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Slide #1
LEO GORDON, MD: I'm going to speak about diffuse, aggressive lymphomas, including diffuse large cell lymphoma, a little bit about lymphoblastic, Burkitt's/non-Burkitt's and try and focus mostly on an overview, a background, give you a little bit of information about where we are today and then spend most of the time, I think, talking about new ideas, new biology, which I think is the way that we're going to make improvements in all of these diseases. So that's what the focus will be.
We'll talk a little bit about the clinical trials that result - new treatments that results from the new biology, a new understanding of these diseases. So that's going to be the focus. I'll take maybe about 45-50 minutes or less than a hour speaking about that. We'll try and leave plenty of time for questions where I hope that you'll be able to kind of voice concerns and cover areas that maybe we didn't get to talk about.
When you do come up for questions, I have been asked to remind people to use the microphone in the middle that's been set up so that everybody can hear you and the taping can go on.
Let me - soon as I can figure out how to work this - let me go ahead and start? This is going to be the format that we're going to use. I'm going to talk a little bit just to give you an overview and a background of non-Hodgkin's lymphomas, the aggressive lymphomas. I'll talk about the clinical prognostic factors that we're using today based upon the so-called international prognostic index that you've, I'm sure, heard about. We'll go over that just a little bit.
We'll talk about results of therapy today and how to predict outcome. Then we'll talk about how we're going to improve or how we'd like to be able to improve treatment options for people with large cell lymphomas. And the way we'll do that is to focus on the concept of targeting antigens using, for the most part, monoclonal antibodies. We're going to talk about the new biology, a little bit about the gene chip and gene array chromosomes. We'll talk about where chemotherapy might fit in in light of this information. We'll talk about, perhaps, combinations of antibody and chemotherapy.
We'll spend a little time - because I think this is now relevant to the large cell lymphomas - we'll talk a little bit about angiogenesis and the role that antiangiogenesis-like therapies are going to play in the large cell lymphomas.
We will talk about stem cell transplantation, its role in treatment and also talk about, again, as a new modality, not only targeting antigens on the surfaces of the cells, but also targeting DNA, targeting cell signal pathways. We're beginning to learn more and more about what makes cells grow. We're going to talk about how to manipulate that to the advantage of treating the disease. So that's the general overview. At the end, we'll see that slide again.
Slide # 2
This slide, I'm sure you may have seen before, but this is just a reminder slide that tells us - this is all of the non-Hodgkin's lymphoma subtypes, classified by the so-called real revised European/American lymphoma classification a number of years ago.
The diffuse, large B cell lymphomas make up a large proportion of these. When you add to that the relatively rare Birkett's and Birkett-like lymphoma or lymphoblastic lymphomas, the anaplastic large cell lymphomas, mediastinal large B-cell lymphomas, we're probably talking about 40% roughly of all of the non-Hodgkin's lymphomas fit into the category of the ones that we're going to talk about, so the aggressive or the diffuse aggressive lymphomas.
Slide #3
If you look at it another way on this slide, this kind of summarizes everything, I think, to some extent. If you look in the black boxes and specifically in the yellow are the ones that we're going to talk about today. When I first made this slide, I included mantle cell lymphoma, but there is another session on that. I may say a word or two about mantle cell lymphoma. Sometimes it sort of slips into the discussion of the aggressive lymphomas.
But we will talk about the others, primarily the diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, some of the high grade lymphomas.
You'll find here sort of an errant category, a difficult one to classify, I think, and that is the follicular center cell, follicular lymphoma grade 3.
We'll talk about the various grades a little bit. I think most people would put the follicular grade 3 lymphomas in the aggressive category, but we've now begun to divide grade 3 into grade 3a and grade 3b. It may be that the patients with grade 3a follicular center cell lymphoma fit perhaps better into the low grade categories, those with grade 3b into the high grade category. But we're going to talk about that a little bit more.
This is the group that we're going to be spending time on.
Slide #4
I thought what I would try to do as a summary is to give you kind of an algorithm for an approach to therapy for clinical management of the aggressive B-cell lymphomas. And this is, again, one way of looking at it. There are going to be two slides here. We'll look at these. We're going to spend a few minutes on these slides.
First of all, when you divide this, you can divide this into presentation, how the disease presents itself. So it might be localized, perhaps one or two lymph node areas and that's all. It might be more advanced, so that patients have more advanced disease, maybe bone marrow involvement or disease above and below the diaphragm, putting them into the Ann Arbor stage 3 or perhaps even 4 disease.
If they present with advanced disease, they may be younger or they may be older. That definition is sort of an arbitrary one, but it's the one that was chosen by the international prognostic index. I like to figure older and younger is I kind of like to add one year to my age and that's younger. Then everything else is older. (Laughter) But that doesn't seem to work.
The localized presentation, I think we know from studies that Tom Miller reported in the New England Journal a number of years ago when there was a comparison trial between giving chemotherapy with CHOP, Cytoxan, adriamycin, vincristine and prednisone for three cycles with involved field radiation, compared with CHOP for eight cycles without radiation. The original data, the original presentation in the New England Journal suggested that the CHOP for three cycles did a little bit better than patients who had CHOP for eight cycles without radiation.
It's interesting to know that actually the update of that data looks like there is probably not a big difference anymore compared to what there was before. So I think either one of these options is a reasonable one for patients with localized disease, stage 1 or 2 disease large cell lymphoma.
Patients presenting with more advanced disease who are younger, I think, are excellent candidates and I think should be treated still with anthracycline-based chemotherapy. Our study back in 1992 and then Rich Fisher in 1993, there were two trials looking at CHOP compared with other chemotherapy regimens. And both studies showed that there was not a difference between CHOP and the other regimens. I think that everybody is aware of those studies.
I think that still curative anthracycline-based chemotherapy in this setting is probably still the standard of care. We still don't know the role for rituxan in younger patients. There is a trial ongoing in Germany, in Europe, looking at the same question that the French group looked at in older patients, now being looked at in younger patients. Otherwise, it has not been looked at in younger patients yet.
For patients who are over 60, the so-called GELA group reported, and I will show you some of the information, some of the data on this, that it was better to add rituxan to CHOP. The Eastern Cooperative Oncology group studied it a little bit differently, a little bit different combination or different regimen of rituxan and CHOP. The data on that are still outstanding. We don't really know the answer to that in the ECOG trial. I think for the moment, we're left with this study, and we will get more information.
The other piece of information that's being addressed in the ECOG study that hasn't been addressed really yet is the role for maintenance therapy with Rituxan in patients with large cell lymphoma. So that's question that, I think, bears waiting for an answer. It's an important - I think an important question.
