27 replies to this topic

[cherylannes]

Please read the interesting paper in the link provided below.  It is from research being done at both the Mayo Clinic and in Portugal and it is recent, 2009.  They have a very positive hypothesis which they have worked out in virtual models of CML patients, which substantiates, in part some of the findings that may be happening with the patients in the STIM trials in Europe.  So, in fact they are saying and this is directly quoted from the paper: Leukemic stem cell extinction:  We evaluated the natural history of a million virtual patients following their disease over time from the appearance of the first LSC. Figure 3A  shows the probability of extinction of the LSC lineage as a function of fitness advantage, illustrating that this probability is maximized precisely in the case of CML in which LSC and hematopoietic stem cells are neutral. Figure 3B displays the increase of the extinction probability as a function of time under neutral evolution. The simulations portray a remarkable and unexpected result in the context of CML: in the vast majority of cases, clonal extinction of LSC occurs. More importantly, by the time the disease is diagnosed (~5 years after the appearance of the first LSC), most patients - 84% - no longer have LSC . Closer inspection of the results shows that LSC extinction is an early event: after 1 year already 50% of the patients no longer have LSC. For those patients in whom LSC are still present, we observed that the average clone size increases by one LSC per year (R2=0.9999). Moreover, since the current model treats certain parts of the hematopoietic tree stochastically, some patients may never be diagnosed with CML, despite initially carrying LSC (see below). - this is from the paper and substantiates what I said a few days ago....

This paper actually illustrates a comment that I made earlier, that there is a finite set of LSC, that do become extinct.  The paper goes on to say that treatment with a TKI should probably be for about 9 years, as long as the patient is having a good response to the TKI, in order to ensure that all cells that could cause repopulation of the disease are in fact eradicated.

I do realize that this is research, but you will note from reading the paper that there are some very interesting references to results that substantiate some of what these researchers are saying so that this all makes a plausible sense.

All quite positive and happy thoughts for a Sunday....

The paper is titled:

Tyrosine kinase inhibitor therapy can cure chronic myeloid leukemia without hitting leukemic stem cells

http://www.haematolo...t/full/95/6/900

[Tedsey]

Thanks so much cherylannes!  I really needed this!  Been feeling a bit scared lately.

Teds

[cousineg]

Hi Cheryl-Anne,

           This article from December 2009 is quite interesting. There are other articles that go in this direction and which stipulate that the time for healing can be evaluated by a mathematical model. http://www.cmleukemi...e-leukemia.html .

Unfortunately, I read another article in which a CML expert said that only 10% of CMLers will heal. The others will relapse in ten or twenty years after stopping the treatment. I try to find this article.

Regards,

         Gilles

Other link:

Patients with chronic myeloid leukemia who maintain a complete molecular response after stopping imatinib treatment have evidence of persistent leukemia by DNA PCR

http://www.nature.co...eu2010185a.html

[Trey]

I wish I could get excited about this "research", but that is not what it is.  It is a series of speculations put into a mathematical model, mixed with a list of assumptions.  The lead "researcher" is a computer scientist, not a medical researcher, and he does not understand CML, he just understands math and computers.  GIGO.

Some of the highly suspect speculation on which this mathematical model is founded are:

1) All patients are "virtual patients", an invention of the author.  No actual patient data was used.  That eliminates those messy real life "facts".

2) Assumes that leukemic stem cells (LSC) act like normal blood stem cells.  In reality, they do not -- they are cancerous; so of course they act differently.

3) Assumes the originating leukemic stem cell is extinct before diagnosis in 84% of CML patients.  That is before taking even one Gleevec pill.  Tell me again how and why this is possible?  It just gives up without a fight?  Makes no sense whatsoever.

4) Assumes that the blood forming (hematopoietic) system, including leukemic stem cells, act in a stochastic (random) manner.  The stochastic theory of hematopoeisis says that "undifferentiated blood cells are determined to specific cell types by randomness".  That is not true.  Blood cell types are determined by complex stimuli and signaling processes in the body, and the various cell types are produced as needed (not perfectly, but generally).  So the entire basis of this LSC extinction theory is highly suspect.

