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Slide #1
SANDRA HORNING, MD: Again, we have a really big room, and I guess a lot of blue dots, so anyone that would like to move forward so that you can be more participatory in the discussion, please feel free to do so. What I thought I would do is kind of set some framework regarding follicular lymphoma and kind of where we've been and where we think we're going. I hope that that sounds okay to you, but what I'd really like is if you felt free to ask a question and interrupt at any time. I think it'll make it less formal, and if we don't get through everything, we don't get through everything, but -- Does that sound all right to people? Okay.
Well, a few of the slides I'm going to show I actually showed earlier, so they might look a little familiar, but again, this is the frequency of the non-Hodgkin's lymphoma subtypes, and it actually came from an international study. It was done in Canada, the U.S., Europe, South Africa, China, so you get a more global view. Actually, in our area, the Bay Area, follicular lymphoma tends to be the most prevalent -- well, lymphoma with the highest incidence as well as the most prevalent, and I think the fact that this audience is probably much bigger than other audiences in other rooms today gives you some idea of the prevalence, because follicular lymphoma is a disorder that tends to be more like a chronic disease, and one in which people live long periods of time relative to other lymphomas.
Slide #2
Dr. Said touched upon follicular lymphoma as not being one disease. And even though it's probably the simplest disease for the pathologist to recognize, because they look under the microscope and they see those nice follicles that he pointed out, if you actually look at the new classification for lymphoma, it's a lot more difficult than that. And the reason I'm showing you this is that it does have some importance with regard to your individual case of lymphoma and how it might be managed and how your lymphoma might change over years.
So here we're looking under the microscope at follicular lymphoma, so we've gotten beyond those follicles and now we're just looking at the individual cells. And if you just glanced at A versus B, what's the difference?
SANDRA HORNING, MD: What? Size. Okay, so these cells are much bigger, right? And those are the so-called CB, or centroblasts, and the small cells are the CC, centrocytes. And what the pathologist is now asked to do when he or she is looking at your specimen is not only to call it follicular lymphoma, but to actually count the number of these larger cells that you see in a high-powered field. And they have to look at multiple fields and they have to have the magnification factor and the objective just right so that they can then relate what they're seeing to others. And this gives you, then, the grading of follicular lymphoma. And in fact there's a special notation in what we have historically called follicular large cell, if you just have sheets of these large cells, which is what you see here.
And then, as Dr. Said mentioned in his talk, there's further definition of whether this is purely or predominantly follicular to a mixed follicular and diffuse or focally follicular lymphoma. That means that when you're looking at it under low power, is it totally nodular in follicles, or are there diffuse arrays of cells, and what proportion? And then in some cases of follicular lymphoma, there are actually separate areas of a more aggressive lymphoma, diffuse large cell, and that's also reported separately. So you need to get, as you can see, a lot of information from your pathology report, and that information is going to have impact on what is recommended for therapy or for management.
Slide #3
Now --
Q: ...
SANDRA HORNING, MD: So the question is, what do you do about the terminology "mixed?" And probably the thing that would be good is to not use that terminology anymore because it's confusing. So you can have both a follicular and diffuse pattern, and you can have both small and large cells, and that's how the new grading system is.
In the old days, when people were given a diagnosis of follicular mixed lymphoma, that meant that they had a follicular lymphoma with both small cells and large cells. Does that answer your question?
Q: Large cell ... diffuse?
SANDRA HORNING, MD: No. If you look at any follicular lymphoma and you look at every cell, you're always going to find a few large cells in a follicular lymphoma. So what is classified is whether it's a really small number of cells -- that's what we used to call follicular small cleaved and now call grade I -- or whether it's a much more pronounced proportion of cells -- grade III, or now follicular large cell. I don't know that it's so critical to hone in on the number of cells except to make the point that not all follicular lymphomas are alike, and they're kind of on a spectrum of gradation, and that spectrum is changing from purely small to a greater proportion of large cells over time, and also going from a purely follicular to having more diffuse elements. And at some point in here, that's what might be called histologic transformation.
I can tell you that investigators and lymphomaniacs have a real difficult time with the term "histologic transformation." I was actually at the FDA on September 11th of 2001, when Zevalin was being presented, right during the attacks, and there was a huge discussion about whether it should be approved for histologic transformation, and what came out is that nobody could really provide a cogent definition of histologic transformation. Yes, we use the term, but it's just a spectrum, and things are changing, often gradually, over time.
Another misconception I think that people have is that if they have follicular lymphoma, they will histologically transform. That's not necessarily the case. One of the great mysteries of this process is knowing exactly how much change there's going to be in either of these directions over time for individual patients, and we know that for some patients they even have spontaneous regressions of their disease that last for many, many years.
Slide #4
So I'm going to start out by presenting a case, and these are the kinds of things that your doctors go to with these response pads. They like to do them, and meanwhile the drug companies can often get research data on how drugs are being used in the community. So if we started out with just a fictitious patient who's a 52-year-old woman in good health, but she notes a lymph node in her right groin -- it was about six months ago -- and then a couple of small nodes in her neck region, which went up and down as she was watching them, over a period of two months, but they didn't completely go away. The patient has no constitutional symptoms, no sweats, no fevers, no weight loss and normal blood work.
A CT scan showed some small lymph nodes in the abdomen and in the iliac region, which is in the pelvis, but not any more than 1 inch. The bone marrow showed minimal evidence of lymphoma -- two little nodules that would probably be 10% or less. And the cervical lymph node biopsy showed follicular grade I. Okay, that's follicular small cleave lymphoma.
So we know that this patient has stage IVA disease, is asymptomatic, she's working full time, has two grown children and one sister. What do you recommend? These are some of the options that might be on the keypad for the physician to select. So one could be watchful waiting. Another could be rituximab. Another could be alkylating agent-based chemotherapy, chlorambucil or CVP; a fludarabine-based chemotherapy; something that contains doxorubicin or adriamycin, like CHOP alone or together with rituximab; or something other, maybe an investigational trial.
Slide #5
Well, this is what I would say is really the case in the state of art currently, and that is that for clinicians, follicular lymphoma, indolent lymphoma is kind of a UFO, and that is that it is characterized by uncertainty as to what to do and when to do it, frustration with everything that we've done in the past that doesn't seem to have really changed the natural history of the disease, but tremendous optimism, because we are on the verge of many new therapeutics, primarily those that involve the immune system, and follicular lymphoma, because it's such an indolent disease, because we know it has spontaneous regressions, it can even go away on its own, is a perfect disease for immune therapy that might not be so easily applied to more aggressive lymphomas or leukemia.
Slide #6
So what's the uncertainty about? Well, when we first see a patient, we can kind of predict how things might go over the short run, but it's very difficult to predict how things might go ten or more years. So we have some uncertainty about the prognosis, and therefore what the initial and subsequent treatment should be, and we're always trying to balance the benefit and risk. At our institution now we expect 75% of patients to be alive at ten years. We don't want to do anything that's going to reduce that likelihood or to diminish quality of life during that time period and beyond.
