CML

Hi Peter,
I'm curious to know how long and how frequent your breaks from IM have been.
As others on this list know, and you may too, I have been cycling off IM for
one month out of every three for the past 3.5 years, without adverse effects
as far as I can tell. On the contrary, over the same period, I have
experienced a decrease in my leukemia burden from a PCR of 0.003 when I
began to 0.000023 at last count. I also feel quite a lot better than I did
when I was taking IM continuously - especially, of course, during my month
off.
Back in October, Emile asked for my rationale for doing this. I began a
post then, but I'm afraid ended up on a rather remote back burner. I
apologize for not getting back to you sooner, Emile. Following is a
continuation of that post.
***
Cycling on and off IM (officially called "pulse therapy"- a term which I'll
use from now on) is frowned upon by most treating physicians. I, too, would
disapprove of certain approaches to pulsing - in particular, skipping a few
doses now and then. I sympathize with the folks who do this when their side
effects become unmanageable, but as their docs and others on this list do, I
worry that this will increase their risk of developing IM-resistant disease.
I'll explain why in a bit.
Many doctors think that my approach is equally risky, but others - including
myself, obviously - do not. On the contrary, given my level of remission, I
believe it's at least as likely that cycling will reduce my risk of
resistance, increase my chances of eradicating quiescent CML stem cells, and
decrease the risk that I will develop long-term adverse effects from IM.
I do want to emphasize, however, that there is no direct evidence to support
cycling. Moreover, by explaining why I have chosen to cycle I am in no way
advocating that you or anyone else should try it. It is my right to
experiment with my own health and life, but not with anyone else's. Nor am I
a specialist of any kind (I am trained and practiced as a family physician),
so you should not place too much weight on what I say because of my
background in medicine. I know what constitutes good science, but I am not a
researcher myself. Finally, you should know that I would not be doing any of
this had I not achieved a 3-log qPCR reduction in my first year on IM. I'll
say more about this later.
To explain why I've chosen IM pulse therapy, I must begin with a rather
heretical statement: chronic phase CML is not really cancer. It inevitably
turns into one if you don't treat it, and a very nasty one at that. But by
itself, CP CML is a pre-malignant condition.
Once I realized this fact a few years back, I was able (metaphorically, at
least) to take a deep calming breath and let go of that initial panicky
desire to kill as many cells as fast and aggressively as I could, never mind
the collateral damage. And I began to ask the question, if CML isn't like
cancer, what is it like? If it resembles other illnesses, what can we learn
from treatment approaches to these?
As a premalignant condition, CML is akin to actinic keratoses of the skin
(see http://www.skincancer.org/ak/index.php): benign, rather slow growing
tumors which are worth treating, because if you don't, many of them will
develop into squamous cell carcinomas. But you can treat actinic keratoses
with topical drugs like fluorouricil or Ara-C once a year. Like IM and CML,
this doesn't kill all the cells, but it prevents them from turning into
cancer - presumably because there are too few of them to make cancerous
mutation statistically likely.
CP CML also shares similarities with dysplastic polyps of the large
intestine to which some people are prone: though benign in themselves, most
of these will develop into colon cancer if you don't remove them. Conversely
if you do take them out - via colonoscopy every every few years (they grow
very slowly so every few years is enough) - you'll never get a colon cancer
even though there are undoubtedly still dysplastic cells hanging around.
By the way, it's understandable that most treating physicians still think of
CP CML as a scary cancer because until Gleevec came along it used to
progress to blast phase so rapidly - and blast phase CML is a true and
uniformly deadly cancer. But the fact remains that genetically,
morphologically (referring to the architecture of the cells), and
behaviorally CP CML cells are not cancerous.
Another analogy I found instructive is parasitic disease such as malaria.
Single celled malaria parasites are just as complex capable as individual
mammalian cells in terms of their ability to defend themselves against
threats such as anti-biotics in the case of parasites, or cancer drugs in
the case of cancers, by way of intrinsic defenses or through mutation. The
kinetics of parasite killing are also comparable to treatment of early CP
CML. The malaria "load" in infected patients prior to treatment is between
one and ten trillion (10^13) malaria organisms - similar to 10^13 Phillies
at diagnosis in CML. A single antibiotic (quinine derivatives in regions
where malaria is not yet resistant to them; or more recently, a new drug
derived from the Chinese herb, artemesinin) can reduce the number of
organisms by up to 7 orders of magnitude (down to one in 10 million), but
not eliminate them. The best you can expect is to reduce to number of bugs
to a million or so - again, similar to the IM experience with CML.
Where a second equally effective anti-parasitic agent is available, by the
way, the second agent can produce a similar log reduction and potentially
kill all the remaining organisms. Similarly in CML a cure may be possible
if we can develop a new agent that kills quiescent CML cells as effectively
as IM killed the dividing ones - but unfortunately no such drug is yet on
the horizon. (Note: some people do get cured from malaria using a single
drug, but in these cases there is always a highly effective second agent:
their own immune systems. Unfortunately, the immune systems of
non-transplanted CML patients are just as ineffective against our remaining
cells as they were against the disease when it first began. Hopefully
vaccine therapies will change this some day, but we're not there yet).
But here's the part I consider most relevant to CML: where parasitologists
have only one effective drug against a given parasite, they use it just long
enough to achieve the estimated maximum parasite kill, then they stop, wait
a while, and start again. Their rationale for pulse therapy is thus: the
various resistance mutations that protect parasites against antibiotics
exact a high metabolic toll on these bugs. This puts them at a competitive
disadvantage during breaks when such burdensome "skills" aren't needed.
During these times, resistant bugs are out-competed and crowded out by their
wild-type, non resistance-bearing peers (an analogy within an analogy:
imagine an army of millions of people trying to travel hundreds of miles on
foot across difficult terrain to a new land. While under continuous attack,
those carrying heavy armor will be more likely to survive, but during
periods of travel though friendly territory, the soldiers carrying lighter
loads will get much farther (or something like that! ;-)). Thus pulse
therapy keeps the level of resistance the same and over time and allows you
to maintain (or even improve upon) your best level of success. Conversely,
continuous use of a single drug that can't kill all the bugs, usually
produces resistant organisms which will increase in number over time.
Will the lessons of single-drug treatment in parasitology apply to CML?
Besides the success I've had with pulsing over the past several years, there
is anecdotal evidence to suggest that it might work in others as well. A
couple of years ago there were reports (from Hochaus' group, I think?) of
patients whose PCR's had plateaued, having to stop IM for a month or more
due to side effects. When they restarted, their PCRs plateaued at a new,
lower value. This all makes sense to me. Given that continuous IM obviously
doesn't kill whatever Phillies remain once you're in MMR, it's not
unreasonable to fear that their level of resistance might increase over
time, leading to relapse. Pulse therapy should not have this effect and may
even decrease the fraction of burdensome-resistance carrying Phillies.
Once again a caveat, though. Since the probability of any mutation is
directly proportional to the number cells prone to mutate, I consider my
chances of any sort of deleterious mutation - either to IM resistance or of
transformation from chronic to blast phase - to be acceptably low even if
I'm wrong about the logic of pulse therapy. However, I WOULD NOT be taking
this chance had I not reached MMR early on, and I'd strongly recommend
against this approach for anyone who has not reached this milestone - at
least until the results of clinical trials (underway in Scotland now) are
in. Logic is one thing; scientific evidence is another.
A couple more points, then I'm done.
Why did I choose a three month cycle time? The idea is that I end each break
right when I'm due for my next PCR so that if I were relapsing, I'd be
likely to catch it right away.
Why do I take month-long breaks? That's actually a work in progress. I began
with two weeks off out of every three months and gradually worked my way up
to month-long breaks. My eventual goal is six weeks on, six weeks off.
Longer breaks improve my quality of life, of course, but I believe they may
also increase the chance that some of my Phillies will come out of
quiescence, start cycling, and get killed once I restart IM.
Why are shorter pulses, such as a few days off every couple of weeks, a bad
idea? Because it takes nearly a week for IM to get out of the system and
during much of that time the IM serum level is high enough to exert
resistance selection pressure but too low kill the Phillies - the ideal
situation for creating resistance. I recommend against this.
What about pulse therapy and long-term adverse effects from IM? There's as
yet no evidence that IM will be harmful in the long run, but not much reason
to believe that it won't be, either. I do take it as a good sign that some
folks have been on IM for seven years now and seem in perfectly good health
(I'd expect any common long-term effects to distribute normally over time,
that is, some would show up quite early, some very late, and most in the
middle term; the fact that I've heard of no early onset nasty effects
suggests that we MIGHT get off easy over time), but I'd rather not take any
chances. Giving my body a chance intermittently to recover from whatever
might be building up seems only prudent.
Phew, that's all. Writing this up took way longer than I expected. I hope
some of you find it interesting. Now, back to ASH.
Regards,
Richard R

Hi Richard,
Do you know how few people would work on CML posts at a ski resort? Foggy or
not! Thank you for keeping the ASH and "IM pulsing" posts on your "vacation"
agenda. You're the best! I'm sure you're having fun, too, and here's wishing
you a new year filled with more accomplishments, lots of fun, and continually
improving health.
Love,
Susan

