24 replies to this topic

[CallMeLucky]

Found this to be very interesting, may help to explain why some do better and why some may be able to stop treatment at some point.

P.S. I like the Bosulif ad on the page!

http://www.cancernet...e/10165/2132178

Laboratory studies have suggested that chronic myeloid leukemia (CML) stem cells are resistant to tyrosine kinase inhibitor (TKI) treatment. A new study, though, showed for the first time the effect of stem cell burden on treatment outcome and actually found that TKIs, including  imatinib(Drug information on imatinib) and  dasatinib(Drug information on dasatinib), can rapidly eradicate most CML stem cells.

The study, led by Satu Mustjoki, MD, PhD, of the University of Helsinki in Finland, was published online ahead of print in Leukemia in February. The phase II trial included 46 newly diagnosed CML patients; the researchers counted Philadelphia chromosome-positive (Ph+) leukemic stem cells (LSCs) and progenitor cells (LPCs), using flow cytometry and fluorescence in situ hybridization techniques.

•        

The burden of LSCs varied widely among the patients, from 0.6% (meaning the majority of stem cells were Philadelphia chromosome-negative) all the way to 100%; the range of LPCs was tighter, at 57% to 100%. The median LSC burden was 79% vs 96% for LPCs (P = .0001). LSC count at diagnosis was correlated with leukocyte count, enlarged spleen size, and percentage of blasts in the peripheral blood.

A higher LSC burden at diagnosis appeared to have an effect on treatment-related toxicity. Patients in a "high group," with greater than 79% LSCs, experienced more grade 2 or higher hematological toxicity during the first 3 months of TKI therapy compared with those in a "low group" (55% vs 19%, P = .024); this was primarily due to a difference in the rate of neutropenia.

The LSC burden also correlated with treatment response. "The proportion of Ph+ cells in the stem cell fraction at diagnosis correlated with the cytogenetic responses at 1 (r = 0.63, P < .0001), 3 (r = 0.48, P = .0025), and 6 months (r = 0.36, P = .0271)," the authors wrote. At 12 months, all patients with samples available for analysis (21 treated with dasatinib and 21 treated with imatinib) were in complete cytogenetic remission. In patients with high LSC burden at diagnosis, major molecular response was more likely in the dasatinib arm than the imatinib arm.

In both treatment groups, LSCs dropped precipitously, contrasting with the in vitro data from earlier work; by 6 months, both groups had 0% burden. Dasatinib did appear to deplete LPCs faster than imatinib, the authors noted.

"We speculate that CML patients with a high stem cell disease burden at the time of diagnosis have a more advanced or biologically more complex disease," they wrote. "Accordingly, the LSC burden at diagnosis carried a strong prognostic value." All patients in the study who did not achieve a major molecular response by 18 months had greater than 75% LSC burden at diagnosis.

"LSC burden is a novel prognostic biomarker and may be very useful in detecting high-risk patients who would benefit from treatment intensification," the authors concluded.

[Trey]

Interesting, but just a few comments.  Although they did categorize stem cells into two levels, there are many more sub-levels.  Because they say that all leukemic stem cells were eliminated by 6 months in 100% of patients, it shows they did not evaluate the highest level stem cells, or possibly that all high level leukemic cells were driven into deeper hiding (quiescence).

Gleevec showed that it works better than previously reported in comparison with Sprycel for leukemic stem cell elimination. 

I am not sure they come to the right conclusion when they say:

"LSC burden is a novel prognostic biomarker and may be very useful in detecting high-risk patients who would benefit from treatment intensification," the authors concluded.

Treatment intensification just drives the patient's blood counts lower.  If the patient has a higher percentage of leukemic stem cells, the last thing that is needed is to drive blood counts lower which leads to longer and more numerous drug breaks, which is counter-productive.  A "proper" level of drug that lowers leukemic burden at a sustained rate while keeping blood counts adequate is a better approach. 

[LivingWellWithCML]

So, how does one "ask" their hematologist for a LSC burden test?  FISH and PCR doesn't give you that data, correct?

[rct]

The article cited by CallMeLucky wrote:

 "We speculate that CML patients with a high stem cell disease burden at the time of diagnosis have a more advanced or biologically more complex disease," they wrote.

