Re: FYI: Gleevec Linked To Heart Failure

[Guest guest]

It's hard to take seriously any article that can't seem to decide on

the appropriate spelling for Gleevec, not to mention the grammatical

error that I've copied below:

> " ....Gleevec, sold under the Glivec in some countries..... "

Also, how many thousands of patients are taking Gleevec right now?

They've found 10 that developed CHF. I'd hardly consider that

statistically significant. People in the general population do

develop CHF for unknown reasons so just because these particular

patients happened to be taking Gleevec at the time they developed CHF,

doesn't tell me there's a cause and effect relationship here.

Tracey

[Guest guest]

>

> Hi all,

>

> Here's a story that's sure to be of ongoing interest. (Apparently in an

> effort to include all possible combinations, the report has 3 different

> spellings of Gleevec! :-) )

>

> G.

> www.cmlsupport.com

> www.upstairswindow.org

>

> =======================================

>

> Study: Cancer Drug May Pose Heart Danger

>

> Jul 23, 1:02 PM (ET)

>

> By RANDOLPH E. SCHMID

>

> WASHINGTON (AP) - A successful cancer-fighting drug may also damage the

> heart, although a researcher says leukemia patients who need Gleevec

> should not abandon it.

>

> While effectively treating cancer, Gleevac can lead to heart failure in

> some patients, said Dr. Force, who teaches medicine at Jefferson

> Medical College of Jefferson University in Philadelphia.

>

> His study, published Sunday in the online edition of the journal Nature

> Medicine, was prompted by reports that 10 patients taking Gleevec for

> chronic myelogenous leukemia developed severe congestive heart failure.

>

> Gleevec, sold under the Glivec in some countries, had worldwide sales of

> $1.2 billion in the first six months of this year, according to the

> manufacturer, Novartis Pharmaceuticals Corp.

>

> " Gleevec is a wonderful drug and patients with these diseases need to be

> on it. It's a lifesaving drug for sure, " Force said in a telephone

> interview.

>

> " This is not a Vioxx situation, " Force added, referring to Merck & Co.

> (MRK)'s painkiller that was pulled from the market because of heart side

> effects.

>

> Force said he is trying to call attention to the fact that Gleevec and

> other similar drugs coming along could have significant effects on the

> heart and that doctors need to be aware of this and watch for symptoms.

> These patients can be helped with heart treatment, he said.

>

> Novartis cited the limited data and said further research was needed to

> better understand the relationship between such studies and their

> potential impact on monitoring patients who are on the drug.

>

> The company said in a written statement that the prescribing information

> with the drug includes data on heart problems. In addition, the drug

> maker said clinical trials and postmarketing safety data have shown that

> the incidence of heart failures among people taking drug is " extremely

> rare. "

>

> Novartis said Force's work does not change " the positive benefit/risk

> ratio of Glivec for thousands of patients being treated for cancer and

> other life-threatening diseases. "

>

> Force said the 10 patients with heart failure were taking Gleevec at the

> University of Texas' M.D. Cancer Center in Houston and had no

> heart problems before going on the drug.

>

> He said doctors took baseline measures of the patients' left ventricular

> heart function and determined that heart failure developed in these

> patients between two months and 14 months after they began Gleevec.

>

> Dr. Jean-Bernard Durand of M.D. discussed these cases with

> Force at a meeting and suggested they try to determine the cause of this

> problem, Force said.

>

> Gleevec targets three specific proteins, including one called ABL.

>

> In chronic myelogenous leukemia, genes known as ABL and BCR become fused

> and produce a hybrid BCR-ABL enzyme that is always active. The

> overactive BCR-ABL, in turn, drives the excessive proliferation of white

> blood cells that is the hallmark of leukemia.

>

> Using viruses that produced for normal ABL and a Gleevec-resistant

> mutant in laboratory studies and in mice, the researchers found that

> Gleevec inhibited the normal enzyme but not the mutant, and the mutant

> ABL " rescued " heart cells from the toxic effects of Gleevec.

>

> The research was supported by the National Heart, Lung and Blood

> Institute, the Leukemia and Lymphoma Society, the Finnish Heart

> Foundation and the Paavo Nurmi Foundation.