Slide #7
Prognostic factors are not very well worked out in follicular lymphoma, and there's been an international group working on that in the last year, and I have to say that despite putting data together from maybe 5,000 patients, it's not clear that we're going to have a very easily used system that can be used by physicians all around the world. But here's one system that's been put forth by the French group, and they either stated that a patient with newly diagnosed follicular lymphoma would fall into what's called low tumor burden or high, and low meant that you did not have any of the symptoms that are listed up here.
This is not a well adapted system. This is just one that's put forth, and the point of this is that there are patients, even at the time of diagnosis, who are going to have different survival characteristics according to how they present. And so this low-risk group, you might say, would be what we call watchful waiting candidates who are asymptomatic. They don't have any pressing need to start treatment. So there are some things that we know at diagnosis that make a difference.
Slide #8
Other prognostic factors that have been published in the literature I've listed here, and I've given an X for each time it appeared in an article. I think you can see just by reviewing these that the patient's age -- over or under 60 years -- whether or not there be symptoms or constitutional symptoms, and how well one responds to the initial treatment, whether they achieve a complete remission or not, are the ones that show up most repeatedly.
Slide #9
What about the frustration aspect? This is from apparent lack of progress. Many of the trials that have been done, particularly in the interferon literature, were negative, or the results were conflicting, and sometimes when we got a good result, like in autologous transplantation as upfront treatment -- and I'll show you what our series showed -- this was marked by concern for secondary effects, such as myelodysplasia or even a secondary leukemia.
Slide #10
So here are some of the treatment options, let's say, at diagnosis and beyond. You can see them here. And I'm going to take you through a few of these.
Slide #11
Now, I showed this slide earlier, and I felt badly when someone came up to me and said, "You know, that series of patients went to zero, and I know people who have participated in that trial who are doing well." Well, the point that I was trying to make in looking at this -- and this was a very old trial from the National Cancer Institute -- immediate, aggressive treatment versus delayed treatment, watchful waiting, is that these curves do not look different. And when you're looking at curves like this, it's important to note that you can have a lot of confidence in what's going on here, in the first five to six years. Down here, it's harder to know, because you have very few patients at risk, and in fact this curve doesn't go to zero. You can see that at this level, about 12 years, about one in three patients is still alive, and in fact, if you look at long-term series, like from our institution, with any trial that's ever been done, or not -- maybe just patients treated in a certain way -- there's always a group of patients, maybe 20 to 25% with follicular lymphoma, who have done well, stayed in remission, and as I mentioned, some have actually undergone spontaneous regressions. We don't understand that. We'd love to bottle it. But you'll see that in any clinical trial, and that's one of the unpredictable features of follicular lymphoma.
Slide #12
Here is another randomized trial, this one from the French group, and they randomly assigned low tumor burden or watchful waiting candidates to upfront interferon; prednimustine, which is kind of a combination of prednisone and an alkylating agent; or no therapy. And here are the five-year overall survival data, which do not -- even though those numbers are different, if you looked at the actual survival curves, there's no difference. There's no difference in starting treatment early versus waiting. So this is a second study in addition to the NCI, and now there's a third study from the United Kingdom. They all show the same thing, that, at least with this older therapies, there was no advantage in initial treatment.
Slide #13
More recently, this summer, we evaluated a group of patients who had stage I and II follicular lymphoma. That's a -- Yes?
Q: ...
SANDRA HORNING, MD: Sorry. It sounds really loud to me. Okay, thank you.
This summer we evaluated a group of patients with stage I and II follicular lymphoma, so these are the less common patients, maybe 20%, who have disease only in lymph nodes, and either in a single lymph node site or more than one site on the same side of the diaphragm. And traditionally, these are patients who have been treated with radiation therapy, and often with durable remissions. However, we collected a group of people who, for some reason, the radiation was contraindicated. Maybe they had radiation for some other problem or they were older or had other medical conditions, so we just watched them. And what we were surprised to see is that the median survival of this group of patients was 19 years. Overall survival, 86% at ten years. And what was really impressive is that two out of three patients that were in this series had never needed any treatment at ten years.
So some presentations of follicular lymphoma, particularly early stage, are very indolent, and in this situation the survival is competitive with any of the other studies that were using radiation alone, primarily, or with chemotherapy.
Slide #14
Well, if we move on to the other group of patients with follicular lymphoma, who are not watchful waiting candidates -- and at least in our experience, it runs about 40/60, about 40% watchful waiting candidates, about 60% need some treatment. So these are symptomatic patients that were in a study conducted in Sweden, and I'm showing it to you to make this point: The randomization was between a very simple regimen of oral chlorambucil, oral prednisone, or CHOP chemotherapy. And there was a statistically significant difference, almost a doubling of the response rate, when the more aggressive adriamycin-containing chemotherapy was used.
If one looked at five-year overall survival in this group -- and remember, this is selected to be a less favorable group -- there was no difference. And in fact, that has been the experience in multiple clinical trials, and it's the reason that many people do not feel that doxorubicin-containing combinations should necessarily be used as a front-line treatment for indolent lymphoma, thinking perhaps that they would rather save them for a time when a more aggressive lymphoma is present.
Slide #15
Here is the experience from the Southwest Oncology Group. Now, this is looking at progression-free survival, so what that means is how long you stay in remission, not whether you're alive or not. And remember that we're looking over many years of time, and their experience with CHOP in two eras were a program of Promace-MOPP, which is what the NCI used in their watchful waiting program, or more recently, a fludarabine-containing combination, really looked strikingly similar. And that's why we would say that there's really not a one favored, upfront treatment if chemotherapy is indicated for follicular lymphoma. They are different. They have different side effect profiles, but in terms of maintaining remission, not different.
And this of course tells us that because the response rates are so high, that there might be some merit in getting that initial remission and then doing something after that to maintain it, or perhaps even lead to cure. So that's the interest initially in interferon after chemotherapy. That's the interest in vaccine therapy after chemotherapy, and more recently, Rituxan.
Slide #16
I also wanted to point out that not all chemotherapy regimens are created equal, and just because you're getting CVP, it doesn't mean that it's the same CVP that someone else is getting or the same in a clinical trial. The doses and schedules, particularly of Cytoxan, can vary widely. Similarly, with chlorambucil. And this combination of fludarabine and cyclophosphamide was one of the sobering lessons that we learned, where we did a small trial, escalating the dose of Cytoxan with fludarabine, then took it to a larger trial, which actually was closed early during the course of the trial because of increased toxicity with this combination.
However, there are other combinations of fludarabine and cyclophosphamide particularly used for small lymphocytic lymphoma, or CLL, that are looking very promising. So even -- They're all called FC, but it's really important to know what the individual doses and schedules are.
Slide #17
Here's an experience from our place. That was a trial that I actually started 14 years ago, and saw patient numero uno a few weeks ago in followup, and what we did was select patients who we thought had high tumor burden, treated them with chemotherapy, primarily CVP, and then we took them to high-dose chemotherapy and autologous transplantation. And what's interesting about these results is that they're so mature, and actually now we have, as you can see, another 18 months of followup, and they really look the same without other events. Very encouraging remission duration, still, projected at ten or more years, that 70% of patients would be in their initial remission. And you can see the overall survival data look encouraging as well.