Really?  I speculate that in the case of my Mrs, she had a high burden because the medical system insisted that she was depressed, or had fibromyalgia, or chronic fatique syndrome.

I bet if the medical system diagnosed based on what was in front of them instead of who the last drug pimp was that visited them there would be a surprising drop in disease burdens by the time peoples got to the oncs offices.

rct

[CallMeLucky]

"last drug pimp"

Love that.....

[pamsouth]

>>>I bet if the medical system diagnosed based on what was in front of them instead of who the last drug pimp was that visited them there would be a surprising drop in disease burdens by the time peoples got to the oncs offices.<<<

Drug Pimp,  that is a fair and proper analyses.

PamS

[sarahboxley]

Ok, people, let's not attack the pharmaceutical industry. I'm not defending it, but play nice please.

[Trey]

Dan asked:

"So, how does one "ask" their hematologist for a LSC burden test?"

It would be an advanced Flow Cytometry focused on certain types of stem cells.  But even then no one really knows which stem cells are leukemic based on their Flow Cytometry markers.  The researchers appear to have combined the Flow Cytometry with FISH, but neither one by itself provides the whole picture, and I don't believe they can be combined to show which stem cells are leukemic.  So overall I think the researchers guessed at quite a bit of the data. 

But to answer your real question, it is a waste of time.  It would not be accurate and it would not change the understanding of your treatment options.  Stick with PCR (and FISH if not yet CCyR).

[janne]

In all fairness, RCT has been through a horrific struggle with his wife in navigating through their own CML journey. We do not hear from him often and his story is just that, it is HIS story...it is his journey and his wife's journey. His concerns have validity. He is very supportive of his wife and not everyone has had a peachy time with their doctors, their symptoms or their drugs. We do not want to alienate anyone and I am sure we will not alienate the pharmaceutical industry in our venting on this board. We cannot always be politically correct in our descriptions which originate from our distress. We can encourage one another and if someone from the pharmaceutical industry is burdened by a CML diagnosis, we will be glad to support them also on this board. In the meantime, I know of people who have quit working for the pharmaceutical industry who would agree with the term "drug pimps". I do not think it was disrespectful as it was not directed at any particular individual and it is a fairly apt description of a facet of our health care system that does not always work well. We have all expressed appreciation for these drugs that have worked well in managing our disease and we appreciate them even more when we feel better on them. RCT we are glad to hear from you. I wish everyone well on this board with all the varied contributions that you bring.

[SoxK9]

No need for the negative energy about pharma reps, IMO. As for me, I'm grateful toward the industry for creating and promoting drugs that help my wife. The negativity is off-putting, frankly.

[hannibellemo]

See what you started, rct?  ; )  Hope all is well with your mrs. and you! Hey, we're still here.

Pat

[CallMeLucky]

"LSC count at diagnosis was correlated with leukocyte count, enlarged spleen size, and percentage of blasts in the peripheral blood."

I believe these are the same factors used in Sokal and Hasford scoring.  I thought the article was interesting and worth posting, but I also didn't think they discovered anything earth shattering.  In the end, I think they are attempting to better understand something they were already looking at.

I think it is reasonable to say that if you have a risk score, indicated by large spleen, high counts, high blasts, etc, then you likely have a higher percentage of leukemic stem cells.  It is reasonable to believe that the disease is more advanced in these patients, and it makes good sense why these individuals take a big hit on blood counts early in treatment as the TKI drugs are knocking out a higher percentage of stem cells then in another patient with a lower risk score.

I also think it is worth noting for those who may be concerned about this information, the gist of the message appears to be focused on early indicators of who would benefit from more aggressive treatment early on (Gleevec vs Sprycel, higher vs. lower dosage).  I don't see anything here that contradicts the fact that once you reach CCyR or MMR that you would be at any higher risk because you started out with a higher burden.  It appears if you have a higher burden you may be at higher risk earlier on, which makes sense and we already knew that (i.e. higher risk score means higher risk!).  For those who overcome the higher burden and do respond to treatment and achieve the milestones, it seems this likely wouldn't effect overall survival.