Richard, Thank God you have answered! I wasn't sure that anyone even saw my
post. Obviously as you can tell from my post I am absolutely confused as to
whether I am ADD or not. But it makes so much sense as to why I have always
had the problems that I do.
However, they have progressed over the years. I am now 40 years old and I
don't recall having problems as a child. Yet I do recall having some when I
was a an adolescent.
I am scared to take 1 more medication, but if I do have ADD then I would
like to get rid of it by taking something that would help me focus as I
should be able to. Its not always fun walking around with this wondering
mind:)
I have had previous problems in the past with addiction. Its been a long 20
years but for the last 5 I have also taken xanax and yes I am addicted to
them but I do not abuse them. I am supposed to take .5MG TID but have never
taken more than 2.
After research I wonder if my previous addictions were related to being ADD
as they have found in many addicts. I also wonder if xanax would still be
necessary. I don't at all worry about abusing any drug like an addict would.
Even with my past, my theory is very simple. People have choices and I
choose NO. I am all grown up now.
Unfortunately, I have hardly any compassion in this area which to me is
amazing since most expect me to understand. But I don't... I just can't no
matter how hard I try. It just makes me angry.
I have had many traumatic events take place in my life and I just can't
imagine going through it stoned. An addict would think that's the answer.
But even though I have had addiction problems in the past, I know now that
the problem will still be there when I wake up and I don't need to add to
it. I guess I am one of the lucky ones. Once I stopped I stopped and never
looked back with the exception of all the bad it brought in my life. That
was always enough to make me think of drugs like a child would a boogey man.
Thank you for answering. I think a psychiatrist would be best at diagnosing
me since there are so many facts to consider in my case.
Now I just have to focus and stay focused on getting an appointment.
Wishing you and yours a Happy & Healthy New year!
Lisa
Message: 3
Date: Thu, 29 Dec 2005 12:00:48 -0500
From: Richard R <rrockef1@...
Subject: Gleevec - CML & ADD - Lisa
Hi Lisa,
I take psychostimulants for ADD. It was diagnosed long before I had CML,
but IM, by making me sleepy, makes the attention worse. I use a very low
dose of Adderal, only 5mg once in the morning and not even every day, but
gets me going sufficiently.
If you had no ADD prior to CML and IM, then it's unlikely it's really what
you have now, but a trial of psychostimulants could still be worthwhile to
deal with Gleevec-brain; the difficulty might be in getting someone to
prescribe for you. I wouldn't try it if you have any propensities toward
addiction, nor if you have high blood pressure.
There is no definitive test for ADD, I'm afraid, though some of the tests
available can be helpful. You're best of consulting a doctor (usually a
psychiatrist) who is well versed in the condition. There are also are a
number of books that can be helpful in helping you sort out whether it's ADD
or not. One that I used to recommend a lot was "Driven to Distraction," by
Edward Hallowell, but there are other, newer (and better? I'm not sure) ones
as well.
This is a topic I posted on a couple of years ago on Rob's list; I'll see if
I can find the post.
Cheers,
Richard R

Hi All,
As forecast, it's foggy and rainy here in Bethel, Maine, home to the Sunday
River ski resort. The snow is actually pretty good, but the visibility is
nil, so I have an excuse to stay inside and work on my ASH posts today and
tomorrow (which is forecast to be even worse). First, though, I'm going to
finish up a post I've been working on for some time concerning IM cycling
(or "pulse therapy" as it's officially called).
Regards,
Richard R

Hi Lisa,
I take psychostimulants for ADD. It was diagnosed long before I had CML,
but IM, by making me sleepy, makes the attention worse. I use a very low
dose of Adderal, only 5mg once in the morning and not even every day, but
gets me going sufficiently.
If you had no ADD prior to CML and IM, then it's unlikely it's really what
you have now, but a trial of psychostimulants could still be worthwhile to
deal with Gleevec-brain; the difficulty might be in getting someone to
prescribe for you. I wouldn't try it if you have any propensities toward
addiction, nor if you have high blood pressure.
There is no definitive test for ADD, I'm afraid, though some of the tests
available can be helpful. You're best of consulting a doctor (usually a
psychiatrist) who is well versed in the condition. There are also are a
number of books that can be helpful in helping you sort out whether it's ADD
or not. One that I used to recommend a lot was "Driven to Distraction," by
Edward Hallowell, but there are other, newer (and better? I'm not sure) ones
as well.
This is a topic I posted on a couple of years ago on Rob's list; I'll see if
I can find the post.
Cheers,
Richard R

Hope your new year is better Susie.
I seem to be having the same trouble, I guess. Not
sure where we are going from here. My counts are all
low. Seems like 400 mils a day is too strong for my
system. I am on weekly blood tests. I go on Tue next
week, and we will know then.. If my WBC goes much
lower than its present 3.1k and my platlets at 17k
and with low Hem I am cold all the time. I do not
know if they will keep me on Gleevec or tansfuse me..
I guess with me having CML so long they are playing
around.. I am on two month PCR testing..Interesting
ride I must say.. So I await your next post to see how
thngs are going with you ... To you and all the rest
of the group a very happy healthy new year from Nova
Scotia
Skipd

Hi all well here we are at the end of 2005. Well for all who new that
i went off Gleevec at the end of November, i spoke to Tim Hughes this
morning and he mentioned that my qpcr went from .174 to .2 in three
days and he is alittle concern what its done for the month that ive
been off. Im having
a blood test on tuesday and he is gonna push it through and hopefully
ill have results in two weeks. He said ive got two options. one is I
can stay off Gleevec and go up to 35% and be avaliable for the new
drug or he has spoken to a american friend of his who is a doctor with
cml and he also cant tolerate the drug so he has two months on and one
month off. Ill have to see not really sure what i want to do at this
stage. Fingers X but im gonna put it at the back of my mind and enjoy
the rest of 2005 and survive the New Year without side effects of
Gleevec. Ill keep you posted.
Merry Christmas to all and hope you all have a happy and safe New Year.
Susie Off Gleevec
Dx Nov 02

December 27, 2005
Preventing Cancer
Slowly, Cancer Genes Tender Their Secrets
By GINA KOLATA
Jay Weinstein found out that he had chronic myelogenous leukemia in
1996, two weeks before his marriage.
He was a New York City firefighter, and he thought his health was great.
He learned that there was little hope for a cure. The one treatment
that could save him was a bone marrow transplant, but that required a
donor, and he did not have one. By 1999, his disease was nearing its
final, fatal phase. He might have just weeks to live.
Then, Mr. Weinstein had a stroke of luck. He managed to become one of
the last patients to enroll in a preliminary study at the Oregon
Health & Science University, testing an experimental drug.
Mr. Weinstein is alive today and still taking the drug, now on the
market as Gleevec. Its maker, Novartis, supplies it to him free
because he participated in the clinical trial.
Dr. Brian Druker, a Howard Hughes investigator at the university's
Cancer Institute, who led the Gleevec study, sees Mr. Weinstein as a
pioneer in a new frontier of science. His treatment was based not on
blasting cancer cells with harsh chemotherapy or radiation but instead
on using a sort of molecular razor to cut them out.
That, Dr. Druker and others say, is the first fruit of a new
understanding of cancer as a genetic disease. But if cancer is a
genetic disease, it is like no other in medicine.
With cancer, a person may inherit a predisposition that helps set the
process off, but it can take decades - even a lifetime - to accumulate
the additional mutations needed to establish a tumor. That is why,
scientists say, cancer usually strikes older people and requires an
element of bad luck.
"You have to get mutations in the wrong place at the wrong time," Dr.
Druker says.
Other genetic diseases may involve one or two genetic changes. In
cancer, scores of genes are mutated or duplicated and huge chunks of
genetic material are rearranged. With cancer cells, said Dr. William
Hahn, an assistant professor of medicine at Harvard Medical School,
"it looks like someone has thrown a bomb in the nucleus."
In other genetic diseases, gene alterations disable cells. In cancer,
genetic changes give cells a sort of superpower.
At first, as scientists grew to appreciate the complexity of cancer
genetics, they despaired. "If there are 100 genetic abnormalities,
that's 100 things you need to fix to cure cancer," said Dr. Todd
Golub, the director of the Cancer Program at the Broad Institute of
Harvard and M.I.T. in Cambridge, Mass., and an oncologist at the
Dana-Farber Cancer Institute in Boston. "That's a horrifying thought."
Making matters more complicated, scientists discovered that the
genetic changes in one patient's tumor were different from those in
another patient with the same type of cancer. That led to new
questioning. Was every patient going to be a unique case? Would
researchers need to discover new drugs for every single patient?
"People said, 'It's hopelessly intractable and too complicated a
problem to ever figure out,' " Dr. Golub recalled.
But to their own amazement, scientists are now finding that untangling
the genetics of cancer is not impossible. In fact, they say, what
looked like an impenetrable shield protecting cancer cells turns out
to be flimsy. And those seemingly impervious cancer cells, Dr. Golub
said, "are very much poised to die."
The story of genes and cancer, like most in science, involves many
discoveries over many years. But in a sense, it has its roots in the
1980's, with a bold decision by Dr. Bert Vogelstein of Johns Hopkins
University to piece together the molecular pathways that lead to cancer.
It was a time when the problem looked utterly complicated. Scientists
thought that cancer cells were so abnormal that they were, as Dr.
Vogelstein put it, "a total black box."
But Dr. Vogelstein had an idea: what if he started with colon cancer,
which had some unusual features that made it more approachable?
Colon cancer progresses through recognizable phases. It changes from a
tiny polyp, or adenoma - a benign overgrowth of cells on the wall of
the colon - to a larger polyp, a pre-cancerous growth that, Dr.
Vogelstein said, looks "mean," and then to a cancer that pushes
through the wall of the colon. The final stage is metastasis, when the
cancer travels through the body.
"This series of changes is thought to occur in most cancers, but there
aren't many cancers where you can get specimens that represent all
these stages," Dr. Vogelstein said.
With colon cancer, pathologists could get tissue by removing polyps
and adenomas in colonoscopies and taking cancerous tumors in surgery.
Colon cancer was even more appealing for such a study because there
are families with strong inherited predispositions to develop the
disease, indicating that they have cancer genes that may be discovered.
So Dr. Vogelstein and his colleagues set out to search for genes "any
way we could," Dr. Vogelstein said. Other labs found genes, too, and
by the mid-1990's, scientists had a rough outline of what was going on.
Although there were scores of mutations and widespread gene deletions
and rearrangements, it turned out that the crucial changes that turned
a colon cell cancerous involved just five pathways. There were dozens
of ways of disabling those pathways, but they were merely multiple
means to the same end.
People with inherited predispositions to colon cancer started out with
a gene mutation that put their cells on one of those pathways. A few
more random mutations and the cells could become cancerous.
The colon cancer story, Dr. Druker said, "is exactly the paradigm we
need for every single cancer at every single stage."
But scientists were stymied. Where should they go from there? How did
what happens in colon cancer apply to other cancers? If they had to
repeat the colon cancer story every time, discovering genetic
alterations in each case, it would take decades to make any progress.
The turning point came only recently, with the advent of new
technology. Using microarrays, or gene chips - small slivers of glass
or nylon that can be coated with all known human genes - scientists
can now discover every gene that is active in a cancer cell and learn
what portions of the genes are amplified or deleted.
With another method, called RNA interference, investigators can turn
off any gene and see what happens to a cell. And new methods of DNA
sequencing make it feasible to start asking what changes have taken
place in what gene.
The National Cancer Institute and the National Human Genome Research
Institute recently announced a three-year pilot project to map genetic
aberrations in cancer cells.
The project, Dr. Druker said, is "the first step to identifying all
the Achilles' heels in cancers."
Solving the problem of cancer will not be trivial, Dr. Golub said.
But, he added, "For the first time, we have the tools needed to attack
the problem, and if we as a research community come together to work
out the genetic basis of cancer, I think it will forever change how we
think about the disease."
Already, the principles are in place, scientists say. What is left are
the specifics: the gene alterations that could be targets for drugs.
"We're close to being able to put our arms around the whole cancer
problem," said Robert Weinberg, a biology professor at the
Massachusetts Institute of Technology and a member of the Whitehead
Institute. "We've completed the list of all cancer cells needed to
create a malignancy," Dr. Weinberg said. "And I wouldn't have said
that five years ago."
The list includes roughly 10 pathways that cells use to become
cancerous and that involve a variety of crucial genetic alterations.
There are genetic changes that end up spurring cell growth and others
that result in the jettisoning of genes that normally slow growth.
There are changes that allow cells to keep dividing, immortalizing
them, and ones that allow cells to live on when they are deranged;
ordinarily, a deranged cell kills itself.
Still other changes let cancer cells recruit normal tissue to support
and to nourish them. And with some changes, Dr. Weinberg said, cancer
cells block the immune system from destroying them.
In metastasis, he added, when cancers spread, the cells activate genes
that normally are used only in embryo development, when cells migrate,
and in wound healing.
But so many genetic changes give rise to a question: how does a cell
acquire them?
In any cell division, there is a one-in-a-million chance that a
mutation will accidentally occur, Dr. Weinberg notes. The chance of
two mutations is one in a million million and the chance of three is
one in a million million million million.
This slow mutation rate results from the fact that healthy cells
quickly repair damage to their DNA.
"DNA repair stands as the dike between us and the inundation of
mutations," Dr. Weinberg said.
But one of the first things a cell does when it starts down a road to
cancer is to disable repair mechanisms. In fact, BRCA1 and 2, the gene
mutations that predispose people to breast and ovarian cancer, as well
as some other inherited cancer genes, disable these repair systems.
Once the mutations start, there is "a kind of snowball effect, like a
chain reaction," Dr. Vogelstein said.
With the first mutations, cells multiply, producing clusters of cells
with genetic changes. As some randomly acquire additional mutations,
they grow even more.
In the end, all those altered genes may end up being the downfall of
cancer cells, researchers say.
"Cancer cells have many Achilles' heels," Dr. Golub says. "It may take
a couple of dozen mutations to cause a cancer, all of which are
required for the maintenance and survival of the cancer cell."
Gleevec, researchers say, was the first test of this idea. The drug
knocks out a gene product, abl kinase, that is overly abundant in
chronic myelogenous leukemia. The first clinical trial, which began
seven years ago, seemed like a long shot.
"The idea that this would lead to therapy was something you wrote in
your grant application," said Dr. Charles Sawyers, a Howard Hughes
investigator at the University of California, Los Angeles. "It wasn't
anything you believed would happen soon."
But the clinical trial of Gleevec, conducted at the Oregon Health &
Science University, U.C.L.A. and M. D. Anderson Cancer Center in
Houston, was a spectacular success. Patients' cancer cells were beaten
back to such an extent that the old tests to look for them in bone
marrow were too insensitive, Dr. Sawyers said.
Gleevec is not perfect. It is expensive, costing about $25,000 a year.
It is not a cure: some cancer cells remain lurking, quiescent and
ready to spring if the drug is stopped, so patients must take it every
day for the rest of their lives. And some patients are now developing
resistance to Gleevec.
Still, Dr. Sawyers says, "Seven years later, most of our patients are
still doing well." Without Gleevec, he added, most would be dead.
As for the future of cancer therapy, Dr. Golub and others say that
Gleevec offers a taste of the possible.
Dr. Golub said he expected that new drugs would strike the Achilles'
heels of particular cancers. The treatment will not depend on where
the cancer started - breast, colon, lung - but rather which pathway is
deranged.
"It's starting to come into focus how one might target the problem,"
Dr. Golub said. "Individual cancers are going to fall one by one by
targeting the molecular abnormalities that underlie them."
And some cancer therapies may have to be taken for a lifetime, turning
cancer into a chronic disease.
"Seeing cancer become more like what has happened with AIDS would not
be shocking," Dr. Golub says. "Does that mean cure? Not necessarily.
We may see patients treated until they die of something else."
That is what Mr. Weinstein hopes will happen with him. The cancer is
still there: new, exquisitely sensitive tests still find a few cells
lurking in his bone marrow. And Gleevec has caused side effects. Mr.
Weinstein says his fingers and toes sometimes freeze for a few
seconds, and sometimes he gets diarrhea.
But, he said, "Certain things you put out of your mind because life is
so good."