But here and here we had two patients who had secondary leukemia. This has been one of the problems that has haunted us with using more intensive treatment programs across the board, but particularly in follicular lymphoma.
Slide #18
And we know that this trial doesn't stand alone, but other trials at the Dana Farber and throughout this country and Europe have shown that this is a risk, that we can look at see what factors relate to it, but our feeling was that we were going to keep this experience kind of on the shelf, let everybody get out at ten years or more, and then maybe go back to the drawing board and thinking about building upon this and making it safer. So safety is an important issue, as well as efficacy, in follicular lymphoma.
Slide #19
I spoke earlier about the conclusions I think that we can draw, then, from the randomized trial: No overall survival advantage to immediate therapy in watchful waiting candidates. No overall survival advantage for adriamycin- or doxorubicin-containing chemotherapy. You can't always take the data from being in remission for a long time and translate that to better survival. It hasn't worked in follicular lymphoma, and there's no one defined best approach to ensure best survival.
Slide #20
And yet, despite all that, I think we have tremendous optimism about indolent lymphoma and where we're going now and what we can achieve. That's the promise of targeted treatments, certainly beginning with rituximab -- and I know there's a high level of interest among many of you in the audience with regard to vaccine therapy. The optimism about potentially being able to achieve a molecular remission, where you can go to analyzing individual patients, primarily blood and bone marrow compartment, to see that the remission is much deeper than what we can tell by physical examination and routine CT scans or bone marrow biopsies, and then moving on to really take a molecular picture of large numbers of follicular lymphomas and begin to dissect them to understand prognosis better and to do a better job of current selection of therapy, and also to identify targets for new therapies.
Slide #21
So enter rituximab, and I showed you this earlier. These are the results of the pivotal trial. The response rate for follicular lymphoma was about 55%, the response duration slightly over a year. With eight weeks of treatment rather than four, not really a significant difference.
In untreated patients, watchful waiting candidates, so selected patients, a higher response rate, and I'm going to show you some more data about that with a more recent trial.
Q: Are these after chemotherapy?
SANDRA HORNING, MD: So the pivotal trial --
Q: No, are these after chemotherapy?
SANDRA HORNING, MD: Yeah. So the question is, are these after chemotherapy? So the pivotal trial is done in patients who have a recurrence, so yes, they were previously treated. Similarly, the eight-week, as the name would imply, the untreated patients had not received any prior treatment. And the re-treated patients are patients who received rituximab the first time, responded for six months or longer, and then received a second course of Rituxan. Did that answer your question? Okay.
Slide #22
So with that baseline, then, we're really kind of off and running to figure out how to make this better. So how can we optimize monoclonal antibody therapy for follicular lymphoma? Well, one obvious thing to do is to combine it with chemotherapy or after chemotherapy, move it forward from recurrent patients to front-line treatment, to enhance the cytotoxicity, to add something to rituximab to kind of boost the immune system and make it work better, to use antibodies as a way to target follicular lymphoma and bring something with it, a radioisotope, radiation, or perhaps a toxin, and to take advantage of what I call the compartmental effects.
And because antibodies are large molecules, they're going to be most effective where the tumor burden is small, because they have to kind of diffuse in. And where they actually work best is in the blood and in the bone marrow. And what you'll see in rituximab-treated patients that's different from chemotherapy-treated patients is the following: When we treat patients with chemotherapy, frequently the most difficult place to eradicate that last element of disease tends to be the bone marrow. If you treat with rituximab, it is often a different picture, where you have a very good effect in the blood and the bone marrow compartment, but you're still left with solid evidence of disease by CT scan or by palpation. And you can imagine that in some ways these things could then be complementary if you put them together.
That compartmental effect is also one that can be very advantageous for our issue with autologous transplantation. I showed you the autotransplant data. They look great, although it was a selected group of patients, but we're concerned about secondary leukemia. We need to treat them up front before the transplant, but if we could perhaps treat them with a little bit of therapy, including rituximab, get those cells out before they are damaged by more chemotherapy, then we might go back and do the same thing with less of that secondary leukemia risk. So there's a lot of interest in the compartmental effect, not to mention if you have a pure stem cell population that you can get from the blood that's not contaminated by lymphoma, one would think that the results might be better in terms of a lesser recurrence rate.
Slide #23
So what about the combination? Well, this is something that many of you probably know about and perhaps have received. It's a combination of rituximab and CHOP that was a study performed in 38 patients in about three or four institutions, and has received a tremendous amount of press and has become very popular among practitioners in the community. And here's how the treatment went. As you can see, rituximab here, in white, and CHOP. And the idea in this study by Dr. Czuczman was you give rituximab, you get the level up, and unlike drugs, rituximab circulates for weeks. So his idea was to kind of get this goal post effect, where you get the Rituxan up, you keep it up, and you have it here at the end, and then you can give the chemotherapy in between. This is the so-called Chuchman regimen of R-CHOP.
Slide #24
The data from this study look very encouraging, have been published on multiple occasions, and this is now the progression-free survival, and we're looking at now months, and the time from the first infusion to disease progression. Here's the 50% mark. We usually expect with typical chemotherapy for that 50% to be at around 36 months. So you can see, it's considerably longer here and looks highly encouraging. But I hope you learned from our sessions this morning that a small number of patients highly selected does not prove that this therapy or any other is necessarily better. In my view, it means it's worthy of further study.
Slide #25
And what are the pros and cons of rituximab as primary combined therapy with chemotherapy? Well, we know it's effective as a single drug. It's got modest toxicity, and that really should be stressed. That's why it's become so popular, and it's so easy to adapt it to many situations. We have a positive trial now of rituximab-CHOP in large-cell lymphoma that we talked about this morning, and it is something that one can get reimbursed for, so it's not a problem of access.
On the other hand, we have issues of the potential induction of resistance. If it's better to give rituximab at a later date, we don't know the best way to use it. When we treat patients with R-CHOP or other off clinical trials, then we lose research subjects for clinical trials, and we spend a lot of health care dollars without established benefit.
Slide #26
So this is the cooperative group trial from the Southwest Oncology Group that is looking at this combination of CHOP-rituximab compared with CHOP or CHOP followed by Bexxar. I hope it's not true, but I heard a rumor last week that because of poor participation in this trial that the CHOP arm may be dropped, and we may never be able to answer in this country what benefit, if any, there is to this combination.
Slide #27
This is the study that we are doing in the Eastern Cooperative Oncology Group in advanced stage indolent primarily follicular lymphoma, and it is a trial with CVP chemotherapy, kind of standard chemotherapy, and then patients are randomly assigned to observation, which would be the usual thing, or to get a prolonged course of rituximab every six months times four, or for two years. And we are closing in our accrual goal now of 515 patients. I think we will be able to answer this question we're asking. We're hypothesizing that if we add rituximab to CVP we're going to have a longer time to progression, and obviously it's going to take a much longer period of time to see what influence that has on further therapy or overall survival.
Slide #28
Meanwhile, this summer, and the Lugano meeting, there was a presentation from the Swiss group, the SAKK group, that looked like there were some promising data utilizing this same approach -- slightly different, but somewhat the same.