5) Assumes that leukemic stem cells divide only once per year.  That is unknown, and doubtful given the de-regulated growth of cancerous cells.  To assume that cancerous cells act like non-cancerous cells is very far from reality.

6) Assumes that it takes 5 years to develop CML from the time of the first leukemic  translocation.  That may be true in some cases, but likely not true in  most cases.

7) It ignores such real world facts as why transplant patients relapse from the leukemia at fairly significant rates after transplant, sometimes years later.  Transplants generally occur years after initial diagnosis, so leukemic stem cells must still be active in a relapse in view of the intense efforts to eliminate the entire hematopoietic system during a BMT.

8) There is more, but suffice to say, no world-class CML researchers have adopted this "theory".

And once again for the umpteenth time, this "research" also does not show that many healthy people are walking around with BCR-ABL but will never have CML.  In fact, this article says the opposite: "Animal models as well as theoretical considerations on the age-specific incidence of CML in human populations suggest that aberrant BCR-ABL expression alone may be enough to explain the chronic phase of the disease."

On the other hand, I have wondered whether CML drugs might allow us to outlive the leukemic cells because they divide faster and might burn themselves out faster than normal blood stem cells.  If so, the drugs would keep us alive until this LSC burn-out occurs over a decade or two or three.  But I don't disguise that as "research", just a dream.

[valiantchong]

I think if the model is base on some assumption that had proven to work on some patients that are off drugs more than 5 years (STIM patients) or 10 years ( Interferon alpha patients). But then again it is only apply for 5%-10% of patients. But time will tell, as the STIM trail patients will prove this for the next 5 years. I really hope this will be true.....

I do believe there is a possibility on the model, but it must be proven to work, with time,....And time is what I do not like, coz it has no gaurantee it will work, as this is part theory and part reality (since it are working on the STIM patient)....

Thank for the positive news.... I do hope we have something more concrete....If they can prove this work in lab, or in mouse model, then I believe this will be certainly working.....

[cherylannes]

I certainly hope all who read this realize that I did state up front that it was a mathematical model.  However, it was a model based on solid research, and as the article points out, in fact, some of the results they achieved with the mathematical model already matched what is happening in the current STIM trials...

For a PDF of a slide presentation that was given from the researchers of the paper: http://s1.acad-cienc...heco/Darwin.pdf

These cells are cancerous.  You asked how is it that LSC can become extinct even before diagnosis?  Because as much as our bodies have deceived us by falling prey to the cancer causing epigenetic event, it still does work in some capacity to correct itself.  It must, otherwise we would develop all sorts of cancers...So, in some cases, not all, and maybe the 84% is much to optimistic, patients can eradicate the LSC

But as regards this specific mathematical model, there is an interesting document on the net that regards the highlights of a workshop that happened in the UK in 2008 and was sponsored by the LLS and the main key players, or shall I say brain trust in CML were present and gave input.  They actually discussed this model and found that it was very helpful to them and proposed some changes for future models, but stated that the model did find similarities that they were experiencing in the real life patient population.  Find the entire document here: http://doc.gold.ac.u...l_Formatted.doc


Trey said: And once again for the umpteenth time, this "research" also does not show that many healthy people are walking around with BCR-ABL but will never have CML.  In fact, this article says the opposite: "Animal models as well as theoretical considerations on the age-specific incidence of CML in human populations suggest that aberrant BCR-ABL expression alone may be enough to explain the chronic phase of the disease."  This sentence doesn't answer the question at all and certainly doesn't say unequivocally that BCR ABL can exist without CML...

Trey you have also said that no CML expert would ever agree to this.  Actually I consider Professor John Goldman to be quite an expert: http://bloodjournal....short/92/9/3362
.
I propose we move away from making generalized statements when talking about these important subjects and I would prefer if we actually site and reference the scientific documentation, as I do, that explains why we are willing to open such discussions....

