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Slide #1
SANDRA HORNING, MD: We're now going to move on to our first of two educational pieces, and we'll have questions and answers after this first presentation of lymphoma biology, and then Dr. Jonathan Said will follow with pathology. I hope our equipment will not fail us here, as it's been resting for some time. Okay. If you'll just excuse me for a minute, I'm going to get this actually set up as it should be.
The non-Hodgkin's lymphomas have been increasing in incidence over the period of the last 15 to 20 years, and in fact, according to some sources, the increase has been greater than any other malignancy in the United States. When I first began giving talks about the non-Hodgkin's lymphomas, we were talking about numbers that looked like about 35,000, and in 2001, more than 55,000 cases were diagnosed.
This now makes lymphomas collectively the fifth most common cause of cancer for both men and women, and as you might imagine, there's been a lot of interest in understanding what the cause of that might be. And while I'm here, I might ask if somebody could give me a laser pointer. That doesn't seem to be here. I haven't easily identified.
So the question is, then, what would be the cause of this increasing incidence? Some of it is related to the improvement in diagnostics. It used to be that pathologists only looked at slides under the microscope, and we now have means that range from immunohistochemical staining to molecular studies to actually make a diagnosis of lymphoma. I think Dr. Said will touch upon that.
Slide #2
In the era of HIV, we saw a profound increase in the incidence of lymphoma in young men infected with HIV who are immunodeficient. That fortunately has trailed off now somewhat thanks to the use of more powerful antiretroviral therapy. Probably the most reasonable cause for the increasing incidence is that we're all getting older. The U.S. population is aging, and the greatest increase in lymphoma is actually in the patient population who is over the age of 60, and that relates to the fact that we become progressively more immunodeficient as we age.
Slide #3
People are always interested in environmental exposures. "Why did I get lymphoma? What did I do wrong?" Many studies have sought to look at this, and in general they have not been conclusive, or one study doesn't agree with another. Perhaps the only certified association is one that is between the use of certain chemicals, pesticides, that's notable among farmers in the Midwest.
There are, however, specific infectious diseases that have a link, if not a causal relationship to lymphoma, such as the Epstein-Barr virus; more profoundly, the bacterium H. pylori and a certain type of MALT lymphoma involving the stomach. We also know there is a virus called HTLV-I which is related to an adult T cell lymphoma/leukemia, and I think many of us feel that this is really uncharted territory, that we're going to find in the next few years a much closer association between specific infectious organisms and lymphoma incidence.
And finally in the last year there have been two articles that have come out that are interesting that relate the lymphoma tissues to the presence of simian virus in polio vaccines that may relate to people who actually took these vaccines in the 1950s, and evidence of the virus was found in as many as 40% of cases. So this has raised another question about exposure and NHL.
On this pie graph, I'm showing you the frequency of the major non-Hodgkin's lymphoma subtypes. Actually, if you look at the new classification -- and again, Dr. Said will be going into this -- there are more than 30 different subtypes of lymphoma, and that is something that confounds our ability to develop treatments and move forward, because when we divide the pie in so many ways, we frequently end up with very small patient populations. Again, if we're thinking about new treatments and getting those treatments studied on clinical trials, if we only have 1 to 2% of people participating, then we may not have a quorum, if you will, for some of these subtypes.
The most common subtypes, as you can see from the pie graph, are DLCL, which is my shorthand for large-cell lymphoma, follicular lymphoma, and then something that's called discordant, and that is basically when both of those subtypes are coexisting at the time of diagnosis, which occurs in a subset of patients, maybe as high as 20%.
Slide #4
These are the anatomic lymph node regions, and the reason we call it lymphoma is that it generally begins in lymph nodes, and these anatomic regions were actually originally defined for Hodgkin's disease, but they're applicable to the non-Hodgkin's lymphomas as well, and they also relate to the staging system that we use.
So we identify these individual lymph node regions that you can see are named here and sketched out, and if there's a single lymph node region, that is a stage I. If there are two lymph node regions that are the same side of the diaphragm, which is splitting the chest from the abdomen, then that's a stage II. Stage III means that you have lymph node regions on both sides of the diaphragm, and stage IV indicates that there is extension beyond lymph nodes to other organs. In the non-Hodgkin's lymphomas, most commonly the bone marrow, the liver, but in some subtypes a variety of organs can be involved. And as opposed to Hodgkin's disease, non-Hodgkin's lymphomas are much more likely to be advanced in stage at the time of diagnosis, and it doesn't have the same adverse prognostic significance.
