RE: Re: Today's Teleconference

September 20, 2007

--

There is something I do not understand. When we saw Dr. Druker he told us that

if you dont respond to Gleevec/Sprycel, and you dont have a mutation, it's not

like there are tons of drugs to try (most other drugs address mutations). This

sort of suprised and I because everyone always talks about how many drugs

there are, and how many are in trials, and how many " options " there are for CMl

patients. But he seemed pretty adement that if doesnt respond to Sprycel,

and he doesnt have a mutation, that he wouldnt keep trying on lots of the

other drugs and would start looking for a bone marrow match. He said if

didnt respond to Gleevec/Sprycel but didnt have a mutation, what would make him

think that would respond to the second and third generation drugs?

Does this make sense to you....? I am not questioning Dr. Druker, or you for

that matter! I am just trying to get a handle on what the thinking is behind

it...

Cervera

@...: traceyincanada@...: Thu, 20 Sep 2007

21:27:59 +0000Subject: [ ] Re: Today's Teleconference

It was my pleasure Lynn. I hope you see a relief soon in those side effects. If

not, you know that there are other drugs right around the corner. You will

always have options which is such a nice thing to have.Take care,Tracey> >> > Hi Everyone,> > > > In case any of you

weren't able to listen to today's teleconference > > but were interested in what

Dr. Cortes said, I've written a summary > > in two parts. This post will look at

his initial " lecture " and my > > next post will have the question/answer

period.> > > > He started with a brief history of CML saying that it was the

first > > malignancy where a chromosomal change was found to cause a > disease.

> > Past goals of CML therapy were simply to control blood counts but > > thanks

to Gleevec and other targeted therapies, our goal now is to > > reach the source

of the disease and allow patients to live long > term.> > > > Between the years

of 1997-2007 there hasn't been much of a change > in > > the number of people

being diagnosed with CML. Prior to 1997, 2400 > > patients died a year from CML

and now there are less than 500 > > patients dying a year due to CML.> > > >

Survival has gone from 3-4 years prior to Gleevec, to now 95% of > > patients

are still alive after 5 years. The IRIS trial has shown > us > > that more than

80% of newly diagnosed patients have achieved a CCR > > which has been very

durable over 5 years. The longer the patients > > are on Gleevec, the lower the

rates of relapse are, which is very > > encouraging.> > > > He said that blood

levels of Imatinib (Gleevec) can predict the > level > > of response a patient

will have. Low concentrations of imatinib in > > the blood, don't give patients

as good of a response as higher > > levels. He also said that serum testing of

Gleevec is now widely > > available.> > > > The earlier the patient responds,

the better the outcome. Patients > > who are in CCR at 1 year, have the best

probability of a durable > > response. He mentioned that proper monitoring of

disease is > > essential. FISH tests can have a false positive rate of up to 10%

> so > > that should be taken into consideration when evaluating a patients > >

results.> > > > A PCR test measures the patient's molecular response. A major >

> molecular response (MMR) is a 3 log reduction. Each lab has a > > baseline

value of what a newly diagnosed patient will have in terms > > of a PCR result.

If for instance, the baseline is 50, then a one > log > > reduction would be 5,

a two log reduction would be 0.5, and a three > > log reduction would be 0.05.>

> > > Standard dose Imatinib has shown wonderful responses but higher > dose > >

therapy can show faster and even deeper responses. He mentioned > > though that

higher dose therapy (800mg) is still considered > > investigational, it's not by

any means standard.> > > > Over the long term, side effects appear to ease up in

most > patients. > > We used to be concerned about the long term effects of

taking > Gleevec > > but after 5 years of use, we're not so worried anymore

because > people > > seem to be doing better and better with fewer side effects

over the > > long term.> > > > Studies that have looked at heart problems have

shown that Gleevec > > does not cause any more heart problems than you would

expect to see > > in the general population.> > > > Dasatinib (Sprycel) is

effective in all stages of disease and is > well > > tolerated. Cytopenias (low

blood counts) are a common side effect > > and pleural effusions can occur in

25-30% of patients but it can be > > managed. Giving 100mg once daily is showing

equal responses as the > > 70mg twice daily dose and there's less side effects

with the 100 mg > > dose.> > > > Nilotinib (Tasigna) is also showing to be very

effective and well > > tolerated in patients who are taking it in clinical

trials. It has > > shown no pleural effusions but can sometimes cause liver

enzymes to > > rise.> > > > We continue to be excited about CML therapy as more

hopeful drugs > are > > on the horizon. SKI-606 and INNO-406 are showing

encouraging > > responses in trials so far.> > > > With so many drugs to chose

from, there will soon be a question as > to > > how to select a drug to use.

Side effects should be considered > when > > choosing a drug. Various mutations

are better targeted with some > > drugs over others so that's another

consideration to look at.> > > > 40%-60% of patients who fail imatinib have a

mutation but most of > > those mutations can be managed with one of the other

second or > third > > generation drugs. MK-0457 is showing activity against the

more > > serious T315I mutation, which is encouraging.> > > > We want to

eliminate the last leukemia cell, the " mother cell " so > > that we can cure CML.

We have had a significant amount of success > in > > treating CML but we still

have a way to go to cure it. We are > > hopeful for a cure in the " very near

future " .> > > > Clinical trials are essential for gaining knowledge so it's > >

important that patients continue to participate in trials if they > > can.> > >

> Advances in CML have been very quick. We now have 3 generations of > >

inhibitors to chose from.> >>

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September 20, 2007

Hi ,

I think the problem is more general than just having or not having

mutations. What pushs a given dr (I am talking the cml specialists)

to start talking about BMB is a set a several factors :

- Age and fitness is probably number one, is relatively young, so

that opens up the possibility of a successful BMB.

- The reason the drug(s) is/are not working. For intolerance recent

studies shows a low cross-intolerance between cml drugs, what means

has a good chance to tolerate dasatinib (sprycel).

- cml can be resistant to one or several drugs for several reasons.

The majority of cases are new mutations in the kinase domain, and new

drugs seems to help on that score, but it can be something else like

the cml cells producing more bcr/abl (amplification), low levels of

the drug getting into the cml cells, not enough drug getting into the

blood, or some other unknown reason. Depending on which, changing the

drug or increasing the dose can be tried.

From what I followed of your past posts, 's main problem was liver

intolerance to imatinib. I have read on the dasatinib studies that

most patients intolerant to imatinib did well on dasatinib or on

nilotinib (Novartis' amn107, now Tasigna).

I cross fingers for ,

Take care,

Marcos.

On 9/20/07, Cervera <weez_555@...> wrote:

>

> --

> There is something I do not understand. When we saw Dr. Druker he told us that