Slide
So looked at in a little bit more detail, we can talk about treatment. This is going to kind of summarize everything that we're going to talk about, and then I'll get to more detail on it. So you can view this as kind of an overview. I said earlier, again, that if you start treatment for aggressive non-Hodgkin's lymphoma, that treatment might be chemotherapy-based, chemotherapy alone. It might be biological, that is cytokines or biologics of some kind, either alone or together with chemotherapy. Then if it's biological, that treatment might be specific like Rituxan, for example, or a number of other options here. We'll get to these in a second.
Or it might be nonspecific -- sort of a nonspecific attempt to increase or improve the immune system like interferon or interleukin might do. Not specifically, but just sort of a generic attempt to increase the immune system. That's what that drug does.
Transplantation - the role for transplantation, stem cell transplantation is becoming a little bit more fussy even than it was, and it was fussy before. The questions that remain, I think, are - first question, autologous or allogenic transplant, which is the best? The second question, if you're going to decide to do a transplant, if you're going to do decide to either one of the two, should it be done upfront as part of the initial treatment, or should it be done at the time of relapse? I think we don't know the answer to that question either.
Then if it's an allogenic transplant, should it be a full allogenic transplant, a traditional or standard allogenic transplant, or should it be the so-called mini- or non-myeloablative transplant that I think Issa Khouri is going to talk about, or did talk about some time over this weekend.
So a couple of points to make about chemotherapy. CHOP or CHOP equivalent, I think, is still the standard or certainly in the United States that's still the standard. In most of Europe, it's still the standard.
In some places in Europe, in France especially, a slightly different regimen, the so-called ACVB regimen, a little bit different than CHOP, is being used. That's been their standard for a number of years.
We have tested and others have tested and there may be some revival, perhaps, of variations of the ProMACE/CytaBOM at increasing doses that we try to do and others have tried to do, maybe addition of Rituxan is going to be looked at with that regimen.
Then the studies from Germany looking at variations on CHOP, a two week CHOP regimen as compared to the three week CHOP regimen. Recently, the German group did reports on improvement with giving the CHOP every two weeks rather than every three weeks. That turns out to be very similar actually to ProMACE/CytaBOM where there is treatment a little bit more often.
In terms of antibody-specific biological therapy, antibody plus chemotherapy, so the standard has become CHOP plus Rituxan, especially in patients over 60. One of the questions that's being addressed now is the issue of how to make monoclonal antibodies better. One way to make monoclonal antibodies better might be to begin looking at radioimmunotherapy, so either Bexxar or Zevalin added to the Rituxan perhaps and added to CHOP. We're beginning some discussion with the National Cancer Institute now about beginning combination trials of CHOP chemotherapy and radioimmunotherapy, perhaps to replace radiation, perhaps to replace Rituxan.
There is a role, we think, for angiogenesis-type treatment in large cell lymphoma. There are reasonably convincing data, and there is now a trial that is open for newly diagnosed patients with large cell lymphoma - I'll talk about that in a moment -- where we combine an antiangiogenesis agent and Rituxan and CHOP chemotherapy. That's ongoing.
The role for vaccines has not really been investigated to a great extent in large cell lymphomas. What I would say is that there are probably two places where it might fit. First of all, the follicular center cell grade 3a patients - so grade 3, but grade 3a - are eligible for the National Cancer Institute vaccine trial of PACE chemotherapy with a randomization to receive or not receive a specific vaccine. So the follicular grade 3a are eligible for that, so vaccines do play a role there.
Then Linda Wilson at the National Cancer Institute has begun a trial in mantle cell lymphoma looking at the role for vaccine in that disease. So I think we're going to start to see more vaccine questions in the more aggressive lymphomas.
Then you'll hear a little bit tomorrow from Julie Vose about antisense therapy and other molecularly-based treatment in the diffuse large cell lymphomas.
I think some of the questions about combinations of Rituxan and maybe Rituxan with transplantation are going to be relevant in patients with Birkett's or lymphoblastic-type lymphoma where that's being used a little bit more commonly.
Slide #6
So a couple of points about the international prognostic index. This is what we currently utilize to try to predict outcome. This was based on a study that Margaret Shipp from Boston reported in the New England Journal in 1993. Basically, this is a fairly common sense assessment of - sorry - common sense assessment of the disease looking at risk factors. So we know that age might be a risk factor. It turns out that it probably is. Patients greater than 60 versus less than 60.
Performance status - this is a fairly subjective assessment, but it tell us whether people at the time that they have the diagnosis feel well and are without symptoms or whether they're sick, have lost weight, have fevers. That influences the performance status. So good performance status - meaning asymptomatic - is better than bad performance status, as it turns out, and not surprising.
The LDH level, either normal or elevated. Our own studies suggested that the higher the LDH level, perhaps, the increasing risk for recurrence. LDH, I think, is a fairly important criteria.
Extranodal involvement, the number of extranodal sites, meaning sites other than lymph nodes. So bone marrow or lung or liver are all considered to be extranodal sites.
Then the Ann Arbor stage, the old sort of old staging system still plays a role, but it's only one of a number - five different criteria that are figured in in trying to assess a risk.
Then if you look at patients less than 60, it sort of winnows down to three different criterion that you can use, performance status, LDH and stage. I actually think that if you look at it carefully, these are probably the most important criteria for everybody, I would say.
Slide # 7
So the staging is something, I think, all of you have probably seen. Stage I through IV, one lymph node region, two or more lymph node regions. But on the same side of the diaphragm, above and below the diaphragm and then multiple sites.
There is one problem with this staging system. It was based - it was developed for Hodgkin's disease. It was developed for a disease that tends to follow an orderly pattern of lymph node involvement from one lymph node region to the next. We applied it many years ago to the non-Hodgkin's lymphoma, but it doesn't, I think, really fit. Non-Hodgkin's lymphoma doesn't have that orderly pattern of progression from one lymph node region to the next. So this is an anatomically-based staging system, meaning that it's based upon locations in the body where the disease might be. It assumes orderliness and the non-Hodgkin's - the aggressive non-Hodgkin's lymphoma don't tend to be as orderly as we'd like them to be. So that's why I think that this staging system by itself falls down quite a bit and we need that other one that I just showed you. But I think it's still an important part of that other one, so I kept it on here and I think it's worth mentioning.