-Thanks so much for your email. I am looking forward to your chat this
evening. What time would that be in eastern time and where fo I go to
find it? Thanks again sherry t

This page was sent to you by: zmiller@....
My hero.
HEALTH | December 27, 2005
Preventing Cancer: Slowly, Cancer Genes Tender Their Secrets
By GINA KOLATA
Scientists are now finding that untangling the genetics of cancer is not
impossible and are basing new treatments on their findings.
http://www.nytimes.com/2005/12/27/health/27canc.html?emc=eta1

---I think the doc is being cautious which is why he'll do another
ultrasound at the end of January. If the problem still appears, I
imagine a needle biopsy would be ordered. In the meantime, I'm trying
to avoid touching the area as that bruises it, and makes me think it's
worse. Funny how we want to go after something like that! Please have
a great holiday, MJ

Dear CML Family,
While I don't post often, I wanted to let you know how special you all
are to me - and how much of a difference you continue to make in my
life - sharing information, resources - but mostly hope.
Sending each of you Christmas Blessings and love, light and HOPE!
Love,
Barbara Heathcote
Raleigh, NC

Hello Everyone,
The Plum pudding is steaming and the gingerbread goes very nicely with Chai
latte! It is hard to believe that the holidays are already here - where did
the month of December go?
I am off on retreat in Vermont and I hope to fit in some skiing too!
Save the dates for the two CML patient meetings in January:
January 28, 2006 in Montreal,chaired by Dr. Pierre Laneuville, along with
Suzan and I
January 29, 2006 in Toronto chaired by Dr. Jeffrey Lipton, along with Anita.
In the meantime I hope that Richard gets some skiing done, but I also look
forward to his "fireside" posts.
Happy Holidays Everyone!

Hi Nancy,
I learned about current dosing at the same lecture, but didn't get around to
writing down the schedule in my report. How come you're on a once-a-day
schedule?
Happy holidays, and say hi to my inlaws out there, if you see them.
Love,
Richard

Dear MJ
I'll be really surprised if these are chroromas, as these are very rare in
chronic phase CML (see http://www.medscape.com/viewarticle/514054_print).
So please enjoy the holidays as free from worry as possible - and let us
know what you find out.
Love,
Richard R

Hi MJ,
Chloromas are basicaly solid tumours made up of CML cells. They are
pretty rare. In all the years I've been on the lists, I think I've
only heard of two people having them and both were not in any type of
remission. They are a sign of advancing disease. There aren't
any "symptoms" per se, other than a lump and maybe some pain. I
believe treatment for chloromas is radiation.
Why don't they biopsy your masses to see what they're made of?
Take care,
Tracey

Hello Everyone:
The best of holidays for all of you whether Christmas, Hannukah, or
just a nice break.
I have two masses on one breast. The radiologst told me they might be
small hematomas which I'm prone to but he suggested chloromas. Anyway,
I return for another ultrasound in a month. How common are chloromas?
What are symptoms? Treatment if one is found? I think he thinks, and
I also that the chloroma diagnosis would not be it. He's pretty sure
it's not cancer.
Thanks for any insights, and Peace and Joy to you! MJ

Hi Susan,
I am sure Richard will provide more information. But, yes, T315I is
the only mutation for which there is currently no drug that inhibit
it's effects. Unchecked, this mutation can cause the cascade of
events leading to blast crisis. That is why patients are being given
a pre trial mutation screening. If you do have T315I, they usually
will not admit you into a trial, either with Dasatinib or AMN107.
Interestingly enough, we had heard at ASH that Dasatinib, and AMN107
may actually improve the effects of T315I, which is a really bad
thing. The good news is that there is current work on a molecule
that specifically addresses this mutation. For the majority of
patients who have had a good response on IM or Dasatinib, CCR or
better, the risks of developing this mutation are significanly
reduced.
Hope this helps,
Cheers,
Cheryl-Anne

Hi Richard,
The phase 2 trial that I started a month ago, (called Study 34 I think) is
a 4 arm
trial...........50mg BID or 100mg once a day or 70mg BID or 140mg once a day
I am on 100mg once a day.
Happy skiing to you......and I hope you have some time by the fire to keep
sharing all your learned with us.......Thanks.
love, Maui Nanc