So this was a study done in both follicular and mantle cell lymphoma. One of the problems that I have, and I hope we've conveyed this somewhat to you, is that not all studies are of equal quality. This is going to be a smaller study. It's including patients with different types of disease, previously treated or not. So very heterogeneous, small numbers, but nonetheless, patients receive four weekly Rituxans, then anybody that was stable or responded went on to either be observed or receive MabThera, which is the European rituximab, every two months times four.
And what this study showed was that the time to progression was about 13 months longer in the patients who received additional rituximab than observation. And I found that a few weeks later I had patients coming into the office with press releases from the pharmaceutical company touting this. Now, it may be an advance, but this is a small study. We need more time. We've got a big study that's on U.S. soil that I think is well done, and it's an important question, and one I think we're going to be able to answer.
Slide #29
It becomes a more interesting question, actually, because of these data from John Haynesworth in a community trial in Tennessee. And what Dr. Haynesworth and his colleagues did was to use rituximab as a typical kind of four-weekly induction, and then to give it, just as we are doing in the ECOG trial -- that is, every six months times four -- and what he could see in follicular lymphoma here -- and these are previously untreated patients. They're patients who, quote, "did not need a rapid response." That's all we know about their prognostic features. It's a phase II, single-arm study. But nonetheless, we're seeing some very interesting data here. Again, if we expected about half the patients to relapse at 36 months, this looks encouraging at this point in time. Do I think that's what we should do tomorrow in the clinic? No. Do I think it's worth further study? Yes.
Slide #30
That's what we hope to do.
We are petitioning the National Cancer Institute now. Actually, I hope they met this week to talk about a trial that we want to do in watchful waiting patients. This is a real departure from anything that has really been done on U.S. soil previously, and instead of randomizing to watchful waiting versus treatment, we have decided to randomize to two different courses of rituximab. The endpoint of our study is going to be different than what's been done previously, because we think it's the endpoint that's important to patients, and that is the time to first chemotherapy.
If you start rather than watchful waiting with rituximab either on a continued basis, or this might be considered a PRN basis, because patients who progress could get Rituxan again as long as it had been six months. And we are going to pair with the United Kingdom, who will be doing a study of watchful waiting versus rituximab in their country. We thought that this would be a way that we could pull off a trial in both countries that would yield useful information. So we'll see what the National Cancer Institute tells us.
Slide #31
Again, I made the point about the compartmental effect of rituximab, and many times we hear about molecular remissions. I don't know if this audience has heard much about that, but it's something that is spoken about in physician circles a lot, and what does that mean? Okay, so you go through a treatment, and then you are restaged, and hopefully there are no palpable lymph nodes. The CT scan looks clear. The bone marrow biopsy is repeated, and there's no evidence of lymphoma and you're in complete remission. However, we know that most patients like that are not really in complete remission, because the lymphoma tends to come back. So is there a more sensitive test for looking at remission? The answer is yes, there is in follicular lymphoma for the majority of patients because there is this specific translocation, which is a break in the chromosome 14 and 18 that's put together, and this can then help identify cells that are related to the follicular lymphoma versus normal cells. And with newer technology, with PCR, or polymerase chain reaction technology, now you can identify readily 1 cell in 10,000, and often 1 cell in 100,000, sometimes even 1 in a million. What we find is that when we use chemotherapy, molecular remissions occur relatively rarely, and you always get fewer molecular remissions than you get complete remissions, by definition.
However, when you use antibody therapy, you can actually see that you have a higher incidence of molecular remission than you do complete remission, and that's again because of this compartmental effect. So none of us should be lulled into thinking that we're making progress because we have molecular remission. It's better to be in molecular remission than not, but it doesn't mean necessarily cure.
Slide #32
And I'll show you a study that's looked at this recently. This is a study from Italy where patients with indolent lymphoma who had this translocation got six cycles of CHOP, and then they had PCR. And if they were still positive, there was still molecular evidence of lymphoma, they received rituximab times four and were followed.
Slide #33
And what you can see here is that they took the patients who were still positive by the molecular test, gave them rituximab. A significant proportion became molecularly negative. Again, that can have very important effects for our thoughts about transplantation as well as for this group of patients and their remission duration.
Slide #34
Here is the remission duration for the PCR-negative versus the -positive. Again, it's better to be negative than positive, but just because you're negative does not mean that you're cured when rituximab or antibody therapy is used.
Slide #35
I showed this slide earlier today. I look at this slide with optimism, and I look at it with optimism, because when you look at that P value, that's highly significant, that patients with follicular lymphoma treated at our institution are living longer, and we look to see if patients are younger or there's something different about their staging. It isn't. I think it's because we have multiple options, and what we're really struggling with right now is how best to use those options, build upon them, and we're not giving up the quest for the cure.
Slide #36
So there are clinical trials that need your participation. There is the hypothesis from the National Cancer Institute and the Genitope pharmaceutical company trial that idiotype vaccine will prolong remission in follicular lymphoma, the SWOG, study, the CHOP plus rituximab or CHOP plus the radioimmunotherapeutic tositumomab will increase failure-free survival, and the ECOG and CALGB trial, that rituximab maintenance after CVP will increase time to progression.
Slide #37
I want to just switch gears a little bit and then talk about more investigational type treatments and start out with radioimmunotherapy. Of course, this is no longer investigational since Zevalin was approved, but it's approved for a very narrow range of use right now, which is for recurrent indolent lymphoma and also transformed lymphoma after that FDA meeting that I spoke to you about.
And again, the advantage of radioimmunotherapy is that you don't have to target every tumor cell because of this crossfire effect that you can get from one cell to the next. And that may be particularly useful, depending on the size of the tumor, but it also has a negative impact, and that is in follicular lymphoma we often have disease in the bone marrow kind of spread out, and if we're specifically attracting radiation to the bone marrow, well, then, normal cells are going to be radiated, too. So it's not surprising that the major side effect of radioimmunotherapy is bone marrow toxicity, very different than what we see with rituximab.
And it's probably also not surprising that one of the greatest concerns of the FDA in releasing this treatment and allowing us to test it in other situations, which we're extremely anxious to do, is their concern, once again, for secondary MDS and acute leukemia as a result of treatment.
Slide #38
For a while there was kind of a neck-to-neck race with two radioimmunoconjugates, one with yttrium, which is Zevalin, and the other one with I-131, which is Bexxar. Both of them are attached to murine, or mouse, anti-CD20 antibodies. The major difference is the isotope and how tightly it is linked to the antibody. The chelater with yttrium is much tighter, and that means that how the body handles this is much more predictable. Therefore, dosing can be based upon patient weight and platelet count, whereas with Bexxar, it's less predictable, particularly the urinary excretion, and therefore there is patient-specific dosing.
For either, it involves multiple gamma camera images -- a minimum of two at least, in many cases three -- to make sure that the radiation is going to the correct areas and not to normal organs in the body.