Slide #8
I didn't show you our data, but I showed you Rich Fisher's data from 1993. He did a four arm trial, basically telling us that as we found a year or two earlier, that there was not a difference between CHOP and any of the other chemotherapy regimens. Now again, this is before the international index. And all of these survival curves I'm going to show you have a caveat here. All the survival curves I'm going to show you are for people with the best and the worst. It's everybody together. None of these specifically apply to anybody here. These are all general curves that reflect patients of all kinds. That's my caveat for any survival curves that I'm going to show you. So don't put yourself here. It's much more important to know where you are in terms of risk factors.
But basically, the point is that these curves are about the same. That's the major point of this slide. So this is telling us that we need to do a little bit better than we have been doing. So how do we do that?
Slide #9
How do we get better at the treatment of these diseases? What are the ways that we can do it?
I'll tell you, the bottom line, I think, is the way that we get better is to do more basic research at understanding what's happening, what's causing the diseases, what's regulating the cell. That's how we're going to get better.
One way to start, one of the early advances was made a number of years ago where it was recognized that there were certain antigens, certain proteins on the surface of the lymphoma cells that were very constant. We want these antigens to have certain characteristics. First of all, we'd like them to be expressed on all the tumor cells. Obviously, if you're going to get rid of all the tumor cells, and you're going to target some protein on the tumor cells, you want them to be present on all the tumor cells. You don't want them to be present on host cells, on normal cells.
This is where actually Rituxan falls down a little bit because as you may know - and I'll point out in a minute - that the antigen that we target for Rituxan is present on normal B-cells as well as on abnormal B-cells. So Rituxan sort of violates this first rule, not present on critical host cells.
We also want there to be no significant toxicity if all the antigen-positive cells are eliminated. So, for example, if we eliminated all the B-cells in the body with Rituxan, which we actually do for a period of time, we want the body to be able to compensate for that. Fortunately, we can. We do compensate, probably with our T-cells and our other cells. So we don't see lots of infections with Rituxan, which is obviously a good thing. We want there to be a lot of these antigens so that it's easier to target.
We want there to be no mutations or variations of these antigens so there can be escape by the tumor. We want the antigen to be required for critical biologic function or cell survival. In other words, if we target an antigen we want it to make a difference. We want it to be able to no longer be able to support the growth of the malignant cell.
Then we want the antigen and the antigens that we've tested before CD-20 have this strange characteristic sort of like a turtle sort of putting its head back into its shell when you target an antigen to it to escape the antigen. It's a very clever system that has evolved unfortunately.
So we want those antigens to not be shattered, secreted or not modulated in their expression.
Slide #10
So fortunately, basic work done by a number of investigators, David Maloney among them, we were able to identify this protein, this so-called CD-20 antigen - this is a schematic of that protein - on the surface of both benign - both benign - and malignant B lymphocytes, sitting right here on the surface of the cell. Fortunately, again, based on the work done many years ago by Koehler and Milstein, who won the Nobel prize for this, the technology for developing monoclonal antibodies - antibodies that are generated against the very specific little piece of a piece of a cell, can be generated by a very simple but elegant kind of technology. Most of the simple technologies that are good technologies and breakthroughs are elegant, I think.
Rituximab or Rituxan is a genetically engineered antibody, which shares both mouse - murine is mouse - or human features. As it turns out, if you look at this schematic, the purple part is human and the variable, the so-called variable region, sort of on the ends of this Y-shaped structure, are the murine part, or the mouse part. So it's part human, part mouse antibody. It was, as it turns out, the first monoclonal antibody to be approved by the FDA for the treatment of any cancer, and made a difference, we think, in the treatment of lymphoma.
Slide #11
This is another schematic showing you the presence of these sort of spikes of CD-20 antigen on the surface of the B-cell and this antibody that's sticking to these antigens, antibody sticking to antigens.
First of all, why CD-20? Well CD-20 fit most of - not all - but most of the criteria that I just talked about. It's membrane bound. It's easy to get to. It's stuck on the surface of the cell. It's not buried somewhere inside the cell. It's expressed in more than 90% of B-cell lymphomas. Not 100%, but 90% or so. It fortunately doesn't shed, it doesn't internalize, or it doesn't modulate. Although when I say it doesn't shed, there is some recent data that I'm seeing from MD Anderson suggesting that if we look for it, we can measure circulating CD-20 in the serum, in the plasma. That might be one of the reasons for variability in response to Rituxan. It's a new observation. It's not published yet, but it's an interesting finding and it's something we'll have to deal with.
Then the data with Rituxan proves this paradigm, proves that you can get responses from a monoclonal antibody - this is mostly in low grade lymphoma - with just using the antibody. About 50% responses or so.
Slide #12
But what about other antigens? Is CD-20 the only one that we want to look at? Well, if you look at the cell on this slide, there are clearly other antigens that are present that might be worth reaching for or targeting. So there are a number. This CD-22 is one of those that I think is going to be important. There are studies with anti-CD-22, something called erpratuzumab, which a number of investigators are doing. John Leonard in New York was one of the first to start doing trials with anti-CD-22. These are being done in the diffuse aggressive lymphomas. So these are the concepts.
By the way, this surface immunoglobulin here, it's like an antibody, just like this, but it also sits on the surface of the cell. This is a unique antibody to each individual patient's lymphoma. This is what we call the IDs, the idiotypes. This is to what the vaccines are being made, this sort of piece right here. Not these, but this piece right here - just as a point of information.
Slide #13
So the monoclonal antibodies that have been tested for the aggressive non-Hodgkin's lymphoma have been these two primarily, Rituxan and LymphoCide or erpratuzumab. Rituxan, as I said is chimeric, CD-20. The erpratuzumab is humanized, meaning it's kind of one step beyond chimeric. It's a little bit more human than the chimeric antibody. It's got more human structure to it, a little bit less mouse structure to it. So these are the two that are being tested in the diffuse aggressive lymphomas.
Slide #14
The other point to make is that there are differences in the amount of CD-20 that's expressed in different diseases. So again, from this slide we can see - and you don't have to look through all of these - but the point to make is that patients, for example, with CLL, chronic lymphocytic leukemia, express very low amounts of the CD-20 antigen on their surface. Patients with hairy cell leukemia - rare disease - express very large amounts. patients with low grade lymphoma are somewhere in the middle, but if you look, patients with large cell lymphoma and patients with Birkett's lymphoma are way up there in the terms of the amount of expression. So it would make sense that we should use, I think, these antibodies in these diseases. There is a question, I think.
Q: Yes, but isn't it also important how sensitive is the cell to the destruction of this?
LEO GORDON, MD: Yes. The question is, "Is it important how sensitive the cell is to the destruction?" Absolutely it is.
Q: Though small, it could be very critical.
