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Slide #1
SANDRA HORNING, MD: At this time I would like to welcome back Dr. Christos Emmanouilides. Many of you know, Dr., Emmanouilides is an Assistant Professor at UCLA. He helped us out yesterday in the indolent lymphomas. Today he is going to talk about radioimmunotherapy for non-Hodgkin's lymphoma as well as other antibody treatments. Thanks again.
CHRISTOS EMMANOUILIDES, MD: Thank you. It's a pleasure to be again here. In the next 10-15 minutes I will cover mostly the basic elements about radioimmunotherapy -- how it is developed, what kind of results we have had so far and what future application we may have in the future.
As you know, radioimmunotherapy is a new modality in the treatment of any cancer. And again, lymphoma has the very first -- after Rituxan. You know Rituxan was the first ever antibody approved for any cancer. It was lymphoma. Then other antibodies followed. Radioimmunotherapy again was first approved for lymphoma. Again we have the first ever new modality product in lymphoma and then I am sure others will follow.
So Zevalin was approved in February of 2002. That means this year by FDA for the treatment of low-grade follicular or transformed lymphoma.
Slide #2
Now Zevalin is radioimmunotherapy. That means it does use an immune product, immunological product which is the monoclonal antibody. The monoclonal antibodies are used to target certain cells, in this case, is lymphoma so that the antibodies that are used to target and adhere to lymphoma cells can also activate some mechanism of destruction of the lymphoma cell, but they can also be used a carriers of important anti-lymphoma agents.
In this case, the type of lethal carrier that the antibody carries is a radioactive isotope. I am sure that you have heard that in other instances we use antibodies to deliver targeting in a targeted way, toxins. So the antibodies are a very good carrier if you want to deliver specifically to your target a lethal sign and thus, spare the normal cells.
Slide #3
Lymphoma is very sensitive to radiation, as you know, with traditionally treated with external beam radiation. But when you do that, you radiate the tissue that lies over and underneath the lymphoma mass. And you do not treat the areas; you do not irradiate.
On the contrary, when you infuse the radioimmunotherapy compound, the antibody will seek all the targeted cells, in this case, lymphoma. It carries the radioactivity with it and will irradiate all of them wherever they are.
Slide #4
As a choice of radioactive isotope, as you probably know, the two most commonly used are yttrium 90, symbolized by Y, and iodine 131, symbolized by I. You've heard that Bexxar uses iodine 131; Zevalin uses yttrium 90. We believe they are equally effective, but FDA approved Zevalin first.
The half-life or physical life of the isotope is 64 hours. That means radiation decays by 50% in 64 hours. If you allow several half-lives to pass, that means roughly a week's period, there is no more radiation left or a significant amount of radiation left.
The other convenience associated with this isotope, therefore with Zevalin, is that it emits beta radiation. And as you probably remember from your high school or maybe junior high, beta rays are electrons. They're particles. They don't travel much in matter. Actually, they travel up to one quarter of an inch.
In other words, if I'm loaded with yttrium 90 right now or Zevalin, you receive insignificant amounts of radiation. On the other hand, iodine 131 emits both beta and gamma radiation. The beta component is emitted locally, that means the lymphoma mass. But the gamma component, they travel through matter and radiate the environment to a certain extent. If I have iodine 131 in me, you will all be receiving a small amount of radiation.
Slide #5
That has a lot to do with radiation safety. Not that much to do with efficacy as I explained to you earlier. The results we have had so far with the two products are essentially equivalent. But if something emits beta radiation, you can handle it by protecting yourself with a plastic sheet or a plexiglas. It's very easy. But if you use a gamma-emitting isotope, you need to have lead protection which is more cumbersome.
Slide #6
This is a schematic representation. This Zevalin is the parent antibody to Rituxan. It is the murine antibody that was first generated in mice that were injected with human lymphocytes. And with making this chimeric (that means, partially humanized) we have Rituxan. And it is bound to yttrium 90 by this linker, which mediates a very strong adhesion here. So yttrium 90 does not really fall of the antibody which would have been a very bad thing. And this ligand is called tiuxetan. You don't have to remember these names. They're worse than my last name. But the murine antibody is called ibritumomab. For the sake of terminology, this linker is called tiuxetan. And thus, you have ibritumomab tiuxetan, which you may see in the publications instead of the trade name Zevalin.
Slide #7
That's how the FDA has approved its use. First, we give a dose of Rituxan which is lower than the conventional use. It lasts about four hours of infusion. The reason for this is to cover the CD20 on the surface of the normal lymphocytes, so that when you give the radioactive antibody of interest, it does not stick to the normal lymphocytes in the blood. They are already covered with Rituxan. So this antibody can go to the tissues and find the lymphoma.