Slide #39
When we look at the data that compare rituximab and radioimmunotherapy, there are two not exactly head-to-head studies -- not randomized, I should say -- but one study that was done by Mark Kaminski in previously untreated patients that showed a high response rate with Bexxar compared to the lesser, particularly, complete response rate when rituximab is used as a single agent in untreated patients. In the randomized trial, which is the one that was used for fast-track FDA approval that Dr. Kunkel mentioned earlier today, it was in previously treated patients who had never received rituximab, and they were randomly assigned to one or the other. There is a higher overall response rate with Zevalin, and a higher complete response rate. Of interest, however, the time to progression was not different in the two arms.
I think the good news is that for patients who had rituximab and then either did not respond or regrew, there's a high rate of response with either Zevalin or Bexxar in this group of patients. So another effective option beyond chemotherapy, beyond rituximab.
Slide #40
This is the time to progression curve for the Zevalin and rituximab in that trial, showing that they are very equal.
Slide #41
Now, if we're comparing the two, I think it's fair to say that the response rate is greater with radioimmunotherapy, and what excites me is that in my practice I have individual patients who are now three and four years in remission after radioimmunotherapy, patients who have had a lot of prior treatment. It's been great for them.
But there are limitations, and they include bone marrow involvement -- this treatment cannot be given if there's more than 25% bone marrow involvement -- if there's preexisting toxicity to the bone marrow from other treatments that would render the platelet count less than 100,000, and then there are all the practical issues of actually administering it, as well as safety concerns. I mentioned the toxicity to the bone marrow and the concern for late effects, specifically MDS or leukemia. And in combination use, clearly, rituximab is more versatile.
Slide #42
In my final slide, I'm just going to let this one rest here a minute and talk about some other targets. One over here on the left is HLA-DR, and there is an antibody to a variant of this antigen which is actually something that's sticking on the surface that's part of the -- related to the immune complex that identifies each of us as individuals. There is an antibody called 1D10, or apolizumab. I don't know if any you have come across that or received that. That is in clinical trials, has been used alone and in combination with rituximab. Again, for the importance of doing things carefully, there have been some toxicities related to the combination of these two antibodies that were unanticipated, and this is being watched very, very carefully by the NCI at this time.
CD19 was actually tested a number of years ago by the Dana Farber group, and they linked an antibody directed against CD19 with a toxin, so-called "B4-blocked" ricin and found that there were some positive effects in patients with follicular lymphoma, and then they went on to actually test this in a phase III trial in the post-transplant setting. And in that setting, as you can imagine, with a more aggressive disease process, there was no benefit.
The surface immunoglobulin was really the stimulus of the initial trials that have now led to rituximab and to vaccines. This is work done by my colleague Dr. Levy at Stanford, where he made antibodies that were unique to each patient. As you can imagine, that was a very laborious procedure. I actually saw the very first patient who received that treatment. I think it has been maybe 23 years ago. He was in the clinic a few weeks ago. He tells me that he is now 89, and sometimes you do have beginner's luck.
But the problem with this approach is it's not practical. You really are unlikely to get a commercial endeavor interested in this approach, and that's why the pan-B cell antigen, something that's on everybody's B cell lymphoma, like CD20, is a much more attractive target.
But the other thing that happened is that this surface immunoglobulin ... [END OF SIDE A] ... that you'd have an antibody that was reactive against the lymphoma that you biopsied, but perhaps when used later there had been mutation and change here so that it wasn't a perfect fit, if you will, and not as effective.
And that led, then, to the idea of a more active immunization to get this piece and make it immunogenic so that the patient's own immune system would have the desired response. And that's really occupied the last 10 to 15 years of research at Stanford in trying to figure out how to produce this, how to make it more immunogenic, as it has stood about a 50/50 chance of having the desired immune response, and the immune response is different, whether it's the B cell compartment or the T cell compartment. Ideally it would be both.
So there's still a lot of ongoing work to try to make this more effective. A lot of people have asked, "Well, why not just use the vaccine and forget about the chemotherapy that goes in front of it?" And I think that that's an interesting question. What we think happens is that when you have lymphoma, the immune system kind of gets blunted in its reaction to it, and that you might need to get to a low level before the immune system can really kick back. There has been a small experience with using vaccine therapy as the front-line treatment, and I think Dr. Timmerman, who's here tomorrow, might be able to tell you a little bit more about that.
We've talked a lot about rituximab and anti-CD20 therapy, and what people are doing now is trying to figure out how to make it more effective, and the thoughts are to possibly combine it with interferon to stimulate the immune system, and there are three or four reports that suggest perhaps modest efficacy with that approach. Another cytokine that's been used is IL-2. IL-2 stimulates natural killer cells which are part and parcel of the mechanism by which rituximab can kill cells, and this is being used in the clinic and in conjunction with transplantation. Also, another cytokine that's not commercially available called IL-12, an interesting trial that came out last year from the Mayo Clinic group. Further research is going on with that.
Someone asked me before we started here about oligonucleotides as a way -- CPGs to stimulate the immune system, and that's another approach that is being taken by a commercial company, and there are phase I escalating trials with subcutaneous and intravenous administration of that. It works very well in mouse models, and now the phase I safety data are in progress as it's going through phase I trials.
Undoubtedly there are going to be other approaches to try to stimulate the immune system and make rituximab more effective. We're not really sure how rituximab acts in different patients at different times. When it's given together with chemotherapy and we may have wiped out the effector cells, it's probably having a more direct effect. In other circumstances, perhaps the immune system is really important.
One of the interesting things that has been published in the last year is that based upon your genetics you may be more or less likely to respond to rituximab. This has been evaluated in that group that I showed you who got rituximab when they were untreated and had the 70-some percent response rate. They went back and they looked at differences, genetic differences in their patients, according to the receptor that engages the cells that come in to kill the lymphoma cells, and they found that patients with a certain genetic type were more likely to have a complete remission or respond, and more likely to have a longer remission.
We're hoping that we can extend those studies in the context of one of the larger trials, and that might also give us some clues that for some individuals rituximab might work best if you have it as a single agent. In others, perhaps, in combination or with the immune stimulation that gives this impetus to go that direction, and maybe we could bring everybody up to that level. Areas of active investigation.
And finally, with the CD22, there is a humanized antibody, epratuzumab, that AmGen is evaluating. There are some preclinical data to suggest that this might be interacting in a favorable way with rituximab, and there are studies that are looking at that combination as well as epratuzumab alone. We're extending that to large-cell lymphoma, as well. One of the problems in further development is that the first thing out of the chute, CD20, was so darned good it's going to be hard for anything else to really measure up to CD20 as a target. For instance, CD22 -- that's what we call modulate or internalize is when the antibody comes along this target goes inside, and it does so rapidly, whereas this is a stable target. And this might be something that would be an advantage if you were taking a toxin or radioimmunotherapy into the cell. But if you have just a naked or a conjugated antibody, that can be problematic. And it's fair to say that there's a great deal of interest in developing this and other antibodies and thinking about combination therapy, combination immunotherapy, in the same way that we thought in the past about immunotherapy -- about combination chemotherapy.