LEO GORDON, MD: Right. In other words, though small it could be critical. There could be other factors which play a role in how sensitive a cell is. But if you look just back at sort of a big picture where to start, it certainly makes sense that you would at least consider starting using Rituxan in some of these diseases because it expresses a large amount. Whether it's going to work as well or not, we still have to show. And how best to use it, we still have to show. There is a lot of research going on in terms of how to use these antibodies and how to combine them with chemotherapy or not with chemotherapy, what's the best combination. Should they be given together? Should they be given separately? So there are a lot of questions, I think, that are still being addressed here.
Slide #15
There have been a number of Rituxan single agent trials for aggressive lymphomas. Bertrand Coiffier from France looked at the question of whether dose made a difference in dose of Rituxan in aggressive lymphomas. It turns out, at least in his study, although there were good response rates, the dose didn't seem to matter very much, the dose of antibody. This is the traditional dose of Rituxan, but he started looking at larger doses of Rituxan given for longer periods of time. It didn't seem to matter, but he did get good responses.
Slide #16
This is for mantle cell lymphoma. There is a study that's being done currently combining Rituxan with a very aggressive chemotherapy. This is the chemotherapy regimen, the so-called hyper-CVAD regimen that was developed by Sharon Murphy for children with lymphoblastic and Birkett's-type lymphoma. And it was adopted by a number of people in adults for aggressive lymphomas also, for Birkett's non-Birkett's, lymphoblastic and also for mantle cell lymphoma. A group at MD Anderson is looking at it together with Rituxan. I'm just showing you the studies that are going on.
Slide #17
Then Julie Vose has published some preliminary data looking at combinations of Rituxan and CHOP chemotherapy for patients with previously untreated, aggressive non-Hodgkin's lymphoma. This is diffuse, large cell lymphoma. Rituxan is given first, and then two days later it's given then with - then chemotherapy is given two days later. So not together, but following a dose of Rituxan.
The reason this was done, there was some concern about the possibility that if you gave prednisone at the same time as Rituxan, you inhibit the activity of the Rituxan. Certainly early on in our studies - in the early studies with Rituxan, that was a consideration.
There are two conflicting pieces of data now that suggest - one suggests actually that giving Rituxan together with Prednisone makes it work better and another suggesting that it makes it work worse. So we don't know the answer to that, unfortunately. Two laboratory studies that are ongoing there. So how best to do it I think we just don't know.
Slide #18
But Julie published this, and then you can see I'm just showing some response rates. Overall response rate was very high. That's not as meaningful, I think, as the complete response rate of after 24 weeks of treatment and then up to 34 weeks of treatment, we're up to 79% complete response rate, which you may remember from some of our earlier studies, you may have heard, those are very high numbers. The usual response complete response rate for large cell lymphoma is maybe about 60%, between 55% and 60%. So seeing this high a number was intriguing. Yes.
Q: [INAUDIBLE COMMENT]
LEO GORDON, MD: Well, I think these are always the caveat when you see small numbers of patients and just response rate data. It means that the disease disappeared. The more important question, of course, is how long did it stay gone? Was the recurrence rate any better than previous studies? We don't have the data yet on this.
The only thing that sort of makes you raise eyebrows a little bit about this in a favorable way is that the number of complete responses were higher. Ultimately, the first step is to try to achieve a complete response, make sure the disease disappears from all sites where it's present. So that's all that this is saying. The combination of Rituxan and CHOP, at least in a small number of patients, gives a little bit higher response rate in the large cell lymphomas. And these are actually younger patients.
Slide #19
This was the result of the study from France looking at CHOP with Rituxan versus CHOP alone chemotherapy. Again, the only one caveat I have about this study is that CHOP as given in France was not exactly the same as CHOP as it was given in the ECOG study or in the US. The dose of Prednisone in this study was 40 mg/m2. The dose of Prednisone in many CHOP regimens is 100 mg per day. The dose at most is 100 mg/m2 per day for five days. So the Prednisone dose in the CHOP arm was lower than what we would normally do here. That's been my concern about this trial. But certainly given the way it's been given - and this is holding up, it looks like - I just heard about a week ago at a meeting in Italy that there continued to be an improvement here when CHOP is added to Rituxan. So these data are holding up from France.
Slide 20
This was the way it was done in the ECOG trial that Tom Habermann from Mayo Clinic led, where the Rituxan is given first for a couple of days and then the chemotherapy and then Rituxan and chemotherapy and Rituxan and chemotherapy. So one, two, three, four, five doses of Rituxan interspersed along with the chemotherapy. Then afterward, there was another question that was asked. That is, "Is maintenance therapy important or not?" We don't know the answer to that question because it's just too early to see yet." So this is also in patients over the age of 60, so similar to the French study. We're awaiting these data.
Slide #21
I mentioned to you that there were studies with other antigens. I just wanted to point out two of them. Here at UCLA, there is a trial, a phase II randomized trial of dosing of anti-CD-22 in patients with large cell lymphoma looking for 150 patients. There is another trial at the National Cancer Institute with a smaller number of patients looking at another anti-CD-22 type antibody. So there are at least two or three trials now in the country for large cell lymphoma for patients for anti-CD-22 - this antigen. I think ultimately - and probably many of you are already thinking - why not combine them. I think that's a good question. I think there may be soon some combinations of anti-CD-22 and anti-CD-20.
We have started a trial of anti-CD-80, a new antigen, mostly still for low grade lymphoma that is shortly going to move into more aggressive lymphomas, alone or ultimately in combination with the anti-CD-20, with Rituxan. So new antibodies being developed really all the time. Yes, a question?
Q: The slide you just showed, the only applicable studies are only applicable to new patients?
LEO GORDON, MD: These studies are only applicable to people who have recurred.
Q: Oh recurrent?
LEO GORDON, MD: Recurrent, yes. Most of the studies with antibodies alone - I think because people are pretty reluctant to move away from what have been reasonably successful results with chemotherapy in the large cell lymphomas. So I think that one wouldn't want to start with antibody alone. At least not yet, unless we know that in patients with recurrent disease it's very active. Then I think that you might start asking those questions earlier on. So those studies are for people with recurrent disease. Yes.
Q: [INAUDIBLE COMMENT]
LEO GORDON, MD: That's okay. Questions are okay, I guess. That's fine. You might as well.
Q: [INAUDIBLE COMMENT]
LEO GORDON, MD: T-cell? The question is, "Why haven't antibodies been developed for T-cells?
Q: Or good ones?
LEO GORDON, MD: Or good ones. The reason is they are harder to find. The antibody - the T-cell antigens that define T-cell lymphomas, they're very common antigens that are present also on most normal cells. But they're hard to elude off. They're hard to get off. People are trying, but there haven't been just good enough antibodies developed yet. I think the technology for that is still not there because of the nature of the antigen.