Hi Folks,
Following is the fourth of five presentations from the Friday Corporate
Symposium sponsored by Bristol Myers Squib, which I began reporting on some
time back. This presentation was by Dr. Neil Shah of UCLA, on Treatment of
IM-Resistant CML. After this, and one more by Andreas Hochaus, I will then
have three more multi-speaker talks to go, along with a bunch of really
interesting ³poster sessions.² I apologize taking so long already. The idea
of reporting on all that remains seems daunting; however, I'm scheduled to
ski for five days after Christmas, and since the conditions in Maine then
are notoriously miserable (unless you¹re a teen) at this time of year, I¹ll
probably spend a lot of time by the fire working on my reports to y¹all.
Shah reviewed the fact that AMN107 (AMN, from now on) is chemically very
similar to IM from which it was derived, whereas Bristo Myers Squibb¹s
BMS354825 (dasatinib, or DS, for the purposes of this lazy typist) is
structurally unrelated to Novartis¹ drugs. Both AMN and DS are at least 2
logs (two powers of ten, or 100x) more potent than IM, so they offer hope
for effective treatment even in patients whose cells have learned to
over-express the bcr/abl enzyme (brief review: BCR/ABL is the CML cancer
gene [oncogene], whereas bcr/abl [in small letters] refers to the tyrosine
kinase enzyme that BCR/ABL codes for, and which actually causes all the bad
things in CML: increased growth and lifespan of the white cells, increased
mutation rate of these white, so that the disease becomes increasingly
cancerous, etc. For ease of typing, I¹m following the convention of many
authors nowadays, in referring to the BCR/ABL gene simply as ³BA² - though
I¹ll continue to refer to the enzyme as bcr/abl).
One reason for the increased potency of these new drugs is that they are
more ³tolerant² of bcr/abl¹s different shapes (called ³conformations² in the
biochemistry's quaint lingo): they bind to bcr/abl no matter whether it is
³open² (inactive), ³closed² (active), or in any intermediate stat. IM, by
contrast, only binds to the closed/active conformation.
In theory, DS offers even greater efficacy because it inhibits not only
bcr/abl, but also one of the kinases (one called src, and pronounced ³sarc²)
responsible for carrying out bcr/abl¹s downstream dirty work (Note: Shah
didn¹t address whether scr inhibition actually makes a difference clinically
nor did I find this out elsewhere at ASH. Do any of you know whether DS¹s
src-blocking has proven clinical utility?).
Shah mentioned a curious thing about the dosing frequency of dasatinib:
although DS has a half life of only a few hours (5-6 times shorter than IM),
it was initially given only once a day in Phase I trials. This means that
patients spent much of each day with very low serum levels, which would be a
total no-no with IM, where continuous serum levels above a certain threshold
are deemed absolutely necessary to avoid resistance. Whatever the reason
though, they a single dose for a while, and it seemed to work just fine. In
fact it worked as well and maybe even better than the twice a day dosage
schedule that was later adopted. I really don¹t understand why they began
with only a single daily dose, and would appreciate any insights any of you
may have. Maybe DS is so potent that it remains at a therapeutic level even
after several half-life periods have passed. But if this is the case, why
don¹t they just give patients much less of it, but spread it out during the
day to keep drug levels stable? Were they concerned about reduced
compliance?
A few other facts:
While AMN and DS treat most IM resistant mutations, they engender some new
resistances of their own. Surprisingly (given that DS and AMN are quite
different molecules), these resistance patterns are rather similar to one
another. The fact that IM is effective against many of the DS or
AMN-specific mutations and vice versa, is one of the rationales for trying a
combination of IM and one of these new drugs together. For more on this,
see the abstract (with Shah as a lead author) at the end of this post.
Similar to the IM experience, some patients on DS experienced low grade
elevations of their liver enzymes (AST, in particular) and of creatinine.
A new and somewhat more worrisome side effect is pleural effusion (fluid in
the lining of the lung) experienced by some patients. Jumping ahead of
myself though, I heard at one of the poster session that these effusions
resolve and don¹t tend to recur if you stop the drug for a couple of days,
give corticosteroids (like prednisone), and then restart.
Many IM resistant blast phase patients showed a response by DS, though as
expected, they shortly became resistant to this drug too (same with AMN).
The ³next frontier² is drugs that will treat T315I, which Shah called the
³Achilles heel of small molecule TK inhibitors.² None of the drugs that
have reached clinical trials show activity against this mutation, though
several compounds under investigation in vitro show promise (see my prior
post on IM resistance). Appropriately, some of these compounds have
mysterious, rather heroic names such as the ³Auror kinase inhibitor,² or
(for sci-fi techies), VX680.
OK, off we go with this one. Stay tuned for Andreas Hochaus on the
Potential for Combining Targeted Agents Against CML.
Cheers,
Richard R
______
[1093] Molecular Analysis of Dasatinib Resistance Mechanisms in CML Patients
Identifies Novel BCR-ABL Mutations Predicted To Retain Sensitivity to
Imatinib: Rationale for Combination Tyrosine Kinase Inhibitor Therapy.
Session Type: Poster Session 251-I
Neil P. Shah, John M. Nicoll, Susan Branford, Timothy P. Hughes, Ronald L.
Paquette, Moshe Talpaz, Claude Nicaise, Fei Huang, Charles L. Sawyers .
Medicine/Hematology-Oncology, The David Geffen School of Medicine at UCLA,
Los Angeles, CA, USA; Hematology, Institute for Medical and Veterinary
Sciences, Adelaide, New South Wales, Australia; Bioimmunotherapy, MD
Anderson Cancer Center, Houston, TX, USA; Bristol-Myers Squibb Oncology,
Princeton, NJ, USA
Point mutations within the BCR-ABL kinase domain represent the most common
mechanism of resistance to imatinib in patients with CML. Preclinical
studies have shown that dasatinib (BMS-354825) is effective at inhibiting
the kinase activity of imatinib-resistant BCR-ABL mutants with the notable
exception of the T315I mutation, which remains highly resistant to imatinib,
dasatinib, and AMN107 (Gorre et al, Science 2001; Shah et al, Science 2004;
Weisberg et al, Cancer Cell, 2005). Clinical data from Phase I and II
studies of dasatinib in CML confirms the in vitro findings. Each of three
imatinib-resistant patients bearing the T315I mutation (CP=1; AP=2) did not
achieve objective hematologic or cytogenetic responses during treatment with
dasatanib on a Phase I study. Additionally, each of two phase II patients
with the T315I mutation (CP=1; LBC=1) treated at UCLA showed no evidence of
objective response. We have also detected the T315I mutation in each of two
cases of acquired resistance in a phase II (LBC =2) study, and in seven of
nine patients with acquired resistance to dasatinib in phase I and II
studies (CP=1; MBC=3; LBC=2; Ph+ ALL=1).
Notably, we detected a novel BCR-ABL mutation, T315A, in one of the two
patients who relapsed without a detectable T315I mutation. The patient is a
53 year-old female whose chronic phase CML had progressed to myeloid blast
phase while being treated with imatinib. The imatinib-resistant mutation
M244V was identified prior to dasatinib treatment. The patient achieved a
major hematologic response (<5% blasts with partial recovery of peripheral
blood counts) on dasatinib 90 mg orally given twice daily, but relapsed with
MBC after six months. Sequence analysis of the BCR-ABL kinase domain at the
time of relapse revealed the presence of the imatinib-resistant mutation
M244V as well as the novel mutation T315A. This finding is of particular
interest because T315A and several other novel BCR-ABL mutations were
recently recovered in a saturation mutagenesis study designed to define
potential mechanisms of dasatinib resistance. Remarkably, many of these
mutations retain sensitivity to imatinib in vitro (Burgess et al, PNAS,
2005). Through periodic molecular monitoring of other dasatinib-treated
patients, we have identified a second novel BCR-ABL mutant, F317I, that
developed in an imatinib-resistant CP patient after 9 months of treatment.
Similar to T315A, F317I was isolated in the saturation mutagenesis screen
for dasatinib resistance and is predicted to retain sensitivity to imatinib.
Taken together, our findings implicate the T315I mutation as the principle
mechanism of resistance to dasatinib, but more importantly, strongly support
the use for combination kinase inhibitor therapy in CML to prevent emergence
of drug resistant clones. A phase I trial to assess the safety of combining
imatinib with dasatinib is planned.

Hi Richard,
Thanks so much for your diligence and thorough reports. Did you hear how soon
they may try a clinical with imatinib and dasatinib together? Also, I feel a
little foolish asking this but is T3151 a killer mutation? I've just always
heard or read it in the context of the boogey man. Since Richard's so busy, if
someone else can answer this, please do so.
Best wishes,
Susan L

Prescription Ills
Seniors in managed-care plans may pay much more for drugs
Rosalie Gregory sits in her kitchen, trying to figure out how she is going
to be able to afford co-pays for her leukemia medication under the new
senior drug plans.
MARTY BICEK/THE BEE
By KEN CARLSON
BEE STAFF WRITER
Last Updated: December 21, 2005, 05:06:50 AM PST
While it's touted as a cost-saving program for seniors and the disabled, the
Medicare prescription drug program is going to cost substantially more for
people enrolled in managed-care plans.
About 38,000 Medicare beneficiaries in Stanislaus and San Joaquin counties
buy health benefits through Kaiser Permanente's Senior Advantage or
Pacificare's Secure Horizons plan.
Those residents are being hit with increased premiums and co-payments. And
some, such as Rosalie Gregory of Ceres, will pay a lot more for lifesaving
medicines.
Gregory, who has Senior Advantage, said she paid $30 a month this year for
Gleevec, a drug that she takes for leukemia. The medication has put the
cancer in remission and she needs to keep taking it.
But it will cost her $3,700 next year, and her costs for medicines will go
from $640 to $4,024, her family says.
Gregory said she doesn't have the money.
"As senior citizens, we were all pumped up about how much we were going to
save with the Medicare drug program," she said. "It is not saving me
thousands of dollars; it is costing me thousands."
In 2004 and 2005, Senior Advantage provided unlimited coverage for gen-eric
medications, and covered the brand drug Gleevec as an exception. (The retail
price for Gleevec is upward of $2,700 for a month's supply.)
But Senior Advantage in 2006 is modeled after the new standard Medicare drug
plan, and that means Gregory has a coverage gap.
The Senior Advantage co-payments for generics will be $30 for a 100-day
supply, triple the previous co-payment, and $40 for a 30-day supply of brand-
name drugs.
If the cost of the drugs reaches $2,250 in a year, subscribers have to pay
full price until their out-of-pocket expenses total $3,600.
Above that, a "catastrophic coverage" is triggered, requiring monthly co-
payments of $3 for generics and $10 for brand drugs.
Senior Advantage members also are being hit with a premium increase from $50
to $96 a month, while the Secure Horizons premium is going from $54 to $68.
"Where is the savings?" asked Howard Olson, a Modesto retiree who takes
medication for his heart. "It is taking an extra $500 a year out of my
pocket."
Deductibles will be lower
Members of Senior Advantage and Secure Horizons, which also has the coverage
gap, were warned they would lose their regular health benefits if they
purchased one of the 48 Medicare drug plans available in Northern California.
Beside coverage for medicines, the health plans provide subscribers with a
network of doctors and hospitals and lower deductibles than the standard
Medicare program.
When Congress approved the Medicare prescription drug program, it created a
standard plan for insurers that would offer drug plans in different regions
of the country.
Jack Cheevers, a Medicare spokesman in San Francisco, said the managed-care
plans were required at least to match the standard plan, but can offer
enhancements, too.
"They can cover all or part of the coverage gap or offer lower premiums and
deductibles," he said.
Some of the stand-alone drug plans do not have the coverage gap. Those plans
generally have higher premiums than others, Cheevers said.
One plan offered by Humana, which does not have a coverage gap, covers 400
milligram Gleevec for a $60-a-month co-pay. The premium is just over $50 a
month.
Kaiser lists benefits
Denise Hanson, director of Medicare and state programs for Kaiser, defended
the changes made to Senior Advantage.
In the last two years, the plan did not cover brand drugs, and it provides
catastrophic coverage for people whose medication costs exceed $3,600 a
year, she said. Senior Advantage also doesn't have a $250 annual deductible
found in the standard Medicare drug plan.
"On the whole, it is an improved benefit," she said. An estimated 15 percent
of members would be affected by the coverage gap, she said.
She added that the increase in co-payments isn't so high for members opting
for Kaiser's mail-order pharmacy.
Gregory said she is applying to Kaiser's charity care program, but it
appears her annual retirement income of $21,000 is too high to qualify. The
family also is asking the drug's manufacturer for a break.
Geoffrey Cook, a spokesman for Norvatis Oncology, maker of Gleevec, said
that nonprofit groups offer assistance for people who can't afford the drug.
He cited research costs as the reason for the drug's cost.
Cheevers said financial assistance is available for low-income residents who
can't afford the coverage gap. Another option for someone like Gregory is to
purchase a more affordable drug plan and fall back on traditional Medicare
health coverage.
If Gregory dropped out of Senior Advantage, she would lose her Kaiser-
affiliated doctor. Under Medicare, her copayments for hospitalizations could
be $1,000 in a year. And her share of the costs for seeing physicians and
specialists would be higher.
The managed-care plans also have coverage for glasses and routine eye and
hearing exams.
Barbara Neer, a retired medical assistant in Modesto, said the new drug
program has been confusing even with her background in health care.
She and her husband, Richard, have struggled to find out if the medicines
they take are covered by their managed-care plan.
"They are doubling and tripling the cost, plus it is confusing for the
majority of people," Neer said.
Bee staff writer Ken Carlson can be reached at 578-2321 or
kcarlson@....