[cherylannes]

@ Valiantchong,

I believe there is a possibility for this model to work.  I also believe that with the advances in PCR such as in PCR DNA, we will be able to determine, at a much deeper level the amount of residual disease.  We also have to consider that combinatory drug approaches will also yield higher successes and deeper levels of response for more patients and this is particularly more possible when we think of the improved potency of the newer TKI's.

Here in Canada we are meeting with Health Care ministers and we are telling them that based on the European evidence we can cure 10% of CML patients with Gleevec alone (after several years therapy), but we could improve that to 30 - 40% of the CML patient population by using the newer TKI's up front.  We are also working on an approach to personalized medicine.  This would allow a doctor to have a better understanding of the status of any particular patient at the time of diagnosis, which would allow a doctor to determine the "right drug for the right patient at the right time ™ " that would allow a patient to achieve a quicker deeper level of response.  Our CML expert doctors are meeting the healthcare ministers with us...

If you look at Clinical trials Gov site (link provided below) you will see in fact there are trials aimed at either inducing autophagy in LSC in combination with Gleevec, or combining the various TKI's with other drugs, such as IFN, and also stopping TKI therapy al together with careful monitoring.  These trials are able to go ahead precisely because we have an ability to use mathematical modeling to help stimulate what might happen in the real world, thereby increasing the chances of success.  But, at the same time, making things much safer for the patient.

We can chose to become encouraged by all of this, or not.  However, I have found it much easier to go through life with a hopeful outlook while continuously educating myself on the intricacies of this disease and doing all that I can to remain. All things considered, otherwise healthy, in order to reap the full rewards of the eminent cure for CML...

Link to clinical trials:

http://clinicaltrial...esults?term=CML

[cherylannes]

Gilles,

We have discussed the ability of PCR DNA to detect residual levels of BCR ABL, but, no one knows what that means, as there are patients who have these detectable levels, albeit sometimes sporadically, yet they have not relasped yet.

10% of patients can be cured on Gleevec as a monotherapy alone.  The percentages of patients that can be cured is expected to increase with the use of the newer TKI's as frontline therapy and also when thinking aobut other strategies such as combining TKI's with other drugs to help the quiescent LSC populaiton circulate and then become targeted by the TKI...

Highly unlikely that patients will relapse 10 or 20 years from now, because as we speak there are techniques to improve DNA PCR and PCR level detection, combined with the newer strategies for going after the disease these patients will be tracked better.  Besides, relapse does not equate to a life threatening situation, those who have relasped on the STIM trials have all regained their good response to therapy.  In 10 to 20 years I expect that there will be many other treatments to try...

For those of us who suffer terrible side effects that sometimes necessitate going on disability, 10 to 20 years of no side effects gives us a great deal of time to live our lives to their full extent...

In the end though, we all must remember in the game of life, no one gets out alive.  The goal is to extend our lives as much as possible and to stay as healthy as possible and to leave this world in a better place then when we arrived.....

Cheers!

[valiantchong]

HI,

I do hope there is a better findings than the present 10%, which is carrying MRD. As you said it, one can choose to keep a positive mind and hope rather than to feel today's progress is not heading towards a cure and being hopeless.

Do keep us updates on the progress towards cure... I certainly hope we all will be cured soon < 10 years time.....Keep my fingers cross.....

Thank you.

[John]

I don't know about the rest of you, but I love it when Cheryl and Trey fight/argue/debate....

I just keep waiting for Phil to jump into the mix!

[Tedsey]

Thanks so much Trey.  I had a list of questions I wrote as I read the article.  You have addressed them all.  Since I am still very green, I rely on you a lot to gauge what the current thinking is regarding stem cells, treatments, and basically all things CML.  You have been a great teacher.  I also think there is a place for this kind of "research".  However, it needs to be well thought out and the use of a "real" population would be most helpful.  This virtual one made the whole article seem like pretend.  Nevertheless, it was a good read, and I am glad Cherylannes posted the article.  It think "research" like this could be useful if constructed differently and, of course, with direct input from CML experts.   