I think I'm going to stop here. I do hope that you got some of your issues addressed. I'd be happy to answer any questions. It is five o'clock, and maybe what we'll do is let people who need to go go, and then those who would like to stay to listen to questions, do so. Thank you for your attention. [APPLAUSE]
Oh, I was also supposed to ask people who are asking questions to go to the microphone, because this is being taped, and then others who are not here are not going to be able to take advantage of your questions.
: Turn your clock --
SANDRA HORNING, MD: What?
: ...
SANDRA HORNING, MD: Oh, yeah. Fall back tonight, right? Yes?
Q: Would you explain the significance and the utilization of PCR in evaluation?
SANDRA HORNING, MD: The question is the significance of PCR. I think it is a research tool at this point in time. I think it is still in the realm of being a research tool. We've talked about a conference that we hope to have in January, and that may be the subject of the conference, so stay tuned. Yes?
Q: How prevalent are secondary cancers after chemotherapy and treatment? Is it quite -- are people -- do they get secondary cancers quite frequently after treatment or chemotherapy? What's a percentage that they --
SANDRA HORNING, MD: After chemotherapy, in general, the only type of secondary cancer that's increased in incidence is leukemia, and the likelihood of that is very low. We looked at a group of patients under the age of 50 that we treated so that we have a long term of followup, and the risk of that at ten years in our hands was less than 2%, so it's a low probability. There are data from the Hodgkin's experience with chemotherapy that indicate that there's a higher risk of lung cancer in smokers. But in general, solid tumors are not increased after chemotherapy for lymphoma.
Q: I had Rituxan four years ago, when I had bulky tumor, and it didn't work very well. I had a four-week treatment. And then just recently, a few months ago, I had another treatment for some skin lymphoma that came up and had a very severe allergic reaction to it. My doctor and I are still considering doing a lower, smaller dose. Is an allergic reaction something that is ongoing, or does it dissipate after time, or -- I'm not quite sure how to take it.
SANDRA HORNING, MD: Did you respond?
Q: Yes. But the allergic reaction was rather severe.
SANDRA HORNING, MD: And what was the allergic reaction?
Q: I had some during infusion, but then a couple of weeks after I had arrhythmia, a heart arrhythmia, and some severe joint pain. So --
SANDRA HORNING, MD: An allergic reaction -
Q: How common is that, actually? And actually, I would like to talk to anybody else in the audience who has had allergic reactions to Rituxan.
SANDRA HORNING, MD: You know, I think an allergic reaction is something that has rarely been seen in terms of a true allergic reaction. That might be seen kind of like a serum sickness, with fever and joint pains, et cetera. That has been a rare reaction. And I would think that the best source of that would be to actually talk with either IDEC or Genentech, because they have an international database of all of the safety, and they can tell you precisely what the incidence of that's been and how it's been handled. And one of the things that can be done is to actually look and see if you have developed antibodies to rituximab.
Q: How would you find that out?
SANDRA HORNING, MD: It's a blood test.
Q: Oh.
SANDRA HORNING, MD: And I think that they would run it for you.
Q: I would have to contact Genentech directly?
SANDRA HORNING, MD: Yes, I would. Yeah?
Q: I was interested in autotransplant in the slide you had up, and you talked about myelodysplasia and leukemia. But what are the other downsides? You had what looked a pretty high survival rate with that autotransplant. What are -- Besides the real obvious ones, I was concerned about what else you have left after you relapse from the auto, and if you have anything left, especially if you transform, if there are any other options.
SANDRA HORNING, MD: Well, for some patients who have autologous transplantation, based upon how much prior therapy they've had, they can be left with a bone marrow that's not at full capacity, so lower blood counts and lesser tolerance for subsequent treatment. How that works practically depends on whether you need subsequent treatment in 24 months or five or more years, because there is a difference there.
Fortunately for us, we haven't had a very high number of people who have relapsed, so we don't have a lot of experience. But, you know, I can tell you anecdotally that for patients who have relapsed that we've been able to treat with rather mild therapy, and I have a patient who probably relapsed maybe four years ago who has had two courses of rituximab and not needed any further chemotherapy. Now, that's not pertinent for the question of histologic transformation, I realize, but I guess the point I was making is that not with every recurrence would you necessarily need to go into chemotherapy mode.
It's a tough question to address, because I think anything I would tell you or someone else might be a bit anecdotal. But you're right on that the concern is using up your ammunition up front. And that's why, at least for us, despite these good results, we haven't wanted to push that forward unless we could think about a reasonable way around it. And in addition, you can only do so many things, and we felt that right now we wanted to put our effort in the phase III vaccine trial.
Q: So you're not recommending an auto at this point for people?
SANDRA HORNING, MD: Not for people who are newly diagnosed. It's a different situation for individuals who have relapsed.
Q: But for relapsed patients, that's still something that --
SANDRA HORNING, MD: For relapse patients it's a very viable strategy. It's again something that's difficult. It's difficult to talk to patients and physicians about when you would recommend that, because it really is a matter of judgment, but I would normally not consider a transplant as the first relapse therapy. On the other hand, if there are patients who do not really enjoy any time in remission, then I think one can think about moving that forward. So it's highly individualized, in my view. Yes?
Q: With regard to the slide showing the transformation of follicular to diffuse over time, for patients in watchful waiting, even taking into account that every lymphoma is different, is there a rule of thumb that would give you some notion of how long it takes for that transformation to take place on average, or a range?
SANDRA HORNING, MD: Well, one of the ways that you could look at it is to graph it out and see when it occurs, and it's kind of a persistent slope. It's not something that peaks at four years and then goes back down to baseline. It's a persistent risk over time. It's not that high of a risk however. At least in our institution at eight years, the actual risk of histologic transformation was 20%.
Q: Is that in conflict with what we heard this morning from the pathologist, who said that over time almost all of them transform?
SANDRA HORNING, MD: I think that as a pathologist -- and hopefully you'll take this the right way -- I think the data he might have been looking at were actually autopsy data, and autopsy data show that if you look really carefully you can see evidence of transformation in more than 60% of patients, and in some series up to 100%. But if you saw it or not, I think the question is, was it clinically important? Was it clinically relevant? Just the same way that you see a large proportion of men who die at an older age who have prostate cancer, but it was never diagnosed. It was never a clinical problem. Yeah?
Q: I have two questions. The first is, can you comment on the use of Rituxan and the maintenance therapy, particularly regarding what I think is a theoretical risk of drug resistance?
SANDRA HORNING, MD: Well, I think rituximab maintenance therapy should only be given in the context of a clinical trial, and I think the question is, is it better to use it at that point in time or to reserve it and use it at a later point in time. We won't know that if we're doing, you know, individual clinical trials in practice. We'll know that in the context of a study. So I think you're making a good point, that that can be a concern, and that might be a concern for why you would or would not want to participate in a study that's looking at that. But I would not encourage doing that in a non-study situation.
Q: My second question is, if I understood you correctly, on your last slide you mentioned that a unique surface antigen can change over time. Does that mean that --
SANDRA HORNING, MD: The idiotype can.
Q: Right.
SANDRA HORNING, MD: Not these others.
Q: Right. So if one has banked tissue in an early biopsy with the hope of using it at some point in the future for vaccine, is that potentially a problem?
