Re: Today's Teleconference-

[Guest guest]

wrote:

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...

________________________________

First, there were a lot of posts in this thread that wrote BMB (biopsy)

when people meant BMT (transplant) and I just wanted to clarify this for

the newbies.

Hi ,

Yes, this makes sense to me. I am one of those people who has a 'primary

resistance'....and Dr. Druker's patient. My blood has been tested several

times over the years....and I have no 'known' mutation. Primary resistance

is not well understood....which is why there are no specific drugs

developed for it. Here would be an example of a reason.....maybe when the

drug crosses my cell membrane but something pumps the drug back out....so

it does not reach the target cell, at least some of it does not reach it.

Having a mutation will almost always eventually cause a relapse.....an

increase in your ph+ cells. This is because you kill off the 'normal cml

cells' and only have the mutated cells left that do not respond to the

drug....so the ph+ % actually increases. This does not happen when you just

have primary resistance. Some people with primary resistance stay 100% ph+

on these drugs.......but there white count is controlled, so the drug is

doing something. There are people who have been 100% ph+ for years. But he

told me (yesterday) that with this you expect a 10% annual relapse

rate....so 50% of patients in 5 years.

So the new drugs are all developed for and tested on known mutations. Dr.

Druker also said that if a patient does not get a cyto response on Gleevec,

he is not likely to get a cyto response to Sprycel either.....that is what

he has seen in patients. These drugs are using the same basic

mechanism/pathway to get rid of the ph+ cells.

And I remember that did not have a response results from Gleevec, so

Dr. Druker could not 'guess' at how he would respond to Sprycel......that

would have been a predictor. But because is young, if he is not a

responder to these drugs (which is NOT known yet), then he would say to

consider a transplant. I hope this makes sense to you........

--------------------------

My own history of primary resistance.............on 400mg Gleevec only

reduced ph+ to maybe 80% at one year, then dose doubled to 800mg.......and

reduced to about 50% and sl lower over several

years....................then switched to Sprycel at 35% ph+ and now (at 2

years) down to 5% ph+.

I was not a non-responder to Gleevec.....I was a sub-optimal responder to

Gleevec, and am getting a better response to Sprycel. I am now a 9 year cml

survivor!!

C.

[Guest guest]

the new drugs are all developed for and tested on known mutations.

Dr.

> Druker also said that if a patient does not get a cyto response on

Gleevec,

> he is not likely to get a cyto response to Sprycel either.....that

is what

> he has seen in patients. These drugs are using the same basic

> mechanism/pathway to get rid of the ph+ cells.

**********************************************

Hi ,

This comment surprised me. Isn't Jerry's board full of examples of

people who had no cytogenetic response to Gleevec but have had a

response to Sprycel? Jerry and come to mind as examples

right away.

Also, isn't Sprycel a dual bcr/abl and src inhibitor, meaning that it

has at least one major different target (mechanism/pathway) than

Gleevec (Gleevec doesn't target src). This makes me think that there

is a somewhat significant difference in the way the two drugs work.

Take care,

Tracey

[Guest guest]

> the new drugs are all developed for and tested on known mutations.

> Dr.

> > Druker also said that if a patient does not get a cyto response

on

> Gleevec,

> > he is not likely to get a cyto response to Sprycel

either.....that

> is what

> > he has seen in patients. These drugs are using the same basic

> > mechanism/pathway to get rid of the ph+ cells.

>

> **********************************************

>

> Hi ,

>

> This comment surprised me. Isn't Jerry's board full of examples of

> people who had no cytogenetic response to Gleevec but have had a

> response to Sprycel? Jerry and come to mind as examples

> right away.

>

>

Depends on Dr. Druker's definition of " not likely "

There is a clinical trial ongoing for people in Chronic phase that

had lost a response or never responded to 400-600 mg Gleevec. They

were randomized to Sprycel or 800 mg Gleevec. There was a set of

patients in the study that never had any cytogenetic response to

Gleevec.

The recent results show 7% in the Gleevec group responded with all

reaching a Complete Cytogenetic Response (CCyR).

For the Sprycel group, 49% made a Major Cytogenetic Response and 31%

made a CCyR.

[Guest guest]

Tracey wrote:

This comment surprised me. Isn't Jerry's board full of examples of

people who had no cytogenetic response to Gleevec but have had a

response to Sprycel? Jerry and come to mind as examples

right away.