Q: [INAUDIBLE COMMENT]
LEO GORDON, MD: I think the question is one of a little bit of frustration about why there haven't been good T-cell antibodies. I think the one thing I would say is that people are beginning to develop antibodies against CD-30, which is common on the anaplastic large cell non-B-cell, T-cell lymphomas. So there are some new antibodies that are just being developed on that particular antigen, which is present in many - not all - but many T-cell lymphomas.
Q: CD-30?
Slide #22
LEO GORDON, MD: CD-30, right. So the other question is if we've got antibodies and we're expecting them to do their job and we're expecting them to get to the malignant cells and perhaps work together with chemotherapy, why aren't they better? One of the reasons for that might be shown on this slide. If you look at this, sort of, these are individual cells, but these individual cells make up a large bulk say of tumor, a large lymph node of lymphoma, malignant cells. If you can just look at the nature of this, some of these cells are buried deep within the tumor. It's quite, I think, asking a lot of the antibodies, shown in these little red schematics here, to get all the way to the middle of the cell.
When you think about it, and you think of the big ball of the lymphoma cells, the antibody sticking onto it probably sticks on mostly to the surface. It doesn't get deep into the cell. So it might be one of the reasons that we see partial responses, but we don't see as many complete responses with antibody.
One of the things that was done was to say, "OK, well, we want to devise a system where you can allow the antibody to stick to some of the cell, but you rely on something else to get the remainder of the cell." Obviously, that something else, as you can see here, is radiation.
If you can take the antibody to the surface of some of the cells - you don't even need it to bind to all of the cells - and then you release radiation beams to get the rest in this sort of cross-fire effect, this has been called, hopefully - at least theoretically - you can get these bigger, bulkier tumors to respond also.
We know that radiation is a good treatment for lymphoma. You knew that from the early study that I showed you from Tom Miller, that when you add radiation to just three cycles of chemotherapy for localized disease, people do very well. We know in low grade lymphoma for early stage disease, radiation by itself might be curative in some patients.
So radiation is an important modality. If you can take it and target it to many cells, then you might be able to achieve some better results.
Slide #23
This is the result of that. There are two antibodies that are being tested, Bexxar, which is antibody - monoclonal antibody labeled to iodine. This one that I'm showing you is Zevalin, monoclonal antibody linked to Itrium-90. Itrium is a pure - it's called a beta-emitter. It's a radioisotope that is relatively easy to get. Not as easy to get as radioactive iodine, but it's probably more expensive than radioactive iodine. But it has some advantages in that it's got a higher energy to it, it's easier to use and it's got what's called a longer path length. So it probably can get to - it's got a 5 millimeter path length - so it probably can get to bulkier tumors a little bit more easily.
One of the major advances in allowing us to do this, believe it or not, was the work of a chemist who developed a way to link the radioactive protein to the antibody. Amazingly enough, beforehand, they tried to use a number of different what are called kelators or glues. The radioactivity fell off the cell. So it wasn't very effective. So it was this development of this kelator, this new kelator that led to the stable bond between the radioactivity and the monoclonal antibodies.
So what this is basically is like a Trojan horse. It's taking the antibody, taking the antibody, asking it to stick to the cell and then the radiation gets released and hopefully takes care of surrounding cells and the cells that the antibody sticks to. That's the concept.
Slide #24
The other nice thing about radioimmunotherapy is that it basically takes two days - or separated by a week - to give. For example, in recurrent large cell lymphoma, if we use this, that's as compared to using, say, ESHAP chemotherapy for six cycles or six months or DHAP or whatever chemotherapy regimen that people actually have to go through for a long period of time.
If we can be as effective with this, it only takes two days. So the question is, "Are we and can we be as effective?" We don't know the answer yet. But basically, the way it's done is the first day zero, people get a dose of Rituxan and then a dose of indium-labeled antibody in order to image where the antibody is going to, making sure you're not giving too much to normal organs. Then a week later, you actually get the Rituxan again. Then you get the treatment dose. So basically it's done in two treatments.
This is the schematic of how it's done.
Slide #25
So, this is just an example of a couple of trials that are ongoing with radiotherapy in the large cell lymphomas. On the left, what I'm showing you -- in many of these next slides, I want to show you a little picture on the left and some words on the right. The picture is meant to sort of highlight some of the things we're talking about. I mentioned that in order to do the Zevalin, you have to scans -- you have to do an imaging dose first and then do body scans to see where the radioactivity is going.
This is just a scanner. This is like a gamma scan like many of you have had if you've had a PET scan or a gallium scan. This is kind of what that would look like. So it's a simple scan like that. You don't have to really lay as still and flat as for a PET scan. But it takes a little bit shorter than that.
From UC Davis there is a trial of Itrium with another antibody that we haven't talked about, the LIM-1 antibody, which is also a B-cell-targeting antibody. It's a little different from Rituxan, but has many of the same features of Rituxan. They're combining it with Taxol and, interestingly enough, cyclosporin in patients with recurrent non-Hodgkin's lymphoma. This is to affect the immune system.
Then Julie Vose in Nebraska is doing a phase II trial of Zevalin alone after stem cell transplant. One of the questions was after a stem cell transplant after there has been a recurrence, can we give Zevalin or not? My bias is I think we probably can, but the question is, "Will the bone marrow allow it?" In other words, will it be too toxic? Will the blood counts drop too much? One of the problems with Zevalin is the blood counts do drop somewhat. So you have to be concerned about that. So she's doing a very careful study to look at what doses of Zevalin we can use following stem cell transplant. Yes.
Q: I'm sorry, did you say that the fellow at the Mayo Clinic was doing a trial for use of Zevalin with recurrent mediastinal...
LEO GORDON, MD: No. So, this is in the process of being sent to the National Cancer Institute. It's for newly diagnosed large cell lymphoma. CHOP followed by Zevalin and that will replace -- maybe -- CHOP followed by radiation. Yes.
Q: [INAUDIBLE COMMENT].
LEO GORDON, MD: Good question. Again, the question is, "Can you have radioimmunotherapy after you have radiation?" It depends on how much radiation. We don't like to give it if you've radiated a lot of the body to very high doses. But the doses of radiation that most people have had, you can get radioimmunotherapy afterwards. And, the other question sort of reversed, I'm sure, comes up, can you get radiation after you've had Zevalin or Bexxar. The answer is you can.
One of the reasons you measure the dosing, the dosimetry is to know how much radiation gets to the tumor. I would say we've had a lot of experience now giving radiation after Zevalin. So you can in both directions, it looks like. Yes, there is another question and then we'll...