[CallMeLucky]

"LSC count at diagnosis was correlated with leukocyte count, enlarged spleen size, and percentage of blasts in the peripheral blood."

I believe these are the same factors used in Sokal and Hasford scoring.  I thought the article was interesting and worth posting, but I also didn't think they discovered anything earth shattering.  In the end, I think they are attempting to better understand something they were already looking at.

I think it is reasonable to say that if you have a risk score, indicated by large spleen, high counts, high blasts, etc, then you likely have a higher percentage of leukemic stem cells.  It is reasonable to believe that the disease is more advanced in these patients, and it makes good sense why these individuals take a big hit on blood counts early in treatment as the TKI drugs are knocking out a higher percentage of stem cells then in another patient with a lower risk score.

I also think it is worth noting for those who may be concerned about this information, the gist of the message appears to be focused on early indicators of who would benefit from more aggressive treatment early on (Gleevec vs Sprycel, higher vs. lower dosage).  I don't see anything here that contradicts the fact that once you reach CCyR or MMR that you would be at any higher risk because you started out with a higher burden.  It appears if you have a higher burden you may be at higher risk earlier on, which makes sense and we already knew that (i.e. higher risk score means higher risk!).  For those who overcome the higher burden and do respond to treatment and achieve the milestones, it seems this likely wouldn't effect overall survival.

[Tedsey]

Luck, you wrote, "For those who overcome the higher burden and do respond to treatment and achieve the milestones, it seems this likely wouldn't effect overall survival."  Luck, from your mouth into God's ears...as my mother would say.  Anyway, what you described is me.  The saga continues. 

And RCT, I went to 3 different doctors for 3 years because I suddenly lost a ton of weight and I couldn't keep it on.  I was even accused, (Drs included), for having an eating disorder.  I think Drs, like most people, see cancer as an older person's disease, so no one thought to look.  Eventually, I was told that I breastfed too much.  Whatever....   CML clearly is more subtle than acute leukemia and tumors.  So, I presented at dx with a very enlarged spleen and liver and a high WBC.  However, I had been palped yearly at all my check ups, and  had another baby in between all that.  Then, my spleen popped "suddenly" (I did not notice it enlarging until it bulged one morning and was sore).  So, I made my yearly check up a few weeks early.  The rest is history.

Tedsey

[CallMeLucky]

I don't know if I would call it negative energy, but either way it is not completely unwarranted.  While I appreciate the drug companies make the drugs that keep me alive I am realistic about the fact that said drug company does not care about me beyond being a customer.  Read up on the history of how Gleevec came to market and you don't exactly see a picture of an altruistic drug maker looking for ways to save people.  And frankly I'm not too bothered by it.  Their job is not to care about me their job is to manufacture something and make a profit.  Do I think it is morally questionable to gouge sick people with prices that no one who isn't exceptionally wealthy could afford without insurance? I suppose I do but I also get the business side of the equation and all the R&amp;D that goes into finding these drugs.  But again I don't think for a second the search for these drugs has much to do with saving people it is about making money and I'm alright with that because that is what motivates people to make the drug.  As they say "that's life".  But getting back to how Gleevec came to market the drug company did not want to produce it because cml was a rare disease (ie not enough customers) it didn't matter that people died from it, not enough people died from it to make it worth the investment.  Even after Druker pushed and they saw how effective it could be they still didn't want to expand the trial again citing that manufacturing the drug was too expensive for such a small population.  Let me repeat that, they knew they had a drug that was working but didn't want to tool up to produce more for a large scale trial because their weren't enough people with cml to make it worthwhile.  Only after patients found out about the drug and partitioned the company and demanded they expand the trial did it happen at which point they realized how the effectiveness exceeded their expectations and they realized they could charge a fortune for it and people would pay.  So again I don't hate drug companies, they are a means to an end, but thinking they are anything more than a profit seeking entity is naive, frankly.  Of course everyone is certainly entitled to their opinion....