>

>

>

>

[Guest guest]

Zavie,

Here's a question: I wonder if the fact that in spite of all the

years you have had on IM you have only just recently achieved a 3 log

reduction has anything to do with your ability - and thankfully so,

to tolerate IM so well given the fact that you suffered CHF while on

IFN. It might make an arguement of wanting to know how well ABL is

being inhibited in your particular case. Additionally, 400mg of IM

is way less toxic than the dose of IFN you were on at the time of

CHF. Which could be another reason why you tolerate it so well.

Maybe it is a bit of both.

Of course, I would have to say, that this paper brings to light the

plight of ten patients and there experience with CHF on IM. Anytime

anyone mentions IFN you remind us all about your CHF while on this

therapy. So, for these 10 patients this is important, not only do

they have a serious disease, they now have, much like you, suffered

through CHF.

I know that I am not willing to brush this off so lightly, and I do

not think this is some sort of media plot to sully the credibility of

IM. When events happen like this, doctors and scientists are

COMPELLED to report them. That is exactly what they have done.

We should all live long and healthy,

Cheers,

Cheryl-Anne

> >It's hard to take seriously any article that can't seem to decide

on

> >the appropriate spelling for Gleevec

>

>

> Tracey,

> Here is another article with a bit more information about the

research

> that

> has been done on this.....it looks legit to me.

> Note that those who developed this problem with Gleevec did so

early on,

> in

> less than a year on the drug.....so maybe they were more

susceptible for

>

> some reason.

> Another similar example of this is that Zavie developed congestive

heart

>

> failure on interferon which is also quite rare.

>

> R. posted this article on Jerry's CML Discussion:

>

> Source: Jefferson University Released: Thu 20-Jul-2006,

18:35 ET

> Embargo expired: Sun 23-Jul-2006, 13:00 ET

>

> " Miracle " Cancer Drug Gleevec Can be Toxic to the Heart

> Libraries

> Medical News Keywords

> GLEEVEC, CANCER, HEART

> Contact Information

>

> Available for logged-in reporters only

> Description

>

>

> Newswise - Gleevec, the wildly successful poster-child of a new

> generation

> of cancer drugs aimed at specific targets in the cancer cell, can

be

> dangerous to the heart. Not only that, but other similarly based

drugs -

>

> called tyrosine kinase inhibitors - could lead to heart problems as

> well,

> say researchers at the Center for Translational Medicine at

Jefferson

> Medical College in Philadelphia.

>

> A team of scientists led by Force, M.D., C.

> Professor

> of Medicine at Jefferson Medical College of Jefferson

University,

>

> has shown in studies in both mice and in heart cells in culture

that

> Gleevec can cause heart failure. The results of the study, prompted

by

> 10

> patients with chronic myelogenous leukemia (CML) who developed

severe

> congestive heart failure while taking Gleevec, appear July 23,

2006, in

> an

> advanced online edition of the journal Nature Medicine.

>

> " We found that the molecular target of the drug, the Abelson

tyrosine

> kinase (ABL) protein, serves a maintenance function in cardiac

muscle

> cells

> and is necessary for their health, " Dr. Force explains. " While the

> cancer

> is treated effectively, there will be some percentage of patients

who

> could

> experience significant left ventricular dysfunction and even heart

> failure

> from this. "

>

> " Gleevec is a wonderful drug and patients with these diseases need

to be

> on

> it, " he says. " We're trying to call attention to the fact that

Gleevec

> and

> other similar drugs coming along could have significant side

effects on

> the

> heart and clinicians need to be aware of this. It's a potential

problem

> because the number of targeted agents is growing rapidly. "

>

> Gleevec is a new type of cancer drug - the first of its kind

developed

> to

> fight cancer by turning off an enzyme that causes cells to become

> cancerous

> and multiply. In CML, an enzyme called ABL goes in overdrive

because of

> a

> chromosomal mix-up that occurs during blood cell development. The

genes

> ABL

> and BCR become fused and produce a hybrid BCR-ABL enzyme that is

always

> active. The overactive BCR-ABL, in turn, drives the excessive

> proliferation

> of white blood cells that is the hallmark of CML.