Hi Lisa:
Thank you so much for sharing your journey with us. I do not take
anything for ADD. After reading all the incredible difficulties you
have endured, I can't help but wonder if you are not suffering from
depression rather than ADD. You certainly have been dealing with
every major stress factor known to man and being overwhelmed and
having some confusion certainly could be depression as well. It is
certainly understandable and I doubt the average person could endure
all you have been enduring for such a long period of time.
You are an unbelievably strong person and I have great admiration for
your courage and fortitude. Have a Merry Christmas and know that we
are here for you.
Best regards,
Fred

Hi Lisa,
You don't actually mention what the symptoms you are talking about being on
the ADD list are? that might help. Gleevec does seem to have some mental
components to it.....like difficulty with word finding, memory, etc. That, in
addition to all the life stress that you have had......could have a big
impact on
you. There are supposed to be some more definite ways to dx ADD I think....
so if you want an answer, I would have a consult with the ?? right kind of
specialist. Dr. Phil has had several programs related to ADD and usually has
a person on who has supposed written the best book on the issue (from a
top facility).....maybe you would find that title on his website.
Also, if you haven't, I would consider working briefly with a counselor who
specializes in chronic diseases.......then discuss everything that has gone
on in your life. You have had way more that your share to deal with.....and
it is
remarkable that you are able to work full-time.
Best wishes to you,
Nancy C.

Does anyone on this list have ADD and take meds for it with Gleevec?
Just curious. I am taking a test currently since I believe I may be - or is
it just Gleevec brain? All the symptoms have just gotten worse over the last
few years. Or is it that it seems more obvious since I am aware of the ADD
symptoms?
I would love to be able to be able to feel normal - whatever that is....
I feel great physically... hardly any side affects after 4 and a half years
of Gleevec.
I have been on anti anxiety meds (xanax) for 5 years now and it helps for
the first few hours after each dose but could I have always had ADD?
I told the doctor that life has been a bit overwhelming for me for sometime
so that he doesn't just dx me with it without knowing all the facts.
I cared for my only sister who died of AIDS in 1994. Then my sister in-law
died and I have been raising 2 of her children since 1998. The youngest
doesn't even know I am not his real mom...Dx'd with CML in 2000, and lost my
son at age 18 in 2002.
I have had to work full time during all of this since the man I have been
married to for 26 years (the father of my biological children) has been an
alcoholic and unable to provide for any one other than the industry that
makes his alcohol...I thought he would have saw the light after loosing our
son but life is even darker for him now - he just drinks even more.
I guess I am confused since I am really not sure if I am ADD or if all of
life's events have just had some additional affects on me.
Trust me as hard as all this has been for me, I have been blessed to find
the will and a reason to get up and keep on keeping on. And no it hasn't
been easy.
I hate to be diagnosed with one more thing but all the symptoms on the check
list for ADD- I have. And it sure would be nice to feel some what normal if
I could.
I guess my real question is: do we know of any problems mixing the 2
medicines? (Gleevec & ADD meds)
Feel free to write me off list if you want or post to the group. Whichever
you choose is fine with me.
Who knows maybe I am not the only one who feels overwhelmed and confused all
the time. Magnesium was helping out for a while, but not anymore.
Thank you and happy holidays to everyone!
Lisa Martinez

Hi K,
While it's true that your PCR results are questionable since it took
48 hours to process (that amount of time can certainly downgrade the
sample) but nevertheless, the results are outstanding! Lets hope
that in 3 months, you'll be able to do another test, hopefully
processed quicker and with the same outstanding results.
Congratulations!! It seems that at least one of your "terminal
illnesses" is completely under control!
As for the other group, well unfortunately, Nancy, Zavie and myself
were banned from it. This of course means that we cannot post
there. I guess you could say that being banned from there was the
catalyst for starting this group here.
Congratulations again on great results,
Tracey

Hey Cheryl, Tracey, Nancy, & Zavie + 2:
I have been looking for some of you for a long time, I found the other support
group through my 'brother' in a cancer chat earlier this year.
With all my fatal/terminal diseases; I was dubbed . . ."Queen of the Side
Effects". . . by one of you. Back then, you guys became my Heroines & Hero.
Your survival pre our gold, becoming "0", and some of you PCRU were goals that I
set for myself after the morbid mortality rate given to me 12/18/03 after my
diagnosis. No matter what I asked, one of you always gave me the answer and
boosted my spirits. I found out I was "0/Negative" in 12/04.
My results for my 1st RT-PCR are worthless, the technician waited over 48
hours but it was 0.00136. I was looking for some information and found an old
email from one of you giving me information Ana had put together to help us
understand the test.
btw Zavie, I don't need you to answer the email I sent to you earlier.
"THANX" Heroines & Heroes . . . for being there for me when I really needed
you. . . you are needed in the other group now for the Newbies. I know I was
very fortunate to have had you all there for me.
"K"
"I AIN'T FINISHED YET"!!!

Targeting T315I
Here is a synopsis of Steven Burleigh (of SGX Pharmaceuticals) presentation at
last Tuesdayâs symposium on IM Resistance, which I mentioned in an earlier
post. The subject was this companyâs search for compounds that zap CML cells
containing the villainous mutant, T315I, but also wild type (unmutated) bcr/abl
containing cells.
Let me say first that the tools and techniques for drug discovery which
Burleigh discussed are nothing short of dazzling, orders of magnitude superior
in sophistication and speed to what was available just a few years back. Whereas
it took about 4 years of work to determine the exact structure of the bcr/abl
oncoprotein, these folk are able to characterize similar kinases (and their
mutant forms) in weeks or months â and design a range of potential drugs to
block them in an equivalently short time.
In fact, because they can do it so fast, Burleighâs group is working
simultaneously all the resistant mutations in Michael Deiningerâs libarary of
bcr/abl kinase domain mutants, but since the T315I mutant causes the greatest
mischief, theyâre focusing on this one particularly.
They have come up with several potential drugs, at least a couple of which show
similar potency as AMN to wild-type BA (bcr/abl), as well as substantial
activity against IM, DS or AMN-resistant T315I. In fact, their most promising
compound targets all the known kinase domain mutations except E255b. Since this
mutation occurs at a very low rate - less then 2% - this should not be of much
concern.
In order to bring these compounds quickly to trial, they use a very clever
method for assessing how toxic each is likely to be by testing against all the
kinases in the human âkinomeâ (the library of all 518 known normal human
kinases â see www.sciencemag.org/cgi/data/298/5600/1912/DC2/1 for a lovely
picture of the âevolutionary treeâ of these kinases), and seeing which ones
it inhibits. Their favorite candidate inhibits 16 of the 518 known kinases, but
as this less than is seen with the existing CML drugs, they are quite confident
that the toxicity of theirs will be minimal. Interestingly, none of their
compounds target C-Kit or PDGFR. At least one of them targets FLT3, however,
which makes it a potential candidate drug for treating AML.
SGX Pharmaceuticals is âbuilding in all the drug-like properties they needâ
to move these compounds toward trial. Their goal is to submit their IND
(investigational new drug) application by the end of 2006, starting with
patients who are resistant or intolerant of the others three STIs. This might
seem long if you have a T315I mutation, but itâs warp speed compared to what
would have been possible only a few years ago.
Assuming they can turn these compounds into effective drugs which pass the FDA
gauntlet, SGXâs hope is that they will be used in combination with one of the
existing STIâs as first-line therapy, to prevent and/or treat resistance.
Burleigh compared this strategy to that of multi-drug anti-retroviral therapy
for HIV/AIDS.
Naturally SGX is hoping eventually the use of their drug for other indications
besides CML as IM is used for GIST, hypereosinophilia syndrome, etc. They are
actively seeking collaboration with other partners for further development.
Cheers,
Richard R

Hi all.
I just returned from MDAnderson. It was a whirlwind trip - as
getting there was quite challenging. The Houston airport closed
(which is rare) on Wednesday due to very bad storms and flooding - so
I was delayed by about three hours in getting there.
All went well - as usual and it was an uneventful trip.
However, I spoke with Dr. Giles yesterday and he wants me to get the
word out to the CML community. He opened a new trial yesterday for
CML patients that have lost their response to Gleevec . . . (maybe
someone who is FISH positive, or is no longer negative on cyto). He
is looking for recruits if anyone has the need. The trial consists
of combining Gleevec with the new AMN107 compound. It sounds very
exciting and is yet another option for all of us.
More exciting however, is the VX trials - which I believe Anjana has
posted about on the Asian list. Dr Giles said it shows incredible
promise for eradicating the dreaded T3151 mutation - that to date -
no other compound appears to have any effect on. He is recruiting
for this trial as well.
If you have any interest, you can contact his PA - Mary Alma Welch at
mawelch@.... You can also reach her at MDAnderson via the
leukemia clinic - at 713-792-8760.
This is an amazing time for CML patients - with many options to look
at should we need it!
I'll continue to keep you all posted on my results. It was a
delightful time to be at the hospital. Everything was awash in
Christmas and holiday finery. Each floor was decorated with holiday
decorations, carolers were singing and even 'Santa' visited in the
bone marrow clinic - handing out candy canes, cookies and juice. It
made a difficult day much more tolerable. The facility truly goes
out of their way to make every patient feel special!
Hugs to all of you!
Love,
Barb