Indium 111 is used for the purpose of imaging because we would like to make sure doing gamma-camera scans here. In other words, the test dose, if you will. We use a test dose of radioactive antibody and then we do the gamma-camera scans which really are a type of moderately sophisticated photographs that read not light, but gamma ray emission -- from the small amount of gamma activity in this compound. That's to make sure that the distribution of antibodies is optimal and for some strange reason will not go to one of the vital organs, like the brain, the lungs and the kidney, etc. It almost never goes. Actually, I think there was only one case where the distribution of the antibody was not optimal.
The nuclear medicine doctor reads these scans with the naked eye. It's very easy. I'm going to show you some pictures and gives the green light for the treatment. The treatment is given one week later, again for a dose of Rituxan for the same reasons, for the purpose of covering whatever B cells may be in the blood. So that the radioactive antibody of interest, which is the yttrium 90 Zevalin, will not stick to the blood but slowly will diffuse to the tissue where the lymphoma is, or the bone marrow. And this is given one week later.
The dose of Zevalin is based on kilograms of recent body weight.
Slide #8
Here is a representative example of some of the scans we do. After we infuse the tracer Indium labeled antibody, we see the heart and the major vessels basically. Which is normal to see, first the antibody sticks in the blood circulation for the first few hours. This particular patient has a mass in the abdomen. Here the conglomerate of lymph nodes which also show positive in the PET scans here.
Eventually, as time passes, you see that the abdominal mass becomes white. White means uptake of radiation. And we know that radiation then goes to where it is suppose to go. The liver is the normal organ that absorbs some of the non-specific radiation, but the level is not high. And the other organs are -- the other bodies are dark. That's how it is supposed to be. The lungs which are here, are not thin. It's supposed to be like this.
A nuclear medicine doctor will read this and give us the okay because we have localization of the tumor and we do not have white-out of the lungs or the kidneys or the brain or so on.
Slide # 9
There have been four major studies with Zevalin before it was approved. But I am going to show you first, the most important I think. And usually in oncology or in medicine in general the most important studies are the randomized ones because they eliminate most of the bias introduced by phase II studies. And you have really two comparable arms to compare.
So in this study that involved patients with low-grade follicular or transformed lymphoma including small lymphocytic lymphomas and other low-grade categories. Patients were randomized. That means randomly assigned to either of the two arms. This assignment was independent of our wish. It's not that we put our best patients to Zevalin and our unpleasant ones to Rituxan. But that was independent of anybody including the patients. So half got Zevalin; half got Rituxan. It was completely randomized the same way as we described it earlier.
Slide #10
Pay attention please to some of the enrollment criteria because you sort of need to be aware. They have state and they govern how we use Zevalin now and commercially outside of a clinical trial. The amount of bone marrow involvement by disease has to be less than 25%. In other words, if patients have excessive bone marrow involvement by lymphoma, they didn't qualify. Performance status has to be fair. But platelet count in this study has to be more than 150,000. And now we know that we can give Zevalin if the patient's platelet count is more than 100,000, but not if it is less than this. That's a major eligibility criteria. So the platelet count is important. If it is over 150,000, it's okay. If it's between 100 and 150, then we give a reduce dose of Zevalin. If it is less than 100,000, we don't give it at all.
In this study we excluded patients with sick lymphocytes like CLL, but there is no good reason why this cannot be treated. But that's another story. No prior high-dose chemotherapy. No prior Rituxan in this particular study. We wanted the patients to be Rituxan naïve and no prior extensive radiation therapy to any part of the body. Spot radiation to a lymph node area was allowed.
Slide #11
To make a long story short, patients treated with Zevalin had an overall response rate -- that means 50% or more reduction of the lymph nodes in 80% of the time. With Rituxan, as expected, the response rate was about 50% which was not a surprise there. Also the complete response, that means complete disappearance of any abnormal adenopathy, lymph node size and negative bone marrow. Lymph nodes less than 1.5 cm and negative bone marrow was more common in the Zevalin arm than compared to Rituxan.
So there is no question that Zevalin is more active compared to Rituxan in terms of inducing response. And that makes a lot of sense because Zevalin incorporates some Rituxan plus radiation which Rituxan, of course, lacks.
Slide #12
The duration of response was not very dissimilar. Duration of response for Zevalin arm was 14 months and for the Rituxan was 12 months so very comparable here durations of about a year.
Slide #13
But the time to next treatment for patients excluding those who had transformed lymphoma who progressed very fast, favored the Zevalin arm. The yellow curve is the Zevalin; the green is the Rituxan. That means although the time to progression or the duration of response was about the same, some growth of the lymph nodes occurred in both arms about on average one year. The growth was less significant in the Zevalin group because the need for treatment was much delayed.