SANDRA HORNING, MD: A problem? I don't think so, because the difference between making an antibody that's got a link to this thing and a vaccine is that when you're making an antibody, it's called monoclonal. When you are vaccinated, you have a polyclonal response, so you've got a lot of different antibodies coming in and recognizing this, and it's very likely that they could overcome some of these minor mutations, which the one specific antibody could not. That's a good question.
Q: I was wondering what the current thinking is on any possible impact of antisense therapy on follicular lymphoma.
SANDRA HORNING, MD: Another good question, and something that I was actually going to talk about in the clinical trials thing, but we didn't get to it. The antisense that is -- Well, antisense is a category for a class of therapeutics that can interfere with protein production, and so you would have a specific antisense for each gene and protein that you're interested in, and the one that's being developed is for something called bcl-2. bcl-2 is a protein that that 14-18 translocation upregulates, so it's overexpressed. It's actually overexpressed in a lot of lymphomas. The highest overexpression rate tends to be in mantle cell lymphoma. So, yes, there is active investigation ongoing in looking at that approach. Actually, the first reports of bcl-2 antisense were from the United Kingdom, and they were done in patients with follicular lymphoma.
What's kind of interesting is knowing where these things are really going to pan out and work. I mean, the thing you would think is, "Oh, these cells overexpress bcl-2. Therefore, that's a good target for this material." On the other hand, it may be that where some of these things work best is actually in the cell populations that are not overexpressing bcl-2, because there's always going to be a dose-response effect, and that's kind of where we're stuck in the development of that, is knowing if we're downregulating the target.
The importance of that to this audience is that -- and it's something that Dr. Said alluded to -- I think as we move forward we're going to need to change the way we think about obtaining tissue and storing tissue. I think we're going to need pieces of lymphoma stored in a way that we can evaluate them, and as we go on trials -- I don't think this is going to happen in practice -- as we go on trials and we have to figure out for all of humanity if this is going to work or not, it's a good idea, you really have to go back in and biopsy that target. There's no other way you'll really know that you have chosen the right dosing schedule of antisense therapy to carry forward. And then once you figure that out, you can go back to those biopsies and maybe see what the level of expression of bcl-2 was in individual patients and correlate that with response.
Q: Okay. Thank you.
SANDRA HORNING, MD: Mm-hm.
Q: I had a question. When I first had rituximab, I wasn't on Premarin because my prescription had run out, and it seemed like I had a great response. My tumors on one side went way down. My prescription came in and I started taking Premarin again. It seems like things slowed down. Do you have any opinion about that?
SANDRA HORNING, MD: How long did you take the rituximab?
Q: Pardon me?
SANDRA HORNING, MD: How long did you take the rituximab?
Q: I was on a one-month schedule.
SANDRA HORNING, MD: Uh-huh. So you're saying that the first two weeks things shrank, and then they stopped shrinking when you started taking your hormones?
Q: Yeah, yeah. I mean, that was just my observation, and I'm wondering whether I should continue Premarin.
SANDRA HORNING, MD: Well, the question to continue Premarin is a hot one --
Q: Yeah.
SANDRA HORNING, MD: -- right now, but we won't get into that. I doubt very much there's a relationship, because we really haven't seen a relationship related to lymphoma at all. You know, we talked this morning a little bit about epidemiology, and I didn't mention it because it hasn't really been validated, but there is a study that was published in the last year from the Mayo Clinic group, and they keep very good records of people who live in Olmstead County, which is around Rochester, and they have actually reported that they think there might be an increased incidence of lymphoma in women taking hormone replacement therapy, and that has not been validated by others, so I don't know that there's an association. I don't think it's a situation where that's interfered with the effects of rituximab in your case, but, you know, as this whole area of hormone replacement therapy becomes more embroiled in effects, I thought I would mention that that's one thing that has come out in the last year.
Q: Hi. I sort of have to rework this question to wrap my mind around it. From what I understand, bone involvement is somewhat not common with follicular small cleaved, and we have a hot spot that showed up on various scans, and from my uneducated mind I envision cancer cells surrounded by healthy cells, thus making it very difficult to get a good needle biopsy, and so I wondered if there is a transformation in the lymphoma, does it always show up in the blood work first, or can the blood work be normal?
SANDRA HORNING, MD: The blood work can be normal. The most significant finding in the blood for transformation is something called the LDH, and that, if it's elevated, is something that you would consider suspicious. If it's normal, it doesn't necessarily help you. A lot of times when follicular lymphoma involves bone, it does so locally, and it's an extension of lymph nodes growing into bone.
On the other hand, bone involvement in follicular lymphoma is generally uncommon, particularly if it's diffusely in many bones. I've got to watch those terms. Under those circumstances I always have a healthy suspicion about transformation, but I have seen patients with follicular lymphoma with multiple bone sites who did not transform. So you really have to try to get a biopsy that tells you the answer.
Q: And am I visualizing it correctly? Does the needle go in? Is it hard? Do you have to hit it right on the mark, even though you have a hot spot that's a whole area, do --
SANDRA HORNING, MD: Yeah. Well, a lot of times in bone you can have necrosis, or dead cells, and you can get a lot of debris when you go in. I'm actually not much of an expert on bone biopsies. They're done by orthopedic surgeons, and I haven't really witnessed them.
Q: Thank you.
SANDRA HORNING, MD: Mm-hm.
Q: My question is on conditioning, both during chemotherapy and when you're out of chemotherapy. Is there a maximum level of physical fitness exercises, whether it's cardio or weight lifting that you should try to avoid? Is there too much working out, I guess, that could have a detrimental effect?
SANDRA HORNING, MD: No. [LAUGHTER]
Q: My second question is on the other end of the spectrum. I enjoy drinking and is there a safe level of alcohol consumption, any level that would be considered safe, during chemotherapy or after?
SANDRA HORNING, MD: Well, I try to discourage alcohol consumption during chemotherapy, because I think it can depress the bone marrow, and once you've entered chemotherapy you want to optimize it. But afterward, I think that there are a lot of data that suggest that very modest consumption of alcohol might be a favorable thing.
Q: Thank you.
SANDRA HORNING, MD: Mm-hm.
Q: I have a two-part question because of your answer to somebody else's question. I had Rituxan on three separate occasions. The third time it didn't work as well as it had before, although I had recurrence each time. Since then I've had two different chemotherapies, and my last one was at the beginning of June, and my oncologist has offered me, and I have started already, maintenance with Rituxan. And the question in my mind is, since it really didn't work for me the last time -- it did shrink it, it did not go away, but it's in a spot that keeps recurring -- how effective it would be as maintenance.
And my second part is, I know of at least three or four other oncologists not in my area that use it as maintenance therapy, so you don't seem to be -- you don't seem to think that that's a very good thing to do unless you're in a study. Where is there a study?
SANDRA HORNING, MD: Well, I did mention the ECOG study. That is for initially untreated patients, but, you know, you've got to learn somewhere with some group of patients. I am certain that your oncologist is trying to do the best job possible in keeping you well and your disease in remission.
Q: Right.
