cancer free.

 

I don't believe it's actually necessary to eliminate 'every' cancer stem cell in order to be "cured". Cancer - all cancer - is a failure of the immune system. We produce cancer cells (at the stem cell level) all of the time. Our immune system (triggered by the way by cell division!) recognizes these newly created cells as 'bad' and destroys them. This goes on all of the time. For some reason, we who get CML, the disease, have failed to detect and then either control or eliminate the cancer. A true cure for us lies in the new immunotherapy now emerging which trains our immune system to once again detect and destroy CML as it occurs. There is evidence that CML stem cell creation is natural - in that the transcription error of the 9 and 22 chromosome occurs naturally (the two chromosomes are tightly bound to each other right at the breakpoint - it's any wonder CML is not more widespread!). But just as natural is the body's ability to detect the aberration and destroy it. 

 

It's my personal belief that once one has CML, we always have it - somewhere lurking. It's likely that for those of us who succeed in cessation (50% of the PCRU patients), their immune systems have simply gained the upper hand. TKI's reduced the CML population sufficiently for the immune system to take over. For all practical purposes - they're cured, but only as long as their immune systems stay healthy.

[Melanie]

Are there any trials or studies looking into just lowering the TKI dosage rather than discontinue? Seems a more gradual approach would be beneficial in determining what dosage is needed to maintain different levels of leukemia burden. Less TKI, less side effects, better quality of life. Many have done this on their own, but would be nice to see some the results on actual studies on this, especially for those who never reach UPCR.

[scuba]

During the drug approval process, they more or less do this (test what dose works best) by increasing dose and measuring against toxicity and response. The reason doses are what they are (100mg for Sprycel, 400mg for Gleevec, etc.) is that these levels are what have been proven through clinical trials to have the best response at a tolerable toxicity. Less is not considered optimum and more may be dangerous. There are always outliers. Some patients can tolerate more and indeed need more (140 mg sprycel, 800mg gleevec). And some patients get the same response on much less drug. The key is recognizing that one size does not fit everyone the same and customizing treatment should be what is practiced. It takes effort on the part of the doctor and patient to try different doses and measuring response. Most patients are fearful of this (i.e. a belief that more drug must work better) and many doctors don't want to take the professional risk of going outside guidelines. 

 

In my own doctors experience, he preferred to start me low and work up to find what works*. But he did so because I had severe myelosuppression and could not tolerate the so-called normal dose. Rather than fail top down, he wanted to see if I can tolerate any dose and work up from that level to see where response becomes sufficient. I was started at the lowest dose for which they manufacture the tiny pills (i.e. Spyrcel 20mg). To me and my doctors surprise, not only did my myelosuppression resolve, but the low dose was all I needed to get a terrific response (... pers. note. although I believe the other things I am doing enabled this to be possible). On only 20mg I am near or at PCRU. I don't have any side effects I can feel (but who knows what damage may be occurring long term).

 

Despite the low dose - I still very much want to get off this drug. And will try cessation again and again to test.

 

(* testing low dose first was possible in my case because I had little or no blasts present at the time. My doctor felt we had the luxury of time to try low dose first before CML could get out of hand. This was an important criteria.)

[gerry]

I believe as Scuba does that we will always have CML, I know of loss of MMR for two TFR people, one at over 4 years and another at 2.5 years.

I hope that my immune system continues to work against CML and that I can stay off a TKI. I had dropped to 300mg  Gleevec for a year prior to stopping, but new side effects were starting to turn up even at that dose.

Until they come up with a cure I will get regularly tested.

[scuba]

The good thing we shouldn't lose sight of however, is that we're on to CML. We know we have it and we know how to monitor it. I am fairly risk tolerant to the disease itself - I believe it is controlled. But I won't go without testing (PCR). PCR testing is the canary in the mineshaft that alerts us if our TKI or cessation attempt is not working.

[CallMeLucky]

Sadly I believe this focus on cessation takes away from figuring out how to eliminate cml. They are focusing on trying to figure out who can stop rather than why they are able to stop.
Killing the cml stem cell is the true goal.
Cessation seems to be more about fun research to doctors these days then about actually figuring out the root cause.

[gerry]

Perhaps it is an easier thing to achieve and being able to reduce costs for countries where the TKI is subsidized by tax payers is a worthwhile fix. Plus if they can work out who can stop, then that allows them to hopefully narrow it down to why it can happen and work out a cure from there. 

[CallMeLucky]

Sure Gerry I agree with that it is a worthwhile road but shouldn't be the only road. The stuff I have read and conversations with doctors has not demonstrated that they are looking at why someone is able to stop only if they can and if they can great, if they can't then oh well.
Where before there would be questions about when they would be able to cure and the doctors seemed to have a sense of responsibility to cure, now they seem to be more of the mindset that "hey, you could try stopping and if it doesn't work that's more on you".

[scuba]

I have a theory on why some of us can stop successfully. The fact that it seems to be around 50% is intriguing. And the fact that patients who had prior interferon treatment and then start with a TKI (primarily Gleevec) have an even greater success rate (very high success cessation rate - upwards of 80+%). I think there is a connection between LSC division activity and cessation success.

 

My thinking is that in order for the disease to re-start it needs a pool of CML stem cells (LSC's) that evaded TKI attack. We know that LSC's are reduced greatly in number with TKI treatment but only when they divide and come out of quiescence. During initial treatment blood cells (cml) are destroyed quickly signalling the bone marrow to make more blood cells. This is a vulnerable time for LSC's as they divide to re-populate the disease pool. This is probably why myelosuppression is such a difficult hurdle early in treatment, but tends to resolve later. For those patients who succeed at cessation, they probably had a much greater pool of their LSC's come out of quiescence. For those who do not succeed, their pool of LSC's are probably more quiet and non-dividing.

 

I believe a potential "cure" or success at cessation may lie in coaxing LSC's to divide. There is a paper which I can't locate just yet that described interferon as causing rapid blood cell turnover. The LSC's may be self-renewing rapidly during this time and then when a TKI is introduced, the LSC's are nailed. Killed off en-masse. 

 

This is just a hunch/theory of mine. I look for ways to encourage bone marrow stem cell division.

[Buzzm1]

Are there any trials or studies looking into just lowering the TKI dosage rather than discontinue? Seems a more gradual approach would be beneficial in determining what dosage is needed to maintain different levels of leukemia burden. Less TKI, less side effects, better quality of life. Many have done this on their own, but would be nice to see some the results on actual studies on this, especially for those who never reach UPCR.

mbrown, I started a new thread on lowering TKI dosage http://bit.ly/1SxgCd1...  

like you, I have wanted to open this for discussion for some time ... 

hope you will join in ... 

[r06ue1]

Could there be a correlation between how much CML (and thus stem cells) were in the body at diagnosis and the ability of that person to achieve a "permanent" remission when stopping therapy?  Seems logical that less cancer cells would take less time to destroy as they would also come out of hiding more quickly due to the drop in blood counts.  

[VickiW]

My dosage has been slowly decreased over several years until now for the past year and a half I have been on the absolute minimum dosage of Sprycel and I have qualified for the LAST trial and will soon be quitting all together.

[Buzzm1]

My dosage has been slowly decreased over several years until now for the past year and a half I have been on the absolute minimum dosage of Sprycel and I have qualified for the LAST trial and will soon be quitting all together.

Vicki, if you'd care to add your history/status into your Signature:

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