Q: If your bone marrow is not healthy enough to recuperate -- for instance, I failed stem cell collection because of my bone marrow. Would that mean I would not be able to tolerate...
LEO GORDON, MD: Good question. The question is, "If the marrow is not healthy enough to be collected for stem cell harvest, would it tolerate Zevalin or Bexxar?" We do like to see a good cellularity in the marrow. It's certainly a note of caution if we haven't been able to collect stem cells. We do worry about the stem cell reserve. However, I think that one of the questions now being addressed is what dose of Zevalin is optimal. We're using a reasonably high dose. We tried to get to the highest dose in our studies, but I think that for patients who have limited marrow reserve, I think there are ways to give less and maybe to give less more often. So that's being looked at too. So that's not something that's out of the question at all. It raises a concern, but it's not out of the question.
Slide #26 windows 45:26
So I'll keep moving a little bit. I wanted to mention a couple of other trials or radioimmunotherapy together with chemotherapy. This is just another mock-up of this sort of crossfire effect that I talked about before. The group at Case Western is doing a study with I-131, radioactive iodine linked to that LIM-1 antibody that we mentioned for patients with recurrent CD-20 positive large cell lymphoma. This is being done at Case Western. This is without a transplant.
Then there are two studies -- there are actually more than that now -- of transplant. In Nebraska they are doing a phase II trial of Bexxar and BEAM chemotherapy, a BCNU-containing chemotherapy regimen, common transplant regimen and autologous transplant in patients with recurrent lymphoma. We are, together with Mayo Clinic and Northwestern, we are doing a trial that Jane Winter, one of my faculty members is doing a phase I/II trial. So we're looking at the dose of Zevalin plus BEAM chemotherapy and autotransplant in patients with recurrent lymphoma. Yes.
Q: [INAUDIBLE COMMENT].
LEO GORDON, MD: So you collect the cells and then usually in most of the trials -- at least in our trial -- we're giving the Zevalin first, and then about 10 days to 2 weeks later, the chemotherapy and then the stem cells back again. So the stem cells come in after all the treatment has been completed. So basically the targeted radiation, the radioimmunotherapy is replacing total body radiation as part of the transplant. That's the concept.
Q: [INAUDIBLE COMMENT].
LEO GORDON, MD: I'm sorry?
Q: [INAUDIBLE COMMENT].
LEO GORDON, MD: No, actually this is after the cells have been collected already. Yeah, that's right. So the preparative regimen is including the high-dose radioimmunotherapy instead of total body radiation.
Q: Now, what is BEAM stand for?
LEO GORDON, MD: BEAM is BCNU, etoposide, Ara-C and melphalan. That's a commonly used stem cell transplant regimen. So those four drugs. It's an acronym for those four drugs.
Slide #27
So I'm going to move a little bit to some of the new biology. I'll take a little longer as I'm taking questions as we go, which is perfectly fine. I do want to leave a little time for sort of uninterrupted questions asking, if I can -- uninterrupted by my talking.
The point of this slide is not to make you look at each of these little dots here, but to tell you that there are some new techniques available. This is just published in 2002 in Blood. This is a new technique for actually looking at the chromosomes. What you're seeing here actually are the chromosomes. It's using something called spectral karyotyping, a SKY technique, which turns out you can identify changes in the chromosome which define prognostic groups. So one way of maybe doing better than this international prognostic index that we relied on; you know, age, LDH and performance status. Those are criteria, but if we can get a little more scientific about it, maybe -- but I'm not sure -- maybe we can do better at predicting outcome. This is one way of doing it.
Slide #28
The other way of doing it equally I'm sure, obscure look here. I don't know if you saw this before in any of your previous lectures earlier today. I don't know if Sandra or Jonathan Said talked about this, but basically this is what's called gene profiling. I'm going to take you through this in about two seconds if I can. This is, by the way, published in the New England Journal of Medicine in 2002, just a few months ago.
Basically, we have the human genome now. So we know what genes -- we have access. We have DNA, pieces of DNA from a bunch of different genes. You can take those genes, just in general -- those are available to everybody -- and put them on a microchip like a computer chip. You can then take samples from patients or from normals, from anybody, and isolate the RNA. Not the DNA, but the RNA. You can then take the RNA from many patients -- and that's what this looks like. That's what this is, the RNA from many patients, and lay it on top of the DNA of these known genes and run it. Basically, just let it incubate for a while. There are different ways to measure whether there has been a mixture or hybridization between the DNA from the genome or the RNA from the patient. What you're looking for are patterns.
This is also one of these simple but elegant, I think, things. When you look at this, it's not obvious to you that there are any patterns here, but I'm going to point out a pattern. The patterns are determined by color. The intensity of binding is determined by the color. So when you have a red color, that means there's lots of binding. When you have a green color, there is very little binding.
What you see when you look at this chip is that a couple of patterns have emerged. This is many, many patients, hundreds of patients with lymphoma on this chip and many, many genes. The genes are listed here.
If you look here, you can see a red pattern -- here -- and a green pattern here. If you look at these genes, you can see a green pattern here and a red pattern here. What that's telling us is that these patients, this group of patients, have lots of binding to these particular genes. This group of patients has lots of binding to these particular genes. They are different genes.
So now you've got this pattern. Now you can look and see, well how did the patients do who had this pattern, and how did the patients do who had this pattern. So what you come up with are the curves on the right side of this slide. It basically is that you can separate at least into two major categories. There is this category, which is basically this group, and then there is this category, which is this group.
So what we found with this observation is that you can predict outcome based upon the gene pattern of your particular lymphoma. So the ultimate aim of this is to say, "Okay, somebody gets a biopsy done. You put the RNA on this gene chip, and you get the answer, 'Are you this kind of pattern,' or 'Are you this kind of pattern.'" If you're this kind of pattern, you're going to do reasonably well with conventional therapy. You'd still like to do better. But if you're this kind of pattern, you're not going to do quite as well. Maybe this is the group of patients that should be treated with transplant. Or maybe this is the group of patients that should get antibodies or something like that.
I think that ultimately this gene profiling will be the way that we're going to look at outcome and we're going to be predicting treatment with these patterns. So complex as it might seem, it translates into fairly simple categories. Those categories are based on new information about genes. We'll get back to this in a second. I wanted to get through a couple of things just to mention.
Slide #29
This slide is just a list. I wasn't going to go through all the chemotherapy agents that are being used to treat large cell lymphoma now, but this is sort of a listing of them. We can go through them if you have questions about them. But they range from Taxol, which we use a lot in breast cancer, to something called geldanomycin, irinotecan. There is a drug called liposomal vincristine on the bottom of the slide here, which is vincristine, but in a new formulation. We've seen some very nice effects with liposomal vincristine just used as a single agent.