SANDRA HORNING, MD: In general, I discourage creativity of this type because I think we often don't know what we're doing, and we don't want to do harm. You know, I would sooner think if you wanted to stay in remission, you'd try something like interferon, because at least that is proven to be a therapy that can keep people in remission, or at least a proportion of people. So to answer your question, I know that physicians are out there and they're doing it. I know that it's being reimbursed, and I think there are a lot of conflicting issues related to its use. It's not something that I would personally do in most situations, but, you know, there are always situations that are different, and they call for different management that's unique to a patient.
Q: I've had interferon years ago, and my cancer recurred, so -- But do you think that there is a possibility that it would maintain, even though the last time I had it, it wasn't really successful?
SANDRA HORNING, MD: Uh-huh.
Q: Is -- I mean, I keep going around in my head.
SANDRA HORNING, MD: Well, that would certainly be -- you'd be less optimistic than if the alternate were the circumstance. But obviously I believe that there's a chance that maintenance rituximab will be beneficial because it's part of a study that I'm involved with, so I am optimistic that we're going to see a result there that will be carried forward, but I also know from a lot of experience that you've got to test it and find out if that's the right direction, or you should be going down the antisense route.
Q: So then there is a study going on at Stanford?
SANDRA HORNING, MD: No, this is a national study.
Q: Really?
SANDRA HORNING, MD: But it is for newly diagnosed patients.
Q: Ah. Okay, thank you.
SANDRA HORNING, MD: Yeah.
Q: My question is on tumor burden. How many tumors and what size puts you into the high burden area? And would you use that as a gauge to start a new course of treatment?
SANDRA HORNING, MD: Well, I think the measurement of tumor burden is one that is subject to the measurer, and has been expressed differently by different people. But low tumor burden or high tumor burden in the French study was based upon having three or more lymph nodes that were 3 cm or greater, or having a single lymph node that was 7 cm or greater.
If you look at the initial radioimmunotherapy studies that were done by Oliver Press in Seattle, they measured tumor burden by adding everything together, and if they came out with more than 500 g, then that was high tumor burden. So there are different ways of doing it.
I don't think it's just the burden of tumor, but it's also how slowly or quickly things are changing. It's whether that tumor burden is distributed in a way that's threatening or not, and it again calls for clinical judgment.
Q: In the translocation, the 14-18, if you have it at some other point is there anything being done right now to identify other than 14-18?
SANDRA HORNING, MD: I'm sorry, I'm not sure I understand your question.
Q: When I had a bone marrow, they said, "It's perfect and everything's fine," but they can't believe that it is. They're saying that I have translocated at something other than the 14-18, which is what they're saying the current test can show, but they don't have tests now that are finite enough to be able to show something more than 14-18. I was wondering if you knew if there were some other studies going on that are looking at other areas, other sites, other breaks other than 14-18.
SANDRA HORNING, MD: Well, it's quite common in the course of follicular lymphoma, particularly for someone who's had the disease for several years and had several treatments, to have multiple cytogenetic abnormalities, and sometimes those are complex chromosomal translocations.
We actually, in that study of patients with autologous transplant, were really concerned about the toxicity issue. These are young patients, and we felt particularly responsible, not just to them, but to other people out there who would be reviewing these results and thinking about this therapy. So what we did is every year we got bone marrow biopsies and we did cytogenetic analyses. And several of the patients on the study had very complex abnormalities. One of these patients has had complex abnormalities for 13 years without any clinical sequelae, another one for 11 years.
So it may be that -- Who knows? If I had a bone marrow biopsy, maybe we'd find something there, too. I mean, I think that people acquire things over time that -- and particularly if you've been exposed to chemotherapy, that may not be clinically significant, but could be found, and then we'd just worry.
Q: Thank you.
Q: Before I ask my question, I just want to say that I'm relatively new to this, and I've learned quite a bit today.
SANDRA HORNING, MD: Good.
Q: Thank you very much, and you in particular have helped inform my understanding of this complex disease.
SANDRA HORNING, MD: Thank you.
Q: The area -- [APPLAUSE] And I think that round of applause is very well deserved. I guess the area in which I'm the most confused, and I think it may just be a confusing area, is the process by which small cells become replaced by large cells. And I don't even know how to ask the question, but what I've thought of asking is, do the large cells, when they come, have the same markers as the small cells? Do the have the -- in an individual patient for which the markers are on, do they have the same idiotype? Is the idiotype expressed? Is bcl-2 protein made by them? Is CD20 on there, some stuff like that. And anything you can say about that process would be helpful.
SANDRA HORNING, MD: That's a really good question. Can I ask why you're interested? Are you just thinking about it from a biologic point of view?
Q: Yes, yes, and yes. I mean, I want to learn about this. It sounds like a dangerous thing. And yes, I know something about biology, but --
SANDRA HORNING, MD: Well, actually, it's very interesting. We talked a little bit this morning about molecular profiling of large-cell lymphoma, which is what is most advanced in the field right now, so you can take individual lymphomas and you can interrogate the tissue, you can ask questions about 12,000 genes. What is the expression like? And then you can find that among 50 individuals with large-cell lymphoma, that you can get two or three subtypes that look biologically distinct.
So what we wanted to do was to take patients who had follicular lymphoma who then transformed to diffuse large-cell lymphoma and see how they compared to their original follicular lymphoma, and also how they compared to the do novo diffuse large-cell lymphoma. That's why I thought this was such a good question. And what we found out I think is really interesting, which is that the large-cell lymphoma that occurs in transformation looks much more like the original follicular lymphoma than it looks like a newly diagnosed diffuse large-cell lymphoma.
So there's not only a very close relationship between sharing the same idiotype and many of the same markers, but at the level of gene expression it's very close. And what we're interested in doing is now figuring out if we could identify individual genes that look most different in those two. And then when a new diagnosis is made, we wouldn't necessarily profile the lymphoma tissue, but we would quantitate the expression of that gene or genes and try to assess whether that has some importance in the overall progress or lack of progress in changes over time and individual patients. And probably the way we'll do that is not start now and see what it's like ten years from now, but go back to our tissue bank and look at that.
Q: How terrible a thing is transformation, and what does it do to the prognosis?
SANDRA HORNING, MD: Yeah, I think if I could say one thing today, I'd like to say that I would like you not all to leave terrified of transformation, because, again, it's a very subtle thing, and it doesn't always occur, and sometimes it's not so bad.
In our experience, the patients who had histologic transformation who did the best were patients who transformed in a single area -- meaning not diffusely around the body, but in a single site -- and who had not received prior chemotherapy, because sometimes what happens is people go from watchful waiting to transformation, and also whether they responded to chemotherapy. And we could identify a subset of patients who had transformed, had treatment for their transformation, and went right back on the curve of follicular lymphoma almost without skipping a beat.
It is true that there are situations in which transformation takes place and it's a very serious event. In my experience, that's been more problematic in patients who have had their lymphoma for many, many years and have had a lot of prior therapy, because I think that what happens is that the cells that do survive all of that have derived mechanisms to survive, and that patients who have had heavy pretreatment may find it more difficult to tolerate, or we may find it more difficult to give them optimal therapy.
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