Hi, friends.
Iâm going to begin discussing abstracts from the most interesting CML-related
âposter sessionsâ at ASH. Ideally I would group these by topic, but Iâm
not that organized so Iâll take them as I found them.
Iâve posted the first abstract below in its entirety. As I go along Iâll
see whether or not this format makes sense.
These authors are seriously French (note the term âlymphoblatique leukemiaâ
â though I only wish my French was as good as their English), so I had a bit
of interpreting to do. If I understand them correctly, it appears that they may
have come up with a reliable method for measuring serum levels of IM (Gleevec).
This is important because, Novartisâ assurances to the contrary, itâs not
true that âone dose fits all.â Itâs quite likely that some cases of
apparent IM resistance are really due to patientsâ failure (for whatever
reason) to achieve adequate serum levels if the drug, while others have to stop
or reduce their IM intake due to toxicity. It would be nice to know who has
levels that are too high or to low so we we can adjust the dose without risk of
resistance or toxicity. For reasons known only to themselves, Novartis has
refused to release their method for ascertaining serum levels from the start, so
itâs nice that others are developing alternatives.
Interestingly, five patients in this study who had had less than ideal
responses were found to have low blood levels of IM. There were pretty
straightforward reasons for this in every case, and once the problem was
recognized they were probably quite easily corrected (though the authors donât
say so). Three of them were on seizure medicines which increased the rate of
metabolism of IM â which reminds me that several years ago a patient on
Robâs list found themselves in a similar boat; it was with considerable
satisfaction that we, the amateurs, the patients, helped them figure out the
problem and correct it.
The technique used here for measuring IM level seems pretty esoteric to me
(itâs the same as is used in astrophysics for measuring the composition of
stars, if I remember correctly). Iâd rather Novartis would just release their
method to commercial labs so we could all use it. Oh well, maybe somedayâ¦
Regards,
Richard Rockefeller

In a message dated 12/15/2005 2:49:09 P.M. Eastern Standard Time,
yrulooknback@... writes:
dropped lower again but my anc count it still OK so
Sheila, I know how you feel. It took me a year and a half to gain a good
remission. That was 5 years ago and I'm still here, so don't freak out. As many
people in the past have mentioned on the groups, this disease is a roller
coaster ride. One minute you're up, next your down, then up again. It takes
patience and of course, lots of courage and mind games, but you can do it.
Someone once told me to imagine the Gleevec as little soldiers that go into
your bone marrow and kill off the evil cells.
As far as all those people dying in the town, I had the same thing happen.
My husband died 2 years before my diagnosis at age 43 of small cell carcinoma.
15 people in our neighborhood (former neighborhood): 4 Leukemias, 4 small
cell carcinomas, 3 breast, 2 prostate, and 2 cervical. Most under the age of
45. So, I can understand how you feel.
Also, you are the second person this week to tell me that they lost their
dog. And the dog died of leukemia of all things!! Well, I told her what happened
with us, when we lost ours. It was terrible because she was like our child.
I know it sounds heartless to say it, but the thing I did was to go right
out and get a puppy. I told my friend that, and tonight she called me to say
her husband surprised her with an early Christmas present. When she got home
there was a little black lab waiting for her in the kitchen! She told me she
still cries over the loss of her ZuZu, but this precious little pup has her
crying for joy.
I have two of my own and I don't know what I'd do without their love, and
company.
So, "freak out", you're definitely one of "us" now, and know that as far as
I'm concerned, I can say I understand you and know what you are going through.
We are all here for a common purpose, and that is to lend support and to
"talk" it through, especially rough times. Hang in there, and any time you want
to "talk" just give me an email, even privately if you'd like. Hugs, Lynne
Andrews

Join in for a discussion on this evenings teleconference on
Current Progress in CML Therapy: Outlook from a Panel of Experts
If you haven't registered for the conference, you can still join in by
calling 1-877-407-8037 . It starts at 8:00 PM EST

Hi, fellow CMLers,
I¹m going to jump forward to some talks that were given today because
they¹re still fresh with me and also really interesting. It was a session
on IM resistance with 6 different speakers, though I only heard 5 of them.
Jeez, these researchers are smart people! I think if I were to start all
over I¹d go into cancer research, just to hang out with folks like this
(also because cancer research is getting more and more interesting. Also
treating cancer patients is more fun than it used to be because there¹s so
much more one can do for them, and the future is even brighter. My
oncologist friend used to be a gloomy lot, for good reason; they seem a lot
happier nowadays!
The first talk was by the ubiquitous Michael Deininger. Unfortunately I got
there a bit late, and the part of his talk I caught didn¹t tell me anything
new, beyond what I¹ve already reported.
Next we heard from Brian Skaggs, from UCLA. He had some really interesting
stuff to say about the many kinase domain mutations that have been
identified to date. Some of these not only confer resistance to IM, but
also greater ³fitness² compared to non-mutated BA (that¹s BCR/ABL, in my
shorthand, remember?). Two mutations, T315I and E255, in particular, confer
growth and/or survival advantages which allow their cells to take over from
the cells with wild-type (un-mutated) BA. T315I and E255 are, by definition,
more transformed, i.e. more cancerous than the wild-type (WT) cells, so
folks unlucky enough to get them have to contend with a double whammy.
Interestingly, these are among the only mutations that show up in patients
with any frequency PRIOR to starting IM which makes perfect sense given
their growth advantages. By contrast, none of the many mutations which show
reduced fitness show up before IM treatment; they undoubtedly occur, but
their host cells die out because they are out-competed by WT cells.
Finally, there¹s a set of mutations with approximately equivalent fitness as
WT cells, and as you might expect, they show up but only occasionally - in
the cells of ³IM naïve² patients. Am I being at all clear here? I hope so,
because this stuff is worth understanding. It¹s pretty cool, actually
unless you happen to be unlucky enough to have one of the bad mutations. If
you are, read on, because there¹s hope for you too.
Skaggs mentioned one more thing I had known but forgotten: that IM only
binds BA in its inactive conformation. Not surprisingly therefore, most IM
resistance mutations occur in sites that hold BA in the active conformation,
to which IM can¹t bind. By contrast dasatinib (DS) binds the kinase domain
in both active and inactive states which makes it more potent (it can bind
more of the time), AND explains why DS overcomes many IM resistance
mutations: it can still bind even when these mutations hold the domain
closed/inactive. The only kinase domain mutations affecting DS binding are
those which affect drug contact with BA. This is all very slick, albeit
sinister (and, btw, requires no intelligent designer, for those of you
interested in that debate).
How come some mutations confer greater fitness on their host cells? The
answer in most cases is that these mutations increase the enzymatic potency
of BA that is, they can phosphorylate more downstream enzymes in less
time, so they crank up cell growth and inhibit cell death even better (or
worse, from our point of view) than their wild-type ancestors. Other
mutations don¹t make the kinase more potent, but turn it into a better
³transformer² by becoming a better autophosphorylator but here he kind of
lost me, I¹m afraid.
Phew! OK, on to Mary Copland in Tessa Holyoake¹s lab, on combination therapy
for targeting quiescent cells a matter of great interest to those of us
lucky enough to have reached high-grade molecular responses (a 3 log
reduction or better in qPCR), as most of our remaining cells are presumably
of the quiescent BA+ stem cell variety. Dr. Holyoake¹s lab has previously
shown these cells to be insensitive to IM, as well as to the newer STI¹s,
AMN107 and DS. Why they¹re insensitive is not yet known, but Dr. H¹s lab
and others are hard at work on that. While we wait to find out, it would be
nice to be able to kill these cells though, and that¹s what this study is
about.
Last June, Dr. T et. alia, published a paper showing that one of the
farnesyl transferase inhibitors (FTIs) in combination with IM could
eliminate quiescent stem cells (again, because I¹m a lazy typist I¹ll call
them Qs from now on) better than IM alone; much better, in fact, because it
turns out that IM not only fails to kill Qs, it actually increases their
numbers, presumably by driving some of the dividing stem cells into the
quiescent state.
Dr. H then decided to poke around in the library of FTIs and see if any of
these could do a better job than lornafarnib, the one they tried last year.
Low and behold there is one: BMS 214662 (B662 from now on no way I¹m
typing that long string!). Turns out that in combination with either IM or
DS, this handy little molecule reduces the Qs to nearly zero - at least in
the test tube. Mouse studies to follow, then hopefully human studies.
A couple of other points made here:
Some FTI¹s only inhibit cell growth, while others actually kill cells.
B662 is of the latter type, and Dr. H¹s studies show that all by itself it
³reaches down² farther into the stem cell compartment than IM does. That is
to say, B662 can kill some cells that IM cannot, even all on its own.
B662 appears to be effective against cancers other than CML, which makes
it MUCH more likely that this compound will be developed because the market
could be substantial.
The combo of IM plus B662 kills Q cells better (in the test tube anyway)
than does DS plus B662. This is interesting given that DS is more effective
at CML cell killing generally.
They don¹t yet know how B662 kills Qs, but they¹re working on it.
They tested B662 on normal white blood cells and found a little toxicity,
but less than from either IM or DS! Of course the question will be whether
the toxicity will be tolerable when these drugs are used together, not just
separately.
Next, Ellen Weisberg talked about combining AMN107 and IM in the treatment
of CML. Though members of the audience questioned some of her results, Dr.
Weisberg appears to have shown that their combined effect is at least
additive, and may actually be synergistic (greater then the sum of the
parts, that is). If this is true, or even if the combo is ONLY as effective
as either agent alone, she argued that combining them may a) suppress
emergence of resistant cells and b) reduce side effects. This work is early,
but it looks promising.
Mary Copland again, this time looking at why Qs are insensitive to IM, AMN
and DS. There are three possibilities: 1) not enough of the drug is getting
into the cells to inhibit BA; 2) enough is getting in and BA is being
inhibited, but Qs aren¹t dependent on BA for survival; 3) enough is getting
in but BA has these cells have developed resistance mutations.
If (1), then the trick is to get more drug into the cells; if (2), then we
need to develop other strategies to kill these cells (using an FTI, for
example); if (3), then we need to figure out the resistance mechanism and
overcome it.
I don¹t think I can explain the supporting data (I didn¹t understand a lot
of it myself), but I think they¹ve concluded that these drugs are probably
getting into the cells just fine, but that BA is being overexpressed. This
isn¹t the whole story though: if overexpression was the only difference
from regular CML cells, then increasing the drug level should kill the Qs.
However, it doesn¹t, so it must also be true that these cells are not
³addicted² to BA as more mature Phillies are.
A couple more points of interest:
As noted above, both IM and DS increase the total number of Q cells, but
listen to this: DS + IM together increase Q cells even more!! It seems to
me that this kind of argues against combo therapy, at least until we find
out how to kill the Q cells.
BA and IM increase the number Q cells by 1-2 logs - quite a lot, really.
The last talk is the one I wrote to Tracey about earlier. It was by Steven
Burleigh of SGX Pharmaceuticals on finding compounds that zap both wild type
and and 315 BA CML cells. More about that when I get the time. Good night
for now,
Richard R

Hey Richard & Cheryl . . .
Thanx for all the information from the ALS, we appreciate if very much.
"K"
"I AIN'T FINISHED YET"!!!