Teds

[Tedsey]

I know I seem like I am playing both sides, but I really want to thank Cherylannes too.  I have learned heaps from your posts.  I trust your knowledge and find your discussions, and even disagreements with Trey, an invaluable source of information.  I know one day that we will find an answer to most of these questions.  Arguments will be settled.  And I know there will be a cure, whether it be through TKIs or other.  But hopefully not through potentially life-threatening and more misery causing measures, namely, a SCT.  Although I may need one one day soon to try and save my life, the risks, possible failure, and the fact that it still employs a "shotgun" apporach makes it look very primitive.  And it makes me very excited to learn that personalized medicine may not be just a dream!

Teds

[cherylannes]

@ Valiantchong,

I think that with the use of more personalized medicine which would allow our doctors up front to make sure that the right patient gets the right drug, at the right dose, at the right time © We will see that many more people can achieve better, deeper responses and then possibly be good candidates to stop the TKI all together.

On every doctor visit, I remind my doctor that my ultimate goal is to successfully stop treatment and not relapse.  By the way, I stopped TKI's last September and for the moment, I am still in CMR (PCRU).  My fingers are crossed that this holds.  Ten years on one drug or another is a lot, and I am grateful that I always responded so well to them, but nothing ventured, nothing gained...

May we all be well and healthy....

Cheers!

[cherylannes]

Teds,

I really hope you do not have to go the way of a transplant either.  I have an update for you from my friend who has been dealing with CML for about 13 years now, and always had problems like you and RCT's wife.  Nothing worked for her, her counts crashed on every treatment.  She was dx in 1998 and so she had to go on IFN of course, that didn't work out for her.  She was lucky enough to get on the early Gleevec trials - when it was still called STI 571, but her counts kept crashing, no amount of Neupogen and Eprex could allow her to stay on therapy.  She even went on the Heat Shock clinical trial at UCONN, in 2003 - nothing.  She was always 100% Ph+.  In 2005 she started on the Dasatinib (Sprycel) trial and came to live with me here in Montreal as she was living in Halifax, Nova Scotia at the time and needed to be close to the clinical trial site at my hospital.  Once again, the road was bumpy, her counts crashed, she even wound up getting intravenous immunoglobulin (IgG i.v.) therapy to try to restore her platelets enough.  Finally, the trial doctor, who is also my doctor, got permission from BMS to lower her dosage, she went down to 20mg a day then after a few months her dose was graduallly increased to 50mgs a day.  Her counts normalized somewhat, and her quality of life was almost at par with anyone else.  The best news aobut this story is that after 5 years of 50mgs once a day of Sprycel she finally, for the first time in 13 years had 0 Ph cells from cytogenetic testing on her bone marrow specimen.  That was just recently, as she was trying to get on the Ariad trial, which she cannot access now as she does not qualify.  She just received this news in Januray.  There is even better news - she just found out that she is now in MMR!!!!  She is estatic - we all are!!!

This friend was told to get ready for a transplant on more than one occasion, she held on...

Hope this helps to inspire you.  She was not quite 40 when she was dxed and her children were in their pre-teens....They are all now living independently on their own....

Cheers!

Cheryl-Anne

[valiantchong]

Hi,

Thank for the information, it realy give us more hope. Since u have stopped TKIs since Sept, now is Feb, it is almost 6 months....I strongly believe you can go thru the 6th months mark, which base on Dr Valent from France data, if anyone could go thru the 6 mths mark, most probably they will stay PCRU, CMR, or functionaly cured....

Good Luck and keep us posted on the good news...

Sending good vibes to you...

I wish I will reach there one day.... I do hope there is some vaccination cure for CML....Wish the ILRAP of LSC trial works...and may we all cured...

[Trey]

The low dosage Sprycel is a good example of how different people require different dosages.  Some can do very well on low dosage, especially with Sprycel.  For some the low dosage would reduce the side effects profile, and especially the myelosuppression.  This is an area where Oncs need some education, because they often simply look at the drug at regular dosages as a failure instead of lowering dosage to the right level for the individual.  The irrational fear of inducing drug resistence has contributed to the reluctance to lower the dosage for those with severe side effects.