Slide #30
Similarly, chemotherapy regimens we're combining with -- new agents are being combined, so gemcitabine and Decadron, platinum and Decadron and gemcitabine. A number of different agents are now being combined in new and novel treatments. So these chemotherapy regimens may be, as it turns out, more applicable to patients with one type of lymphoma -- a large cell lymphoma -- than with another. So that might also be predicted based on the gene chip data that I showed you.
Slide #31
So there are a number of other regimens and clinical trials that are being looked at. These are chemotherapy and Rituxan combinations. I won't go through all these with you now, but just to say that there are studies at Ohio State University. There are studies in the Netherlands. The BLNI is the British National Lymphoma Investigation, and then Wyndham Wilson at the National Cancer Institute, on the bottom part of the slide, are looking at various combinations.
I think I mentioned that Wyndham Wilson is looking in mantle cell lymphoma at combinations of R-EPOCH -- that is R-Rituxan combined with chemotherapy followed by vaccination. So as I said earlier, the vaccine therapy is starting to find its way into the more aggressive lymphomas.
Slide #32
So many combinations are being looked at and many more here -- I'm not going to go through these in detail. These will be on the slides when you look at them.
So we're looking at DHAP and Rituxan and ICE and Rituxan and EPOCH and Rituxan. There is some Rituxan in high intensity chemotherapy in people with Birkett's and Birkett-like lymphoma and lymphoblastic lymphomas. So those kinds of combinations are ongoing.
Slide #33
Another concept that I wanted to get to just briefly to introduce is the antiangiogenesis idea in patients with aggressive lymphomas. On the left side of the slide here is a diagram, which I'll take you through in maybe 20 seconds or so. You have the tumor and you have the blood vessel cells that the tumor sort of runs around in. We find, I think, two things happen. The tumor sometimes makes a substance which makes the blood vessels grow. That's not a good thing because those blood vessels feed the tumor. The tumor obviously wants to do that to get more blood vessels to support its own growth. Sometimes the blood vessels make substances that make the tumor grow.
One of those substances is something called VEGF, vascular endothelial growth factor. That turns out to be an angiogenesis agent, meaning it grows blood vessels and supports tumor growth. We don't like that obviously, so we want to do something, find ways to inhibit VEGF if we can. So now there are a bunch of studies looking at anti-VEGF in patients with recurrent large cell lymphoma. There are studies at Memorial, at the Southwest Oncology Group, at the University of New Jersey and Rutgers, a number of studies looking at ways to inhibit angiogenesis in large cell lymphoma.
Slide #34
This is just a rationale for maybe combining chemotherapy with this antiangiogenesis therapy. This is a schematic of a study that just started about a couple of months ago that's a combination of Stanford Group, the Indiana University Group and our group at Northwestern with Kristen Ganjoo from Indiana University being the study chair, for patients with newly diagnosed large cell lymphoma, untreated, who we've started now treating with a combination of CHOP chemotherapy and Rituxan and this new anti-VEGF. It's called Avastin. It's a newly manufactured monoclonal antibody against VEGF.
The concept is to inhibit angiogenesis, to inhibit the growth of blood vessels around the tumor site. Because previously this was all done in solid tumors, in lung tumors and melanoma, in kidney tumors, it's new that it's being looked at in lymphoma. There is enough reason, enough basic science research to suggest that it would be active in lymphoma as well.
Slide #35
Let me continue a little bit because I don't want to run too far behind. So that's new and that's started and those studies are open for newly diagnosed patients.
I wanted to get close up with these last two issues. One is stem cell transplant and the other are some novel targets that we're going after now in the tumor cells.
I'm going to show you three slides or so about stem cell transplantation. I wanted to just make the case. I'm not making a case for transplant. I'm showing you the argument for why this is even being done. For autologous transplant, the group in France, published in the New England Journal in 1995 a randomized study looking for patients with recurrent lymphoma. So these are patients with large cell lymphoma or aggressive lymphoma. These actually included some of the Birkett's/non-Birkett's type who were treated initially with chemotherapy but then had a recurrence. At that point, they were actually randomized to receive regular chemotherapy or transplant.
What's clear -- and this has held up -- is that transplant results were better than with standard chemotherapy. So that makes the case for doing an autologous transplant in patients with recurrent lymphoma.
Another study went back and asked the question, "What about patients who are just getting CHOP chemotherapy, but are not responding as quickly as you'd like them to respond?" Should you do a transplant in those patients, or should you continue the same therapy or should you switch treatments? As it turns out, surprisingly in this study, there really was no difference. In fact, those patients who had a transplant did a little bit worse than those who had continued to get CHOP.
There is a lot of controversy about this study. It's a relatively small number of patients, but still important enough to say that transplant isn't necessarily the answer if you're not responding well to the initial CHOP. It's clearly the answer if you responded well, did well for a while and then unfortunately had a recurrence. For that group of patients, it's absolutely the right therapy. But maybe we need to do better in this group of patients before moving to transplant.
Slide #36
The next slide makes the case for allogenic transplant. I want to show you something that might surprise you a little bit. These are data in leukemia. Not lymphoma but leukemia. This is looking at probability of recurrence or relapse. These are different types of patients who have had different types of allogeneic transplant. Remember, an allogenic transplant is from a brother or sister -- a sibling of some kind. Surprisingly to some maybe, if you had a transplant from a twin, you did okay from the transplant standpoint, but your leukemia tended to come back more frequently. Okay, a surprise maybe.
On the other hand, there is a feared complication of allogenic transplant, which is graft versus host disease. Many of you may have heard about that. That is the graft that you got from your donor attacked your normal cells and caused skin rashes and problems with diarrhea and lung problems and immunosuppression. Those patients who had that complication had a less likely chance of recurrence from their leukemia.
So the finding was, the observation was that not only do you get graft against your own normal cells, but you may get graft against the malignancy. So the concept was that if you got graft versus host disease, maybe you'll get graft versus lymphoma or graft versus leukemia and less of a chance of leukemia or lymphoma coming back.
What that did is it led to new studies, the so-called mini- or non-myeloablative transplant, where you no longer needed very high doses of chemotherapy prior to the allogenic transplant, but maybe just minimal doses and then you get the cells back from your donor and you get graft versus lymphoma without the complications of the transplant. That's what's being done more and more. That has opened the door to allogenic transplant to patients that are 60, 70-even years old. Before we used to stop at maybe 50 or 55 for an allogenic transplant. But now it's possible that as we begin to perfect these regimens we'll be able to use this technology in people a little bit older with a lot safer outcome.
