Cancer Therapy May Cause Heart Troubles The anti-cancer drug Gleevec has been highly successful in treating stomach tumors, and a blood cancer called chronic myelogenous leukemia. But new research shows that Gleevec may cause congestive heart failure. Researchers say there's no cause for panic. But they advise doctors to monitor their patients for signs of heart trouble.
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Cancer Therapy May Cause Heart Troubles

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Cancer Therapy May Cause Heart Troubles

Cancer Therapy May Cause Heart Troubles

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JOE PALCA, host:

For the rest of this hour, a look at what's happening on the frontlines of cancer treatment. The anti-cancer drug Gleevec has been highly successful in treating stomach tumors and a blood cancer called chronic myelogenous leukemia. Ninety-five percent of patients who have taken the drug have reached complete remission from their leukemia.

But new research shows that Gleevec may cause congestive heart failure, according to an article appearing in the July 23 online edition of Nature Medicine. Researchers say there's no cause for panic and that patients shouldn't stop taking the drug, but they advise doctors to monitor their patients for signs of heart trouble.

Joining me now to talk more about this are my guests. Thomas Force is James C. Wilson professor of medicine at the Jefferson Medical College of Thomas Jefferson University in Philadelphia. He joins us from the studios of WHYY in Philadelphia. He's an author of the Nature Medicine article. Welcome.

Dr. THOMAS FORCE (Professor of Medicine, Thomas Jefferson University): Thank you.

PALCA: And also we have Brian Druker. He is JELD-WEN Chair of Leukemia Research at Oregon Health and Sciences University Cancer Institute in Portland, Oregon. Welcome back to SCIENCE FRIDAY, Dr. Druker.

Dr. BRIAN DRUKER (Chair of Leukemia Research, Oregon Health and Science University): Thanks for having me, Joe.

PALCA: So thanks both of you. Dr. Druker, we should start with you. You have an enormous amount of experience, probably more clinical experience than anyone with Gleevec. First of all, tell us what makes Gleevec different from other cancer drugs and how it works.

Dr. DRUKER: What's different about Gleevec is as compared to chemotherapy, which kills dividing cells relatively nonspecifically, Gleevec only targets the cancerous cells. And in this particular leukemia it targets an active enzyme that triggers the growth of the white blood cells; it shuts it down and leukemia cells are killed. So it's a very specific targeted therapy for this particular type of leukemia.

As a consequence, the response rates, as you quoted, were quite high and overall the side-effect profile has been pretty minimal.

PALCA: Right. So Dr. Force has produced this paper, and we'll come to him in a moment, that says - you just said that it only affects cancer cells. He's seeing an effect in other cells. What do you make of that?

Dr. DRUKER: It's absolutely clear that the enzyme that's targeted by Gleevec is present in normal cells. So it wouldn't be surprising that there might be some side effects on normal cells. And certainly when we went to clinical trials, that was one of our earliest concerns is that it might damage some normal cells. But as it turns out, it seems to be extremely well tolerated.

PALCA: Right. So turning to you then, Dr. Force. You - first of all, what made you suspect there was any problem with the heart in taking this medication?

Dr. FORCE: I had given a talk at the annual Heart Failure Society of America meeting a couple of years ago, and after the session I discussed Gleevec as sort of the ideal design going forward for not only targeting cancers, but also targeting heart disease. And afterwards, J.V. Doran(ph), who's a co-author on the paper, came up to me and said that he had seen several instances of fairly advanced heart failure in patients in whom he knew they had baseline normal function going into Gleevec treatment.

And he basically asked did I think anything was there and could we try to figure out what was going on, and that's what started it.

PALCA: Right. And I mean, these are sick patients presumably, with many health problems. Isn't it possible that their heart issues are related to something other than the drug they're taking?

Dr. FORCE: Well, it's possible, but the most important information that we had on the patients was that they had absolutely normal heart function going in. So it would be really unusual to have these patients develop really frank congestive heart failure with marked deteriorations in left ventricular function if it were due to something else. And then furthermore to support that, when the patients were withdrawn from the treatment, their left ventricular function improved.

PALCA: We're talking this hour about Gleevec and it's positive - clearly positive benefits for patients, but it's possible concern that's been raised about certain negative qualities it may have for the heart. We welcome your calls. The number is 800-989-8255. That's 800-989-TALK. Dr. Force, staying with you for a second, what's the take-home message about this for Gleevec patients?

Dr. FORCE: Well, it's a wonderful drug and patients need - it's a life-saving therapy. They have really no option. So what we're saying is we do not know the incidence of congestive heart failure or deterioration in left ventricular function in patients taking this agent. And that's really what we need to find out.

We need to find out what the risk is and identify patients who are at risk early so that they can be treated with standard heart-failure therapies. And they may well. There's a paper we have in preparation, suggests that patients can actually maybe even continue on their therapy even if they have some deterioration of left ventricular function if they're aggressive addressed.

