RE: Re: FYI: Gleevec Linked To Heart Failure

[Guest guest]

I honestly think the spelling in other countries is different. We spelled it

Gleevec and they spell it something like Glivec. I have read this in other

web sites. I'm not alarmed over the report.

[Guest guest]

I would take it pretty seriously. That's not to suggest that anyone stop

taking Gleevec because the risk is small. But it's a real risk. From my

own experience with pulmonary emboli and subsequently finding out that

it's a known adverse effect of Gleevec, even if rare, real people do

develop these problems!

The thing I posted was an AP news article. It was NOT the journal

article. The news article was probably written on a very tight deadline

on a Sunday afternoon (!) and thus more error-prone.

I do have a copy of the actual journal article. I wouldn't consider MD

something to not take seriously, or the journal Nature

Medicine. It was big enough news to get published in a leading journal,

ahead of regular publication.

This doesn't have just implications for people with CML. The

cardiotoxicity is a result of inhibition of c-Abl by imatinib. This

could have bigger implications for other uses of Gleevec and for other

drugs that may inhibit c-Abl. The study authors suggest that people

taking Gleevec be watched for developing signs of heart failure (didn't

we just have a series of posts about pesistent edema?!). The authors

conclude by stating that " our data ... suggest that imatininb is

cardiotoxic. "

No one is saying to panic. In the vast majority of people, this probably

will never, ever be a problem. But in some people, it will be, and heart

failure is to be taken seriously. I happen to think that 10 is a lot of

people for a potentially deadly adverse event.

G.

www.cmlsupport.com

www.upstairswindow.org

[ ] Re: FYI: Gleevec Linked To Heart Failure

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]

At 08:01 PM 7/23/06 +0000, you wrote:

>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.

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

© 2006 Newswise. .

[Guest guest]

Uh, that was a joke. (Except for the spelling of Gleevac -- that's not

correct in any country.)

G.

www.cmlsupport.com

www.upstairswindow.org

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

I honestly think the spelling in other countries is different. We

spelled it

Gleevec and they spell it something like Glivec. I have read this in

other

web sites. I'm not alarmed over the report.

[Guest guest]

Hi ,

Unless we have the specific details of the study, there is not much to

worry about. Here is some data from the report that clearly states that

the patients were already prone to heart problems.

From Jerry's site.

7/10 had hypertension

4/10 had diabetes.

4/10 were on 800 mg

3/10 were on 600 mg

3/10 were on 400 mg.

The dosage information does not have meaning unless we can normalize it

to the total CML patients taking Gleevec at this institution where the

10 were patients. What percentage at this institution were on 800 vs 600

vs 400. Only by comparing to the total CML pts, can we know if these

doages within the 10 pts carry inferences.

Pre drug all 10 patients had a NY Heart Assocation funcational class as

" 1 " After treatment, their average NYHA class was 3.5

Predrug the ejection fraction average was 56 +/- 7

After drug the average was 25 +/- 8

--------

In the IRIS study, I don't recall any mention of CHF as being a side

effect of Gleevec.

Also, in my case, one would think that with my history of CHF, you

wouldn't continue to prescribe Gleevec if there was any further danger.

It almost seems like the media is trying to punch holes in Gleevec's

outstanding success.

Zavie

PS Let me know if you want to see the original paper.

Zavie (age 68)

67 Shoreham Avenue

Ottawa, Canada, dxd AUG/99

INF OCT/99 to FEB/00, CHF

No meds FEB/00 to JAN/01

Gleevec since MAR/27/01 (400 mg)

CCR SEP/01. #102 in Zero Club

PCRU 5/02 at RVH

2.8 log reduction Sep/05

3.0 log reduction Jan/06

e-mail: zmiller@...

Tel: 613-726-1117

Fax: 309-296-0807

Cell: 613-202-0204

ID: zaviem

Zavie (age 68)

67 Shoreham Avenue

Ottawa, Canada, dxd AUG/99

INF OCT/99 to FEB/00, CHF

No meds FEB/00 to JAN/01

Gleevec since MAR/27/01 (400 mg)

CCR SEP/01. #102 in Zero Club

PCRU 5/02 at RVH

2.8 log reduction Sep/05

3.0 log reduction Jan/06

e-mail: zmiller@...

Tel: 613-726-1117

Fax: 309-296-0807

Cell: 613-202-0204

ID: zaviem

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

At 08:01 PM 7/23/06 +0000, you wrote:

>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]

At 06:35 PM 7/24/06 -0400, you wrote:

>7/10 had hypertension

>4/10 had diabetes.

>

>

>It almost seems like the media is trying to punch holes in Gleevec's

>outstanding success.

Zavie,

Nobody is saying to be alarmed about this........but this is new

information and it needs watching and further study. Many people actually

have hypertension these days (they have lowered what they consider to be

hypertension).....so there are probably many people with hypertension on

Gleevec.

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.