Hey folks - I sent this yesterday, but it didn't seem to go though.

SGX Pharmaceuticals Presenting Data at American Society of Hematology Annual
Meeting on Inhibitors of Wild-Type and Gleevec(R)-Resistant BCR-ABL Kinase
Tuesday December 13, 9:00 am ET
SAN DIEGO, Dec. 13 /PRNewswire/ -- SGX Pharmaceuticals announced that it
will present data today at the American Society of Hematology's 47th Annual
Meeting and Exposition showing that compounds discovered by applying its FAST
(TM) lead discovery platform potently inhibit wild-type and Gleevec-
resistant BCR-ABL, including the most clinically challenging mutation T315I.
The clinical success of Gleevec has demonstrated that BCR-ABL kinase
inhibitors can provide effective treatment of Chronic Myelogenous Leukemia
(CML). However, some patients develop resistance to Gleevec therapy, which
occurs due to point mutations in the BCR-ABL kinase and there is currently
no approved pharmaceutical treatment for such Gleevec-resistant CML.
Although effective against many of the other clinically relevant mutants,
second-generation BCR-ABL inhibitors currently in clinical studies have not
been shown to inhibit T315I, which represents about 20 percent of clinically
observed mutations and is one of the most common causes of resistance to
treatment with Gleevec.
During an oral presentation in the session entitled "Chronic Myelogenous
Leukemia: Molecular Mechanisms of Disease and Resistance" taking place today
at 9:45 a.m., Stephen K. Burley, M.D., D.Phil., SGX Pharmaceutical's Chief
Scientific Officer and Senior Vice President, Research, will present in
vitro and in vivo data showing that compounds in SGX's most advanced lead
series potently inhibit proliferation of K562 cells and Ba/F3 cells with
wild-type BCR-ABL and most clinically-relevant mutations, including T315I.
SGX expects to file an IND in late 2006 to permit clinical development of a
compound from its lead series of BCR-ABL kinase inhibitors for treatment of
drug-resistant CML.
About SGX Pharmaceuticals
SGX Pharmaceuticals (SGX) is a biotechnology company focused on the
discovery, development and commercialization of innovative cancer
therapeutics. More information can be found at www.sgxpharma.com .

Hi Richard -- Add my thanks to those of others for your ASH reports.
I'm enjoying reading your posts & appreciate the time you are taking to
fill us in on all the news.
best wishes,
Kathy

Hey Sheila:
Don't "FREAK OUT! ! ! I think my counts could possibly be Guinness Book
material; and I was never taken off the gold after diagnosis except for surgical
procedures. My dosage was 400 mg Daily, no matter . . . 'side effects' etc.
My dosage was upped to 600 mg later which was too much; after adjusting to the
gold, I've taken 300 mg daily for over 1 1/2 years.
btw. . . WELCOME to the Group, I didn't find until I had reached "0". Your
sister & brother survivors are here for you. Don't hesitate to post any and all
questions and/or concerns. We're here for you; and been there/done that.
All are in my prayers. . .
"K"
"I AIN'T FINISHED YET"!!!

That last post of mine looked so jumbled that I'm sure few were able
to follow it :( Unfortunately, it didn't come out as clean as I had
written it on my computer (where I used different colours to
differenciate between Richard's words and my own, so here goes a
better, easier to read post.
Once again, thank you Richard so much for taking the time to share
all of this with us. I have a few comments on this latest report:
What an exciting thought! I hope it pans out to be that we can
actually halt the progression of CML. Wow, the thought of it just
makes me want to jump :)
Measuring phosphorylation of CRKL sounds like it could be of such
important clinical value (if they actually measured it in patients).
Any idea why they aren't doing it?
Was there any news on the new drug that was rumoured to be in trials
(or soon to be in trials) that specifically targets the T315I
mutation?
When you talk about the 30% of medication that isn't taken, do you
mean that people aren't consistant with taking their Gleevec (some
days they take it, others they don't) or that they'll take half as
much as they're supposed to? Or perhaps both? We can't always blame
the patients either (unfortunately), it seems that there are still
some doctors out there who aren't familliar enough with Gleevec and
are still playing around with sub theraputic doses or playing the
intermittent game (take it when you feel like it or don't take it if
you don't feel like it etc).
Also, how did they come to this conclusion? Is it from interviewing
patients or by comparing written prescriptions with orders put in by
the pharmacies? Sounds kinda high to me, so I wonder what criteria
they used to form this conclusion. Is someone who missed one dose in
6 months considered to be non-complient or does it take a couple of
doses? I just wonder how they define "poor adherence".
With much appreciation for your time and insight,
Tracey

Reminder Tuesday 9:00 PM EST

Hi Jackie,
Here are 4 CMLers from Melbourne. All members of the Zero Club. Hope to
assign you a number pretty soon.
Zavie
310 George Nearchou gnearchou@...
Melbourne AU
590 Cindy LOUEY CINDYLOUEY@...
Melbourne AU
699 Judy Telford judi@...
Melbourne AU
825 Peter Howlett hottuna@...
Melbourne AU

Once again, thank you Richard so much for taking the time to share all of this
with us. I have a few comments on this latest report:
Richard Rockefeller <rrockef1@...
whether we can stop clock of CML progression with IM, or just delay it (note
from me: the pendulum of belief is clearly swinging toward believing that we can
stop it.
What an exciting thought! I hope it pans out to be that we can actually
halt the progression. Wow, the thought of it just makes me want to jump :)
⢠Weâre getting better at predicting relapse. One way is by following the
phosphorylation of CRKL (pronounced âcrackleâ) â one of the enzymes that
bcr-abl works on downstream by putting a phosphate group onto it. When
phospo-CRKLstarts going up, you know that bcr-abl is no longer being inhibited.
Iâm not sure what clinical utility this has (I donât know of any docs
measuring phospho-CRKL on their patients), but it was interestingâ¦
This sounds like it could be of such important clinical value (if they
actually measured the phosphorylation). Any idea why they aren't doing it?
Unfortunately, one relatively common mutation, called T315I (how annoying
these names can be!), is a real baddie: it not only confers resistance to IM,
desatinib and AMN107, but it heralds advancing disease.
Was there any news on the new drug that was rumoured to be in trials (or soon
to be in trials) that specifically targets this mutation?
⢠Novartis believes that a critical factor in IM resistance is poor adherence
by patients. According to them, some 30% of the medication prescribed is not
actually taken.
Do you mean that people aren't consistant with taking their Gleevec (some days
they take it, others they don't) or that they'll take half as much as they're
supposed to? Or perhaps both? We can't always blame the patients either
(unfortunately), it seems that there are still some doctors out there who aren't
familliar enough with Gleevec and are still playing around with sub theraputic
doses or playing the intermittent game (take it when you feel like it or don't
take it if you don't feel like it etc).
Also, how did they come to this conclusion? Is it from interviewing patients
or by comparing written prescriptions with orders put in by the pharmacies?
Sounds kinda high to me, so I wonder what criteria they used to form this
conclusion. Is someone who missed one dose in 6 months considered to be
non-complient or does it take a couple of doses? I just wonder how they define
"poor adherence".
With much appreciation for your time and insight,
Tracey

Hi again, friends. Cheryl-Anne and Suzan left this afternoon, so Iâm your
only remaining ASH denizen. It was great getting to spend time with them.
Iâve known Cheryl for a while now, both via the various listservs, but also in
New York because for a while we shared the same doc at Sloan Kettering. Iâve
known about the famous Suzan McNamara for years of course (for newbies on the
list, to her goes much credit for getting Novartis to develop Gleevec; get her
to tell you about it sometime!), but had not met her. What a delight she is.
Now I miss both my ASH buddies, but will shoulder bravely on by myself â
though tomorrow morning anyway, when it ends and we all head home.
Ok, where am I? I reported Talpazâ Friday presentation a couple of days ago,
nothing yesterday because we were too busy absorbing, then reviewed one of
todayâs talks this morning. For now, Iâll go back to the Friday symposium
and try to cover a couple more speakers. But since Iâve since filled in a few
of the gaps left by Fridayâs speakers (or maybe by my poor understanding of
what they were saying), I will unabashedly cut and paste where I see fit, in
order to lend coherence to the narrative.
Michael Deininger was the second speaker on Friday evening, and his subject was
mechanisms of IM resistance â a subject much covered in the course of ASH this
year. Not because resistance is becoming a worse problem â the reverse is
true, happily â but because quite a bit more has been learned about this
subject recently. Also because things are progressing at a walking pace only
on the treatment front, and these folks have to talk about SOMETHING, after all!
Deininger was a new name to me, btw. Heâs a colleague of Brian Drukerâs at
OHSU, and quite an up-and-comer, apparently. Hereâs a bit of what he said:
⢠We donât yet know whether we can stop clock of CML progression with IM,
or just delay it (note from me: the pendulum of belief is clearly swinging
toward believing that we can stop it. A couple of years ago most speakers
averred that progression is just a matter of time; this year it seemed that most
believe that, as one hematologist speaker said, âweâll die before our
patients do!â It wasnât clear which camp Deininger is in).
⢠Weâre getting better at predicting relapse. One way is by following the
phosphorylation of CRKL (pronounced âcrackleâ) â one of the enzymes that
bcr-abl works on downstream by putting a phosphate group onto it. When
phospo-CRKLstarts going up, you know that bcr-abl is no longer being inhibited.
Iâm not sure what clinical utility this has (I donât know of any docs
measuring phospho-CRKL on their patients), but it was interestingâ¦
⢠Deininger mentioned a lot of potential mechanisms, but he did it so fast I
couldnât type them all. They include: amplification of the bcr-abl protein,
duplication of gene, mutations in bcr-ablâs kinase domain, constitutive
activation of alternative tyrosine kinases, such as the SRC-family kinases (much
was made of these in the various talks, because dasatinib targets them along
with BCR/ABL), such as Lyn. Thereâs a lot still to learn about resistance,
such as how much of it is due to loss of uptake of IM into cells, or increase of
efflux out of cells. Altered plasma binding of IM may also play a role, though
this has not yet been confirmed in humans.
⢠There are some 30 to 50 (depending on how you count them, and who you ask)
known mutations in the bcr/abl kinase domain. They vary a lot in frequency.
Fortunately, some of the most frequently encountered mutations donât seem to
have much clinical significance. While several of them cause some resistance to
IM, most can be overcome by either increasing the IM dose, or by switching from
IM to desatinib or AMN107. Unfortunately, one relatively common mutation,
called T315I (how annoying these names can be!), is a real baddie: it not only
confers resistance to IM, desatinib and AMN107, but it heralds advancing
disease.
⢠Some KD (kinase domain) mutations merely confer resistance; others also
seem to change the biology of the disease. T315I is one such.
⢠Novartis believes that a critical factor in IM resistance is poor adherence
by patients. According to them, some 30% of the medication prescribed is not
actually taken.
Gosh, it seems to me that Deininger said a lot more than this, but I donât
have it in my notes. Maybe Cheryl or Suzan can fill in. If I have time, Iâll
also report on some of the âposter sessionsâ of which Deininger was a part.
Richard R