So the basic idea is find out what the risk is, identify patients early, treat them aggressively, and in many cases they may hopefully be able to continue on therapy.

PALCA: So Dr. Druker, I credited you with having an enormous amount of clinical experience with Gleevec. I hope that was accurate. But it makes me wonder if this is something that jumped out at Dr. Force, how come it's not appeared on your horizon or on your radar?

Dr. DRUKER: It has and it hasn't, meaning in my experience with probably close to a thousand patients, we've seen some evidence of heart failure in one or possibly two patients. So our view is it can occur but it seems to be exceedingly rare.

And I would agree with Dr. Force that we clearly need to continue to investigate exactly how common this is, but as I polled other experts that have treated a fair number of patients with CML with Gleevec, they would agree that the side effect of heart failure is extremely uncommon.

Again, awareness is important. There's certainly no need for panic. And what's very comforting to me is also, as Dr. Force has said, is that patients are able to continue on Gleevec, which suggests that there's no permanent heart damage caused by the drug.

PALCA: Well, now that there is all this experience with Gleevec - I mean I quoted the figure of 95 percent remission rates. Is that holding up? Is the drug proving with more experience to be as attractive as it was initially?

Dr. DRUKER: What's been amazing about the experience with Gleevec over time is that yes, the five-year survival rate is 95 percent, but if you look at the relapse rate over time it's actually decreasing in the third, fourth, and fifth years of follow-up. And although that's a trend and not statistically significant, our view is that if that trend continues, that long-term survival with this drug is entirely possible, if not likely.

PALCA: All right. Let's take a call now from one of our listeners. Let's go to Margery(ph) in Philadelphia. Margery, welcome to the program.

MARGERY (Caller): Hi. I'm a medical student in Philadelphia, so this is very interesting to me. And my question is actually more about the FDA approval process. It seems like lots of these side effects happen later, after the drug's been approved. Is there any drive to make that process longer so that you have longer clinical trials before these drugs go into the public?

PALCA: Good question, Margery. Dr. Druker, how long did it take for the FDA to approve Gleevec?

Dr. DRUKER: From the start of clinical trials to approval it was three years. And it's an excellent question and one I've thought about quite a bit. I would actually say that we need to continue, particularly for cancer drugs, to try to move them along more quickly. But what we clearly need to do is to have a lot of post-approval surveillance looking for these kinds of side effects as the drugs are used in larger and larger numbers of patients.

The issue is that rare side effects are always going to be rare. You're only going to see them in maybe one in 1,000 patients. And if you require every drug to be used in 10,000, 20,000 patients, you'll never get a drug for a rare condition to the market.

So my view is what you need to do is you need to be able to get drugs to market very quickly but continue to have very vigorous post-approval surveillance to look for these rare side effects.

PALCA: Dr. Force, I wonder, so you spotted this possibly rare, although still to be determined how rare, side effect of Gleevec just by happenstance at a scientific meeting. Who is in a position to do this post-marketing analysis?

Dr. FORCE: Well, actually if you don't mind, I'd like to go back to one thing Dr. Druker said and that was about the incidence of heart failure being extremely low. I'd just like to ask how heart failure was diagnosed or how you would evaluate heart failure as a diagnosis in these patients.

PALCA: Actually, since we're going to talk more about it, Dr. Force, can you explain to those of us who aren't doctors what heart failure is, because it sounds catastrophic but I gather it's not really catastrophic, or it's bad but it's not fatal.

Dr. FORCE: Well, heart failure, the image that most people have is of someone sitting in bed with oxygen, sort of bed-bound and unable to get around. But there is a whole spectrum of heart failure, from the least affected is so-called - they're patients with asymptomatic left ventricular dysfunction, meaning they have a heart that is not working properly but they've not yet developed symptoms.

Now, those patients have, with that diagnosis, about a five percent mortality per year. And then that progresses all the way up to New York Heart Association Class 4 heart failure, which has about a 25 percent mortality per year. So there's a very wide range, and the idea is that the very advanced heart failure patient is quite easy to diagnose, but the patients with more subtle degrees of it are really quite difficult to diagnose, especially in a setting of a sick patient.

PALCA: So what you're saying to Dr. Druker is, maybe some of the patients that appear not to have heart failure actually have a preliminary version of it, or how would he know for sure that they didn't have the beginnings of heart failure? Is that right?

Dr. FORCE: It's probably a certainty.

PALCA: So let's go back to Dr. Druker and get the answer.

Dr. DRUKER: I certainly would not disagree with Dr. Force that there's a possibility that the incidence could be higher than we suspect because there could be patients who have relatively asymptomatic disease. But you also have to recognize that many, most of our patients not only are asymptomatic, but let me give you an idea.