And in a clinical trial if you have a lymph node which is half an inch and it becomes three-quarter of an inch, we call this a progression so even a small increase of no significance can qualify as progression. I think that's what happened here.
Slide #14
The absorption of radiation to the vital organs was all within the safety. The safety is less than 2,000 of these units centigray. And the liver which looks the hottest, still is 450 on average, well below the safety level and in fact, we have not seen any liver toxicity with this product when given at the allowed doses.
The tumor area received on average 1400 rads but the range is very high. And some nodal masses receive up to 20,000 rads which is a very high dose.
Slide #15
Side effects. You don't get so much improved response without paying the price. And the price is that as opposed to Rituxan there is a drop of the white cell count with Zevalin. So that the average say person's neutrophils will drop to 800. If you remember, neutrophils normally are over 2,000 in steady state. With chemotherapy they usually drop to between 500 and 1,000 with CHOP, let's say. So the drop of neutrophil we see here is very comparable to what we see with chemotherapy. We see somewhat more drop of platelets compared to what we see for chemotherapy. The duration of this low white cell count is about two weeks.
Slide #16
But in contrast to chemotherapy, this drop occurs later.
When we give chemotherapy, the drop occurs on the second week here. The curve would go like this. This ANC means neutrophils. It means the white cells and with chemotherapy they would have gone like this. The same, the platelets would have dropped like this and then gone up.
With this treatment, the drop is much delayed -- something to remember in case you get treated with Zevalin. Expect the low blood counts to occur on week 6 or 7, after the treatment.
Slide #17
But what about in the Rituxan world? As you remember in the previous studies, patients did not have Rituxan treatment before. There was another study actually now published in the Journal of Clinical Oncology for those of you who like to review papers. It's an interesting paper.
Fifty-seven patients with follicular lymphoma who had Rituxan and Rituxan didn't work anymore or worked for a very brief period, were given Zevalin the way we discussed it. 74% of them had a response rate; 15% had a complete response and the duration of response was over 8 months. So still Zevalin retains a substantial activity even if Rituxan is not effective any more.
Slide #18
Because of incorporation of radiation in Zevalin we had the concern about older patients. If you examined the patients over 65, not very old, but that's the usual cutoff when we talk about elderly in oncology -- 65. They may not be, but what can we do.
Anyway, so those were 65 years old or older. There were 71 patients or more enrolled in these studies in the four clinical trials. They still had the same response rate as the younger patients with a very high complete response rate, the same type of neutropenia. They did not have increased infections compared to the other people.
Slide # 19
That brings me to this slide that shows that Zevalin really is not associated with a high risk of infections. And that is reassuring because with the amount of drop of the white cells we see sometimes with Zevalin, which compares to chemotherapy, we would be worried. But in fact, it looks like we see much less neutropenic infections compared to let's say chemotherapy course. And my explanation for this is that when we give chemotherapy and we induce a drop of the white cells, we also damage to a certain extent (sometimes it is not perceptible) the lining of the mouth and the bowel. And the bacteria that live in the mouth and the bowel find little cracks through the lining and they enter the blood stream and they cause infections.
Because Zevalin targets only the B lymphocytes and not nonspecifically other replicating cells like the lining of the mouth and the bowel, we see much less infections. We see no opportunistic infection like PCP or things like that. And the level of I to G, that means the native antibodies does not change over all with Zevalin.
Slide #20
Okay, there is no question that Zevalin is an active treatment, has very few side effects. The patients feel well when they get it. The only reaction really they get is the reaction to Rituxan, to the infusion of Rituxan. And actually because the reaction to Rituxan usually occurs in the first infusion, and I show you that Zevalin is given in two weeks. One week apart, there are two treatments. The first is a testing dose with Rituxan. That's when people experience the fevers and the hypertension, etc.
The second week when they come for the actual treatment with Zevalin we give the Rituxan, they have no side effects because it is the second treatment. Usually, the side effects occur with the first. Then we give the Zevalin over 10 minutes and that's the active treatment and people are conditioned to associate an efficacious treatment with a lot of side effects. So they don't get nausea. They go home they feel fine. They can go to work the next day as opposed to chemotherapy. They don't feel down. They don't glow in the dark because the radioactive compound doesn't show. [LAUGHTER] It's not perceptible. They think nothing happened so it is a little bit anticlimactic. But then, they do see a response a few days later and people become happy again. [LAUGHTER]
So the results shown to be induced by Zevalin are equivalent, I think, to most chemotherapy would use for relapsed lymphoma. So you can think of this instead of chemotherapy.