Cheryl Anne -- I believe you are still on Interferon therapy?

[HeatherZ]

I was thinking the exact same thing John - I love when they go toe to toe and always wait for Phil to jump in.

[gunner]

"Essentially, all models are wrong, but some are useful"  (George Box)

I just received a very good lab report. This bloodwork was drawn exactly two weeks after I purchased a new vehicle. I would highly reccomend that folks purchase a vehicle two weeks before their labwork.

[cherylannes]

Mark this date in History - Let it be known far and wide, on this date I have agreed with Trey... Actually I do agree with Trey on quite a few things, but I wanted to inject some humor in some of the seriousness that goes on from time to time....

I agree that it is irrational for our doctors to not try to reduce the dose of Sprycel to ease side effects, but monitor the patient closely.  This is even more relevant when the patient has had a good response.

To answer your question is not so easy.  The very short answer is that I am currently enjoying a holiday from Peg IFN.  But there is more to it than just that, as always, it isn't a straight and easy answer.

Quick re-cap, I had been on some form of treatment for CML for the last ten years.  Starting treatment was with IFN as a monotherapy for a few years, then 400mg of Gleevec (daily)  - monotherapy, then 1.5 MIU of IFN (daily) as a monotherapy, then 70 mg Srycel (Daily)- Monotherapy, then 50mg sprycel/daily and Peg IFN weekly (for just over two years).  With the exception of about one year, I have been CMR for most of this time.  Since the hospital I am treated at is a university treating hospital which does clinical trials, PCR were done at an approximate sensitization of detecting 1 in 100,000 cells.

Through all of this time note that the doses of IFN and/or Peg IFN has been relatively small.  For Newbies, back in the day pre- Gleevec, a patient had to take anywhere from 10,000 MIU - to 15,000 MIU and I know someone who endured close to 20,000 MIU on a daily basis...

Side effects at low doses is practically non existent. 

When I stopped Sprycel in September I stayed on 90 UG once a week of Peg IFN, but by December, that dose was reduced to 45 UG once a week.  By mid December I developed the begining of rheumatoid arthritis(RA).  This isn't a strange thing, it is after all a genetically inherent disease and runs in my family, but the IFN seemed to be exacerbating it.  So, I opted to stop taking it and see what happens.  Predictably, the RA has greatly subsided.  There is some literature in research out there that suggests that both IFN and Sprycel can cause "drug induced Lupus".  See the link below.  I hope this is my case, because I would rather see the RA clear up entirely.  If it doesn't clear up entirely, then the Rheumotologist would probably like to start me on Hydroxychloroquine (HCQ).  It just so happens that Dr. Tessa Holyoake is doing a trial combining Imatinib with HCQ which might potentially cure CML. The link in the clinicaltrials.gov website: http://clinicaltrial...Holyoake&rank=1

However folks I should point out that the dose of HCQ for RA is only 200 - 400 mg per day, and Professor Holyoake is using 800mg of HCQ with 400MGs of Gleevec once a day.  I very much would like to think that I can stay off of TKI's and hopefully not take HCQ.  Personally, I feel a bit "overbaked" with the drugs....I would absolutely love to have a few years of no drugs.

The results of a PCR taken on January 13 (after my first three week break from Peg IFN due to severe fatigue and RA symptoms) came back undetectable.

I am followed very closely by my doctor with monthly PCR & FISH.

Rare occurence of IFN induced Lupus: http://lup.sagepub.c...8/1/78.abstract

A reported case of Dasatinib induced Lupus: http://www.thelancet...printerFriendly

Many drugs have the potential to induce either lupus or another syndrome caused DRESS - Here is one showing a case reported with Imatinib: http://www.ncbi.nlm....pubmed/18457727

Bombs away.....(again, just joking)

Peace and Cheers,

Cheryl-Anne

[PhilB]

Apologies to those waiting for me to jump in.  This time I'm just tiptoeing around in the background hoping that maybe the kiddies will play nicely