I had on young woman who sent me a panicked email, should I worry about this? I'm doing well on Gleevec. Should I go for a bone marrow transplant, which has potentially a 15 to 50 percent mortality rate, or should I stay on my Gleevec? I wrote back to her with some reassuring words that I thought this was uncommon.

She then wrote back to me and said, well, thanks, actually, I feel better than I have in years. I went for a five-hour hike earlier today. So I don't think -I'm not worried about heart failure in a patient like that who's going for a five-hour hike. Other patients who might come to me with symptoms of shortness of breath or of some ankle edema, I would certainly think that we would want to evaluate their cardiac status a little bit more carefully.

PALCA: We're talking about the drug Gleevec, its fantastic ability to treat certain forms of cancer, but also a question about whether there are some negative consequences to the heart, not necessarily serious but maybe we just don't know yet. I'm Joe Palca and this is TALK OF THE NATION from NPR News.

So Dr. Force, just coming back to you. I mean, what do you think would be the appropriate next step here if you found these cases and you're concerned?

Dr. FORCE: Well again I think the diagnosis of heart failure is often made on the basis of symptoms and signs, as Dr. Druker pointed out, and those are notoriously ineffective ways of diagnosing heart failure, even when you have heart failure experts making the diagnosis.

So basically I think in relation to this agent, the same thing should be done that was done with Sutent, which just was released in January, and that is a baseline determination of left ventricular function and then a determination of function with the patient on treatment. And then we can really get a good idea of how rare this is.

Now, I don't think it's by any means common, but I think it's certainly not extremely rare, which is what has been quoted for this. So I just think we need to know. All we want to do is alert oncologists to be aware of this and if they see someone with fluid in their ankles and shortness of breath, check a BNP level - it's a simple blood test - or maybe get a determination of an echo, and that is simply not being done today enough.

So I think we need to address this issue, and with new agents going forward I think we need to consider making a determination of left ventricular function prior to and on treatment.

PALCA: Let's take another call now and go to Dave in Philadelphia. Dave, welcome to the program.

DAVE (Caller): Hi. Dave. I'm actually in Pueblo, Colorado.

PALCA: Oh sorry, Dave. I had a little glare on my screen. Pueblo, Colorado. All I could see was the P.

DAVE: Well, okay. Well I've got CML. I was diagnosed the 22nd of January and my white blood count at that time was 128. I took a blood test and a bone marrow just a couple of weeks later, it was 132. And then about the third week of March, second, third week of March I took - I started on a Gleevec regime.

And in a matter of - by May, I think it was, May or June, it had dropped to under 4,000.

PALCA: Well, now hold on. Since most of us happily aren't too familiar with what these numbers mean, maybe Dr. Druker, you can explain what Dave's just told us about his condition.

Dr. DRUKER: A normal white count should be 4,000 to 10,000. So his white count of 120,000 at diagnosis was quite a bit higher than a normal white blood count, and certainly very typical for a patient newly diagnosed with CML.

PALCA: Okay. So Dave, your experience with Gleevec sounds like it's been fairly positive.

DAVE: Positive. The only problem I've had with it, and it's not really attributable to it as far as know, is just a little bit of stomach discomfort. And that's tough. You have to take it with food, of course, and stuff like that. But it's wonderful. Now it's down to 3,000, and the last test I had I haven't received the results - it was last week - I expect it to be staying steady.

PALCA: Okay.

DAVE: So it's wonderful so far.

PALCA: Good. And hiking isn't a problem?

DAVE: So far I haven't done that. I don't get out and exercise a lot. Right now I do my walking, a little bit, probably a half a mile or so. But I don't really push it. It's not something I want to try to do. I mean, I'm still tired. I wake up in the morning tired, go to sleep at night tired. It's a very tiring and exasperating disease. But you know, I didn't want to walk a mile and find myself unable to get back.

PALCA: No, I understand. Well Dave, thanks for the call. It does - I mean, I only ask that question because, you know, I wanted to see one person's experience. But I guess, Tom Force, you would say that anecdotal evidence is probably not what's called for here.

Dr. FORCE: Well, that's a wonderful story, and that's what this drug has done. It's totally revolutionized the treatment of this disease. And all we want to do is not trade one disease for another and trying to get a sense - now, again I want to reassure anyone who's listening, this is not going be a common side effect. But what we're trying to do is identify how common it is, treat it aggressively so that they can continue on this life-saving treatment.

PALCA: Okay. Well, I wish we could go on and ask more questions, but I'm afraid that's all the time we've got. So I'd like to thank my guests this hour. Thomas Force is James C. Wilson professor of medicine at the Jefferson Medical College of Thomas Jefferson University; and Brian Druker is the JELD-WEN Chair of Leukemia Research at Oregon Health and Science University Cancer Institute in Portland, Oregon. Thank you both.

Dr. FORCE: Thank you.

Dr. DRUKER: Thank you.

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