>

> According to Dr. Force, 10 patients taking Gleevec at the

University of

> Texas' M.D. Cancer Center in Houston developed fairly

severe

> heart

> failure, with no prior symptoms. Because physicians there took

baseline

> measures of the patients left ventricular heart function, the team

was

> able

> to determine that heart failure developed in these patients between

two

> and

> 14 months after beginning Gleevec.

>

> The research team probed the potential mechanisms behind the drug's

> possible toxic effects on the heart. Dr. Force explains that at the

> outset,

> the scientists couldn't tell if the toxicity was from the drug's

effect

> on

> the known drug targets, or from an off-target effect or even a

> non-specific

> problem. " Sorting that out is important because then we can say,

for

> example, if there are 10 more ABL inhibitors coming on line soon,

and if

>

> the problem is really with inhibition of ABL, then these may have

> toxicity

> problems as well, " he says.

>

> The team proved that ABL was the guilty target by using viruses that

> coded

> for normal ABL and a Gleevec-resistant mutant. Gleevec inhibited the

> normal

> enzyme but not the mutant, and the mutant ABL " rescued " the heart

cells

> from the toxic effects of Gleevec, proving that ABL is the relevant

> target.

> As a result, second-generation Gleevec drugs might also have

similar

> toxicities in the heart.

>

> " This finding is a big surprise and there may be a lot more of

these, "

> Dr.

> Force notes. " It's not a class effect like COX-2 inhibitors. The

drugs

> are

> all tyrosine kinase inhibitors, but each tyrosine kinase is

different.

> It's

> difficult to predict what tyrosine kinases will have protective

roles in

>

> the heart and inhibition of them will be toxic. "

>

> Newer drugs tend to be 'dirtier' - that is, companies are developing

> drugs

> that hit multiple cancer cell targets at once to up the chances of

> effectiveness. Finding the exact target that, when inhibited, can

cause

> problems with the heart, is critical to designing agents to

counteract

> this

> effect.

>

> In Gleevec, for example, blocking the PDGF receptor is crucial to

its

> effect in thwarting gastrointestinal stromal tumors. Designing a

drug to

>

> inhibit the PDGF receptor but not ABL, then, could still work

against

> such

> tumors but not cause heart problems.

>

> " We've learned something about the biology of the heart, " Dr. Force

> says.

> " ABL is important for cardiomyocyte health. We also can learn

something

> about how to stay away from these targets that are important and

> optimize

> the drugs. "

>

> In other studies, the researchers attempted to find the biological

> pathways

> involved in causing heart cells to die. They found that Gleevec

appears

> to

> cause endoplasmic reticulum stress, which is initially a protective

> response by the cell, but if sustained, leads to cell death. They

also

> found that treating mice heart cells with Gleevec led to the cells

> losing

> mitochondrial function, leading to cell death.

>

> Jefferson, in collaboration with M.D. , the Cleveland

Clinic and

>

> one or more European centers is planning to begin a registry for

new

> tyrosine kinase inhibitors. " As these drugs come out, we can more

easily

>

> collect data on larger numbers of patients as they take the drugs

to get

> an

> idea of the incidence of heart problems, " Dr. Force explains.

>

> Dr. Force doesn't think it's possible to screen for potential heart

> problems that could be related to Gleevec. He notes that physicians

> involved in pre-release clinical trials of tyrosine kinase

inhibitors

> will

> be aware of the potential problems and evaluate heart function if

> symptoms

> or signs possibly due to heart failure appear.

>

>

>

> --------------------------------------------------------------------

----

> --------

>

> C 2006 Newswise. .

>

>

>

>

>

>

>

>

[Guest guest]

Hi,

Yes, it's important that we remain aware. Things do change over time as

more becomes known about a drug. Over time, Novartis has changed the

prescribing material for Gleevec. For instance, blood clots were only

added as a potential adverse event in 2004 -- three years after the drug

was approved. Other stuff has been changed as well.

, I must have missed the urine testing/bladder cancer thing. That's

new to me. What is that all about?

Thanks!

~ G.

www.cmlsupport.com

www.upstairswindow.org

RE: [ ] Re: FYI: Gleevec Linked To Heart Failure

<snip>

We need to remember that we are ALL part of ongoing research into the

long

term effects of Gleevec........until you have data for maybe 10-15

years,

you cannot say what the long term effects (if any) of the drug will be.