[Barb@Anderson]

CallMeLucky, I agree whole heartedly with you about the drug companes.  My onc told me that Gleevec for CML was actually discoverd by accident to treat CML.  He said they were testing the drug for AIDS and found that in this testing the drug seemed to reduce the white cell count hence the trial testing for CML.  If the drug had worked for AIDS, in my opinion it would have immedatley been made available for testing since there is an epidemic of AIDS.  Nothing against that idea of course but it all come back to the drug companies making money.           

I was blessed to have a primary care doctor that is on top of any complaint the patient comes in with.  When I complained of being fatigued for the last few months, she startted doing test right away.  Hence the blood work showed my WC count to be extremely high.  She sent me to Onc that day and a bone marrow was set up for next morning.  Had she not been on top of it, I could possibly gone on for awhile not knowing I had CMl..  Maybe even going so far as being to late for TKIs to work.  Again the Gleevec was so high I could not afford it.  I got my first prescription using credit card because I knew it was imperative that I get started on it.  My Onc helped to get me some patient assistance after that but when I get the invoice that comes with the script every month, I am astounded at the cost the drug company is charging.  It went up a thousand dollars from Jan 2012 to Dec 2012.  And my Onc says that in May when I go back, he may change to another med since the Gleevec seems to have stopped working.  He increased my dosage til then just to to try.  If I have to go to another med, then I wonder what I will have to do to get approved again for assistance. Guess I will cross that bridge when it comes.  In the meantime, I am trying to stay positive and thak God He has put good doctors in my path. 

[Trey]

That is a myth about Gleevec being discovered by accident and the whole AIDS thingy.  Gleevec was a a product of "rational drug design", meaning it was planned and bio-engineered to do a specific thing, which was to inhibit leukemic BCR-ABL.  The drug designers accomplished  what they set out to do, and the result is there are many thousands of us alive who would otherwise not be.

[SoxK9]

Agree with Trey's post.

And I still don't see how demonizing the drug industry adds anything constructive to one's CML story, especially if it makes people want to stop reading. I guess we'll have to agree to disagree about that one. If your doctor is unduly persuaded by a "drug pimp," it seems like the appropriate thing to do is find a new doctor, not blame the pharma rep for doing her job. I am really sorry to hear about the financial struggles some are having with Gleevec, and I agree that this does not seem fair. But it's equally unfair to blame this primarily on the drug industry. There are numerous patient relief programs and funds, funded in large part by the pharmaceutical companies themselves. These are publicly traded companies, and they can't pour billions into R&D without recouping that expense.

At the end of the day, Gleevec has either a) saved my wife's life or at the very least made it so that she does not need to have a risky and invasive transplant. I can't express how grateful I am for that drug and the company that made it, so I guess that's why this particular issue struck a nerve for me.

[Barb@Anderson]

Trey, thanks for clearing this up about Gleevec being discovered by accident.  I have been teeling others the same thing I posted.  I will have to recant my story.

SoxK9, sorry if it appears that I am not grateful for the durg that has let me keep going for the past almost two years now.  I just wonder why it cost so much to manufacture a little tablet.  I calculated the price of one tablet from my last invoice and it was $215.66. I know this is little compared to what Chemo through IV cost as my late husband was treated for 5 months before he died.  The Chemo to me seemed to speed up his cancer rather than slow it down.  He had no quality of life after starting treatment.  As his primary caregiver, I was exhausted all the time but you do what you have to at the time.  Afterward you wonder how you made it.  Anyway, his bills were astronomical for the 7 months he lived after dx.  So the Gleevec I know is a bargain compared to that.  Again I am not complaining but what of those that do not have any insurance at all.  Do the drug companies work with them to make sure they can get their meds and still afford them?  Just wondering.. 

[sarahboxley]

Barb,

I agree that the medicine is extraordinarily expensive. I am fortunate enough to have good insurance coverage, but the invoice does take my breath away each month.

To answer your question, I looked at Pfizer as an example of a company that manufactures many oncology drugs, including bosutinib. This company has a whole collection of patient assistance programs. Some are for the uninsured, some for the "underinsured", and some for specialty drugs. This program is specifically for oncology drugs:

http://phahelps.com/...etails.aspx?p=7

I am sure that the application process is "thorough", but it does appear that most drug companies have programs like this.