Slide #37
Finally, the next slide addressed the problem of donors. Remember that we talked about allogenic transplant, but each of us, any of us has only a 25% chance of having a donor with each sibling. So if you have one sibling, you have a 25% chance. If you have two siblings, each one of them has a 25% chance. It doesn't double up to 50%. Each one has a 25% chance. So in general, because of the genetics of how this works, there's only about a 1 in 4 chance of having a potential donor.
So one of the observation was that if you look at cord blood -- I think somebody was asking me about core blood earlier today -- if you look at cord blood -- there's blood from an umbilical cord from a newborn, those cells, those stem cells are there in that cord and they are immunologically naïve -- is how I like to put it. In other words, they haven't seen anything yet. So they don't react to anything. As it turns out, it almost doesn't matter what the HLA type is if you take cord blood. The main advantage of cord blood is that you don't have to be matched. You can use a cord blood from just about anyone without essentially having problems of graft versus host disease. Now that's the good news.
The bad news of cord blood is addressed in this slide, and that is cell dose -- the dose. So for kids -- the kids being the recipients -- 8-years-old, 10-year-old kids, who get cells from a donor from a cored blood, they have engraftment pretty rapidly because they are not big and they're not getting a lot of cells. So the engraftment happens quickly. For an adult, a normal sized adult, when you get a small number of cells, it takes a long time for those cells to engraft. That's what this slide is showing, that when you give more cells, people do better in adults.
So what we haven't done yet is perfect this concept of cord blood for adults. For kids, it's done all the time. The pediatricians have an easier time in terms of cord blood transplants because they can use the cord bloods all the time. For adults, we have to find a way to get more of these cells. And people are looking at ways to grow these cells and to expand them in some way so you get more cells given. So that's the concept for transplant.
Slide #38
There are a number of trials I'm just going to mention very, very briefly. For transplant there are some phase III trials for transplant that are ongoing. One of the questions raised has been, should you do a transplant early on or should you wait for recurrence? There is a study going on through the Southwest Oncology Group and the Eastern Cooperative Oncology Group randomizing people to get a transplant right after say five cycles of CHOP chemotherapy or not, or to do it only at the time of recurrence. And the answer to that isn't known yet.
There is a phase III trial of chemotherapy and Rituxan followed by transplant -- with or without Rituxan followed by transplant. This is being done in Belgium. There is a phase III trial of giving radiation following transplant. That's not known yet. There is also a trial looking at the value of interleukin-2. Remember I pointed out before that interferon and interleukin are nonspecific ways to stimulate the immune system? Well, now it's being looked at in the transplant setting -- in autologous transplant setting. So those are some of the questions that are being addressed.
Slide #39
A couple more slides and a couple more points and then we'll go to questions. EB virus is an important component, especially in some of the very aggressive non-Hodgkin's lymphomas. The point of this slide is just to remind us that EB virus is important, number one. What I'm showing on the left here is infectious mononucleosis -- just mono basically. You get infection with the virus in the saliva. It goes to the throat. It gets to the B-cells and those B-cells just die off right away. Nothing happens. Plenty happens. My daughter just had mononucleosis not long ago and they get very sick -- people get sick.
But if the immune system is in some way malfunctioning, what happens or what can happen is that this virus can live in the cell. If it lives in the cells, it sends signals to the cells to make them immortal. In other words, it can turn these cells into lymphoma cells. In fact, in patients whose immune systems are severely suppressed that get EB virus infections, they develop EB virus-related lymphomas. What's interesting about these and fascinating is that if you simply reduce the immunosuppression, you can make the lymphoma disappear.
So now there are ways to look at in patients who develop EB virus--if you look at patients who just develop EB virus-related lymphomas, we're trying to look at different ways to make those cells sensitive to new treatments, make them sensitive to antibiotic. That's one of the studies that's going on.
There is a study in the central nervous system lymphomas, which are commonly associated with EB virus, and this is the marker for EB virus here, where people are using drugs like ganciclovir, which is an antiviral drug, to treat these lymphomas. So there's many ways actually that we can manipulate the EB virus infected lymphoma cell to make it sensitive to antiviral antibiotics, just simple antibiotics.
Slide #40
Last, I think, two slides and we're done. Oncogenes and tumor suppressor genes, which many people view as the real Achilles' heel cancer cells, the concept on the left side of the slide is that there is a cancer cell, which can either -- you can manipulate in one of two ways. One is you can cause it to die off by a process called apoptosis. You've heard about that. The other is you can make it differentiate into a more normal cell. If you happen to manipulate certain oncogenes and tumor suppressor genes in the right way, you can make it do this, or you can make it do this. I think that's one of the objects and one of the points of one these kinds of approaches. You've now identified some proteins that regulate these tumor suppressor genes.
Slide #41
Now there are a bunch of studies with -- and this protein is called NF-kappa-B. It's something called a transcription factor actually. If you inhibit this NF-kappa-B, you may be able to send tumor cells toward apoptosis and kill them off. This has been mostly studied in patients with myeloma.
There are now studies just opening with NF-kappa-B inhibitors in patients with recurrent or refractory large-cell lymphoma or mantle cell lymphoma. These are studies that are ongoing.
There are known NF-kappa-B inhibitors. The most commonly used one is this so-called PSC-341, which has been used in myeloma, but now is being used in lymphoma. It's a way of targeting.
Slide #42
These drugs also target these genes and make these genes do what you want them to do.
The goal here -- remember we've been talking before about targeting membrane proteins. But now we're talking about targeting the genes, actually the DNA themselves and regulating them in some way.
The more we understand about these genes, the more drugs -- and this is just a small handful of the ones that people are looking at now -- the more drugs we'll be able to use.
Interestingly, the third one on the list, this 5-azecytidine, I had on there it's rediscovered. We used to use that 25 years ago to treat leukemia and some lymphomas. We had no idea at all what it was doing or how it worked. It just seemed to work a little bit. Now we're beginning to understand more of what it does, and we can begin to use it in better ways.
Slide #43
I think just to close this part of it, we've talked about a lot of different things; new treatments, I think, we're excited about. I think the outlook is getting better because the learning curve has gotten so much better as we begin to understand more about the molecular biology of these cells, the biology of this disease. So I think the slope of improvement over the next five years is going to be much better than it's been over the past 15 or 20 years. So I think there is a lot of reason -- a lot of cause -- for optimism in the treatment of these diseases.
Why don't I stop and take some more questions, if I can. (Applause) Thank you. Yes. There is a question over here. Yeah, go ahead.
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