Would the two people from Melbourne, Australia with CML please contact me.
Thanks.
Jackie Petropoulos

Hi Sheila,
Funny but it has been my experience in the last 5 years that many of us have
these problems when first starting Gleevec. I too had to have my Gleevec
stopped and then restarted every @ other day 300 mgs and then 300one day and
400 the next and finally we worked back up to the standard dose of 400 every
day once my counts became stable.
I think your Oncologist made the right decision. Most Oncologist who are not
as experienced with Gleevec wouldn't have thought to do this ...
In these cases where they are trying to get your counts under control is
absolutely where they would take you off so as not to let your counts get to
a dangerous level.
Also keep in mind that it is a sign that the Gleevec is working and killing
off those nasty bad white cells which we had too much of when diagnosed.
So being on the low side doesn't mean its such a bad thing with the
exception of you will want to be careful since your immune system is unable
to protect you form things such as colds etc.
Gradually your body will get use to the medicine and your counts will
stabilize. It sounds right now like Gleevec is doing what it's suppose to be
doing.
When I first started my Onc sent me to the lab every other day just to make
sure I was ok.
As for your emotions- that's normal too... almost all of us have been there.
It takes some time to adjust to our new life:0 ) I say that with a smile
because I know just how much my life has changed since being dx'd.
Do the best you can to take it easy and convince yourself that it is all
going to be ok.
See how long I have been here and I was dx'd at 35
Lisa Martinez
Dx 5-2000
Interferon/arc/ hydrea
Gleevec 6-2001 400 MGS
PCRU 8-2001
essage: 6
Date: Sun, 11 Dec 2005 19:42:47 -0800
From: Nancy Cogan <ncogan@...
Subject: Re: Freaking out again!

Hi Gang,
Richard R here, with info from Hagop Kantarjian on the AMN107 experience with
CML and Ph+ ALL, from a talk on Sunday, December 11.
Starting with IMâs basic chemical structure, Novartis ârationally
designedâ AMN107 to address various ways that bcr-abl has learned to become
resistant to IM. They succeeded in that AMN107 binds 20-50x more tightly to
bcr-abl than IM does, and overcomes all the resistance mutations except the one
big bugaboo, T315I.
The Phase I AMN trial included CML patients in chronic phase who are IM
resistant, patients in advanced or chronic phase, or patients who have relapsed
on or are refractory to IM. The purpose of the trial (as in all Phase I trials)
is to determine the safety, activity, pharmacokinetic profile AMN107.
The trial involved 119 patients over one year in 3 sites. The approach was to
escalate drug dose continuously until toxicity was observed. AMN was given as a
single dose at first, but investigators found that at above 400mg, blood levels
were saturated (suggesting that the gut canât take up more than 400mg at a
time), so when they went above 400mg, AMN was given at a twice daily dose.
Reported side effects were similar to those from IM, but fewer and less
frequent. We are cautioned, however, that with most drugs, side effect profiles
tend to increase over time. The most frequent side effects were skin rashes and
neutropenia (low white count).
Here are some (but not all, because I couldnât type fast enough, and you
werenât allowed to photograph the Powerpoints) of the results from the trial
are as follows. Keep in mind that these patients had all flunked IM therapy:
⢠35 % of CML patients reached CCR by 6 months.
⢠A couple of patients with PH+ ALL did very well, but I didnât catch the
baseline number. It was something like 25% who responded, I think.
⢠Patients got a better response with bid dosing
⢠Durable responses were seen in patients in accelerated and chronic phase,
but not in blast phase.
⢠Patients in CP experienced an average 2 log reduction in qPCR (13
patients). Patients in AP saw a 1 log reduction, and patients in BP saw no
reduction at all.
⢠43% of the patients in the trial had BCR-ABL mutations, but except for
patients with T315I, these folks responded the same as folks with no mutations.
⢠Myelosuppression was the main factor limiting AMN dosage.
⢠Based on Phase I results, the plan is to use 400mg bid (twice a day) for
phase II studies.
Cheerio,
Richard R

Hi:
I have been on Gleevec since June of 2002 and am in molecular
remission. I haven't posted much lately or read the postings, so if
I missed some of your postings I am sorry. There are people who
respond right away and others where it takes a little bit longer,
sometimes a lot longer. I would continue to take your dose daily
and just wait. I would ask why your doc is altering the standard
protocol of either 400 or 800 mg/ day. If you are not having
terrible side effects, you should be taking it every single day, bar
none! You can split the pills and take half in the am and half in
the pm, if you are getting nauseous. It helps to eat and drink when
you take your gleevec. Some side effects are common. I had some
earlier on but now just have a spot of peripheral edema.
Being diagnosed is frightening- we all were frightened, so be of good
cheer- you are not alone. There is all kinds of information and
websites where you can get more information and support. You can see
countless stories of bravery and all sorts of response time to
treatment. Before Gleevec, CML was a death sentence, unless you had
a bone marrow transplant. Gleevec and the other 2 new drugs have
changed CML's complexion to a manageable chronic illness. Just try
to take comfort in the success others have had and are having and
enjoy the fact that CML is on the ropes.
God bless you both
Fred

Hi Folks,
Cheryl Ann, Suzan and I are here at ASH, working away to find out the latest
in CML research and pass along whatever we can to y'all. Cheryl has created
a new website just for the purpose, www.cmlsociety.org, just for the
purpose, but since not all the bugs have yet been worked out of it (it does
something odd to the formatting), I'm going to post my first report here as
well as there.
My first post is from one of the Friday Corporate Symposium meetings: ³CML:
A Paradigm for translating Sciences to the Bedside² which was sponsored by
Bristol Myers Squib. Five experts spoke at this one: Moshe Talpaz, Michael
Deinninger, John Goldman, Neil Shah and Andreas Hochaus. I'll fill you in on
Talpaz' talk first. When we next get back to our laptops, we'll decide who
will report on the others.
A lot of what Talpaz and others told us was not new. This is partly because
there¹s not all that much that¹s new in the CML world (at least compared to
when a number of us came aboard this train a few years ago), and quite a few
people want to tell us about it, so the new stuff gets parsed pretty thinly
among them. Still, there were a few nuggets worth passing along:
Talpaz believes that any given patient¹s risk for becoming resistant to IM
will decline over time, rather than remain constant or increase as some
investigators have suggested. The average incidence of resistance in the
first several years for all patients in chronic phase is 4%/year, though
it¹s higher than this for patients in late CP or who do not achieve major
molecular response (MMR a 3 log reduction in their qPCR, that is), and
much lower for patients who show a rapid and highgrade response. Whatever
your risk of resistance/relapse though, it¹s good news that it¹s likely to
decrease over time. Talpaz is a well-known optimist, but it¹s nice to hear
him say this stuff just the same.
Since IM was approved in 2001, the rate of CML-related death has been only
3%/year. Interestingly, the annual death rate for CML from all causes is 9%.
This includes deaths from stem cell transplantation. Unfortunately Dr. T
didn¹t specify what those other causes were, nor what percentage is
attributable directly to transplant. He did say that if this were the
1970¹s (before interferon, SCT and IM, that is), more than 50% pts diagnosed
over the same five years period would be dead by now. Here I pause for yet
another moment of gratitude!
Dr. T mentioned in passing that PCR is a better indicator of risk at all
levels of remission than is conventional cytogenetics. For example,
patients who reach CCR have quite varying levels of qPCR; those with the
lower values are at much lower risk of progression than those with higher
values. He didn¹t say this, but extrapolating from his talk, I¹d say that
achieving a 3-log reduction in qPCR is a more important milestone than
reaching CCR.
Since this was Dr. Talpaz (³Mr. high-dose IM,² right?), he naturally had
to mention the stats on high dose IM. In particular, patients on higher
doses achieve all milestones sooner than do patients on the standard 400mg
dose, and higher percentages of patients reach these milestones. For example
90% of patients on 800mg reach CCR by 18 months, compared to 74% of patients
on 400mg. What he did not mention (but has been pointed out elsewhere at
the conference) is that no one has yet showed any difference in progression
or survival between patients on low and high dose IM. Dr. T suggested that
adverse side effects were a little higher on higher doses.
I liked Dr. T¹s description of resistance to IM, as ³a persistent but not
a huge problem.² 16% of patients in CP (chronic phase) develop resistance.
He mentioned that desatinib is better, but that we¹ll have to wait until
Monday to get the new stats on this. He did say that the new drugs
(desatinib and the AMN drug) don¹t do any better than IM in treating
advanced disease, and that there¹s still much work to be done on this.
Can IM cure CML? Probably not in most patients, and maybe in none, because
(for reasons yet to be determined), quiescent CML stem cells are insensitive
to IM. No big news here. However, I found it of great interest that Talpaz
believes that most disease progression results from mutations in committed
cells, not in stem cells. If this is so, then we¹ve greatly improved our
chances of living a long time by killing off all those committed cells, and
that our little residual pool of quiescent cells is no big deal (still, it
would be nice to get rid of them).
He talked a little about the use of immunotherapies, especially
interferon, along with IM therapy. He mentioned the experience of patients
who stopped IFN after several years good response, many of whom have not
relapsed, even though they¹re not on any therapy and their qPCR¹s are still
positive for BCR-ABL. This has something to do with IFN activating CTLs
(cytotoxic T-lympocytes) and PR1, though I didn¹t follow all this. The
question is whether IM and IFN can be combined in such a way as to achieve
similar results (an ³operative cure,² he called it) in some patients.
Perhaps by using the two drugs sequentially? He thinks it will only require
low doses of IFN, not high doses like in the bad old days.
Dr. T raised bu