Also, isn't Sprycel a dual bcr/abl and src inhibitor, meaning that it

has at least one major different target (mechanism/pathway) than

Gleevec (Gleevec doesn't target src). This makes me think that there

is a somewhat significant difference in the way the two drugs work.

_________________________

Hi Tracey,

Jerry absolutely did have a response to Gleevec (although brief) and then

relapsed and had a known mutation....so he is in that category, and Sprycel

was effective against his mutation.

is one example I know that was always 100% ph+ on Gleevec (but

only tolerated a very low, suboptimal dose I believe) who has had a cyto

response to Sprycel.

There is a lady posting now on Jerry's site (JL) who was 100% ph+ on

Gleevec for one year and has now been 100% ph+ on Sprycel for one

year...........and this is what Dr. D is seeing. So, if you were a

responder to Gleevec but then developed liver intolerance and have to

switch to Sprycel, he expects that you will also respond to

Sprycel......same for other side effects.....like on this list.

She is a good responder to Gleevec but with bad side effects....so she

should have a good response also to Sprycel.

This does not mean that there are not some exceptions.....but in general

this is what he is seeing.

No, right from the start, Dr. D has said that he does not think that the

2nd pathway of Sprycel is of much significance. Sprycel is a more potent

(and therefore should be more effective drug) because it can work in both

the open and the closed cell phase (which I do not understand

well)........whereas Gleevec only works in one of these phases.....and this

is why he thinks that Sprycel is more effective.

All I can ever bring to the list is what Dr. D tells me directly.....I do

not do a ton of research....but because of my medical background, I usually

have a pretty good handle on what he tells me and his 'thought process'.

I asked him about the upcoming ASH conf. in Dec and if there will be any

big news coming out....he said 'no'............he thinks that all 3 drugs

(Gleevec, Sprycel and AMN) are good drugs. He still will start a newly dx

on either 400 or 600mg of Gleevec.

C.

[Guest guest]

wrote:

There is a clinical trial ongoing for people in Chronic phase that

had lost a response or never responded to 400-600 mg Gleevec. They

were randomized to Sprycel or 800 mg Gleevec. There was a set of

patients in the study that never had any cytogenetic response to

Gleevec.

The recent results show 7% in the Gleevec group responded with all

reaching a Complete Cytogenetic Response (CCyR).

For the Sprycel group, 49% made a Major Cytogenetic Response and 31%

made a CCyR.

______________________________

Hi ,

there is a flaw in this type of study I think.....they are lumping those

who lost a response to Gleevec with those who never responded.......and

these are 2 very different groups of patients (as explained to Tracey

above).........so they should be separated. We know that those who lost

their response mostly have a mutation and that the new drug addresses the

mutation better, because the drug binds better. But those who have never

had a cyto response are a different category.....maybe you are saying that

they kept them in a separate category???

Right from the start they (the cml specialists) have all said that treating

those with primary resistance will be harder.....because you do not know

what the obstacle is to the drug working.

C.

[Guest guest]

______________________________

>

> Hi ,

> there is a flaw in this type of study I think.....they are lumping

those

> who lost a response to Gleevec with those who never

responded.......and

> these are 2 very different groups of patients (as explained to

Tracey

> above).........so they should be separated. We know that those who

lost

> their response mostly have a mutation and that the new drug

addresses the

> mutation better, because the drug binds better. But those who have

never

> had a cyto response are a different category.....maybe you are

saying that

> they kept them in a separate category???

>

> Right from the start they (the cml specialists) have all said that

treating

> those with primary resistance will be harder.....because you do not

know

> what the obstacle is to the drug working.

>

> C.

>

The results of 49% Major CyR (MCyR) and 31% Complete (CCyR) in those

switched to Sprycel are only from the group of people that never

exhibited any cytogentic reponse (100% Ph+) to 400-600 mg Gleevec.

The report does list the overall response to switching to Sprycel.

The results included those people who developed a mutation as well as

some people who had some cytogenetic response but seemed to " stall "

and never achieved at least a MCyR. The overall response to Sprycel

(15 months follow-up) was 53% MCyR and 40% CCyR.

The mechanism of primary resistance does need to be studied.