For patients who want to have a treatment complete over one week as opposed to several months of chemotherapy, Zevalin is a good alternative. When Rituxan ceases to be effective and the person does not want to go on chemotherapy, then Zevalin is a good alternative. When chemotherapy is given, but the result is not satisfactory and people are still bothered by the presence of a lymph node or lymph nodes, then Zevalin can treat this residual disease. But we cannot use Zevalin if the bone marrow is too much involved or the platelets are low.
Slide #21
And this is the final slide. How can we incorporate Zevalin in the future to manipulate it so it becomes more useful in our hands? And you heard some things earlier today.
First of all, in aggressive lymphoma it is active to a certain extent. The very early studies show that 40% response rate, but there is no FDA indication right now. But I can see a patient who does not want to have aggressive treatment with chemotherapy and wants to have palliative treatment, then Zevalin may be a good treatment.
The treatment with Zevalin it looks like it is possible -- the studies are going on at Mayo Clinic right now. The treatment seems to be successful. Given immediately after chemotherapy, studies are going on and you've seen something earlier in an effort to consolidate, as we say, or further treat the residual disease after chemotherapy. Before or after stem cell transplant -- you heard this earlier. In CLL, Waldenstrom macroglobulinemia, studies are going on. And finally in patients with more than 25% bone marrow disease, studies will be starting, I hope, next year at UCLA.
Thank you for your attention. I think questions will be at the end of the session.
[APPLAUSE]
SANDRA HORNING, MD: We can take a couple of questions for Dr. Emmanouilides.
Q: Dr. Emmanouilides, can this be done as an outpatient -- the whole treatment?
CHRISTOS EMMANOUILIDES, MD: Yes, definitely outpatient. It requires two full-days of treatment one week apart.
Q: Hi, doctor. I was wondering, you indicated that for the actual study you did, you didn't accept patients that had high doses of chemotherapy, like autologous stem cell, I guess, transplant? Now that Zevalin has been approved is this an option for someone who has recurrent lymphoma after radiation and stem cell transplant?
CHRISTOS EMMANOUILIDES, MD: That's a very good question and I have it myself -- there is an answer. The answer is that there is a clinical trial going on by Dr. Julie Vose and I am afraid she is gone. It looks like that she has escalated the dose of Zevalin up to .25 millicuries per kilogram. So this is a possibility.
I would suggest that if somebody wants to have this treatment to contact Dr. Vose and get an opinion. I think that if the other conditions are met, .25 millicuries per kilogram seems to be a safe dose.
Q: Great. Thank you very much.
Q: I wondered if there were any studies being done using Rituxan and Zevalin together as an initial front-line treatment for follicular lymphoma or any tests that might be in the planning stages for that as an initial treatment?
CHRISTOS EMMANOUILIDES, MD: There are studies going on using Zevalin followed by Rituxan in relapsed lymphoma. Now the upfront treatment requires some thinking because this is a new drug and we don't know the long-term side effects. And it has to be in a setting of a clinical trial. There has been a clinical trial with Bexxar upfront and the response rate was 100% in patients with low-grade lymphoma. I suspect similar response we will see with Zevalin. Right now there is no study like this to my knowledge, but there is a study with abbreviated course of chemotherapy and Rituxan, but it's not full six cycles (but three cycles) followed by Zevalin. And this study is going on, I think, by Dr. Hainesworth.
Q: What is the issue with platelets? I mean you can get platelet transfusions?
CHRISTOS EMMANOUILIDES, MD: Platelets is a surrogate marker of a weak or damaged bone marrow. And actually, it's one of the most successful markers for a subdued or heavily pretreated bone marrow we have. And we're afraid that if we treat with radiation, radioimmunotherapy which involves some small but some bone marrow radiation, and bone marrow is already sick, we may have prolonged cytopenias and we want to avoid that.
Q: Mine isn't a question, Doctor. I'm one of your poster children. I participated in Leo Gordon's arm of the clinical trial and I am cancer free four years out from it.
CHRISTOS EMMANOUILIDES, MD: That's wonderful.
Q: Just wanted to let you know that.
[APPLAUSE]
CHRISTOS EMMANOUILIDES, MD: Congratulations. That's the longest I've heard. You taught me something.
Q: How soon after Campath can Zevalin be administered?
CHRISTOS EMMANOUILIDES, MD: I don't think there is experience about this. But it makes sense that if you have somebody with CLL -- actually I had proposed this study to some sponsors -- to use Campath to eliminate the bone marrow disease and then for the nodal disease in CLL, or small lymphocytic lymphoma use Zevalin. There is definitely a possibility there. There are some safety concern about the sequence but something that needs to be explored in the future, I think. I think it may be very promising sequence.
SANDRA HORNING, MD: Okay.
CHRISTOS EMMANOUILIDES, MD: Thank you.
[APPLAUSE]
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