Normally a drug would only be used in a trial for about 10 years, but

with

these fast-tracked drugs, we are all part of the ongoing research.

I think it was great that this information was put out there and not

hidden

(like has happened with other drugs!!!).

We will have to see how the CML specialists decide to monitor

patients.........just like Druker now wants a urinalysis every 6 months

(I

think) to monitor for any bladder cancer (like the little mice got).

C.

[Guest guest]

At 08:45 PM 7/24/06 -0500, you wrote:

>, I must have missed the urine testing/bladder cancer thing. That's

>new to me. What is that all about?

Hi ,

Apparently in the lab, some mice have developed some bladder cancer....they

might have been on a higher than we would take dose???? but Dr. Druker

added a urinalysis to his testing protocol (can't remember if it is every 6

mo or just annually....I can check. I don't keep track of the details

because I see Dr. Druker). I asked Carolyn once what they were looking

for....and mainly it would be red cells (bleeding) and then investigate.

Along with this current heart issue discussion, here is a top CML

specialist who thinks....if it is 'even a possibility', then monitor for it.

C.

[Guest guest]

Thanks, .

Do you recall if Dr. Druker has said anything about monitoring of bone

loss (you may recall that it recently came out that Gleevec may impair

bone development)?

There's a big cancer conference coming up in ealy Aug, and CML is on the

agenda. It would be nice if a cohesive and comprehensive management plan

comes out of that, with details about monitoring for bone loss, heart

problems, bladder problems, etc.

RE: [ ] FYI: Gleevec Linked To Heart Failure

At 08:45 PM 7/24/06 -0500, you wrote:

>, I must have missed the urine testing/bladder cancer thing.

>That's new to me. What is that all about?

Hi ,

Apparently in the lab, some mice have developed some bladder

cancer....they

might have been on a higher than we would take dose???? but Dr. Druker

added a urinalysis to his testing protocol (can't remember if it is

every 6

mo or just annually....I can check. I don't keep track of the details

because I see Dr. Druker). I asked Carolyn once what they were looking

for....and mainly it would be red cells (bleeding) and then investigate.

Along with this current heart issue discussion, here is a top CML

specialist who thinks....if it is 'even a possibility', then monitor for

it.

C.

[Guest guest]

At 11:03 AM 7/25/06 -0500, you wrote:

>Thanks, .

>

>Do you recall if Dr. Druker has said anything about monitoring of bone

>loss (you may recall that it recently came out that Gleevec may impair

>bone development)?

Hi ,

I did take the posted article about bone loss to him at the time....I

believe it came out of Sloan. It was one of those things were he shook his

head subtly in the 'no' direction. I think he did not think the research

was valid or scientifically controlled.

But he did say this to me.......once you get CML, your bone marrow does not

look normal on an MRI.....so 'things' may be typical CML changes. This is

similar to Dr. Talpaz saying that a lot of things that look like tumors in

a CML patient are not. So whoever is reading these tests needs to know what

a typical MRI looks like after the dx of CML.

>There's a big cancer conference coming up in ealy Aug, and CML is on the

>agenda. It would be nice if a cohesive and comprehensive management plan

>comes out of that, with details about monitoring for bone loss, heart

>problems, bladder problems, etc.

That would be nice and we will have to keep our eyes open for that...and if

it does not happen, maybe we can request if of one of the specialists. Good

job for a reporter!!

Take care,

>

>

> RE: [ ] FYI: Gleevec Linked To Heart Failure

>

>At 08:45 PM 7/24/06 -0500, you wrote:

> >, I must have missed the urine testing/bladder cancer thing.

> >That's new to me. What is that all about?

>

>Hi ,

>

>Apparently in the lab, some mice have developed some bladder

>cancer....they

>might have been on a higher than we would take dose???? but Dr. Druker

>added a urinalysis to his testing protocol (can't remember if it is

>every 6

>mo or just annually....I can check. I don't keep track of the details

>because I see Dr. Druker). I asked Carolyn once what they were looking

>for....and mainly it would be red cells (bleeding) and then investigate.

>

>Along with this current heart issue discussion, here is a top CML

>specialist who thinks....if it is 'even a possibility', then monitor for

>it.

>

> C.

>

> -->