Slide #5
So the staging system that we use is really borrowed from Hodgkin's disease. It's called the Ann Arbor system. Patients are given a stage of I through IV, and then they are further sub-designated as asymptomatic or symptomatic, an symptomatic means fever, night sweats or weight loss of more than 10% within the last six months, and that's why you're frequently queried about those questions at your appointment.
Slide #6
Well, I'm going to now break down my talk into the particular subtypes of non-Hodgkin's lymphoma, and begin with follicular lymphoma. This is a disorder that usually presents in an asymptomatic fashion, where in the large lymph node or lymph nodes is discovered. Frequently, we get the history of a waxing and waning course. Yeah, the lymph node was there. It may have gotten larger, then it got smaller, and now it's back again. Very common.
This is a disorder that generally occurs in middle age, the average age, 55 to 60 years, and is usually limited to lymph nodes and spleen, as well as liver and bone marrow. Most commonly it's stage III or IV, advanced stage, at presentation, but is know for its long median survival, which we can measure currently as ten years or perhaps more, but is often marked by multiple relapses through the course such that we currently don't have a defined curative therapy.
Slide #7
I'm going to try to show you very few survival curves, but they do come up, and I want to just take you through how to interpret these. So you have on this axis the probability, and at the beginning, 100% of people are alive, because we're looking at survival. Here we have time. Please note that this is years, so we're going out now to 30 years, and when you look at a lot of survival curves or you hear about them, your eyes can play tricks on you, because you can imagine, if we were measuring this in months and we looked up at maybe 36 or 24 months, these curves would have the impression of being much flatter, as if perhaps we were looking at a treatment that might have more long-term control. So it's something that we need to pay attention to.
But also when we're looking at these curves, I'd like to point out that because the median age is 55 to 60 years, and because lymphoma is not an immortalizing event, we would expect that just on the basis of age we would come down to a number of about 50% at 25 years, so we have to correct for that.
The way I look at this is even though we don't have a curative therapy currently for follicular lymphoma, in our experience, at our institution, patients are living longer, and we attribute that to the fact that we have multiple treatments to offer, and if you've gone through a transplant and if you had a relapse, maybe you could go on to rituximab and have a successful treatment with this, and so on and so on. And it's going to be important for us not to do anything that is detrimental to this anticipated survival, which is now in our institution 75% at ten years.
Slide #8
Follicular lymphoma over the years is a spectrum, and the spectrum goes from how it looks at the time of diagnosis, which is usually small cells, small cleaved cells, and follicular. Over time there's a tendency for this lymphoma to become more diffuse and to have a larger cell component. And many of you with this disorder have heard about histologic transformation, and that is kind of a subtle event that can occur along this course.
Yesterday, before I left, in clinic there was a patient being seen by one of my colleagues who had a referral for management of histologic transformation 26 years after his original diagnosis of follicular lymphoma. This is a disorder we measure often in long periods of time. But it also tells you that you may not want to use all your ammunition up early on in the course of the disease. It should be measured according to the individual features for a patient.
Slide #9
There have been a lot of randomized trials in indolent lymphoma, and I'm just going to give you the sound bites, the conclusions. One, there is no overall survival advantage to immediate therapy in patients who have asymptomatic presentations, at least with the agents that have been studied thus far. That's why watchful waiting is an option. There's no overall survival advantage for doxorubicin -- that's Adriamycin -- containing chemotherapy in unselected patients. That doesn't mean that it isn't the right thing for some people at diagnosis, but in the randomized trials that have been done so far, not better than other approaches. A few years ago there was a lot of interest in interferon. The results of these trials are inconsistent, and generally the field has moved forward.
Very important to note that in the Annals of Indolent Lymphoma, having a longer initial remission does not reliably translate to an overall survival benefit. That may be because we have multiple treatment options. It won't keep us from looking for that treatment that is going to be the cure. And again, in this disorder, no defined approach that is better, that has an established overall survival benefit.
Slide #10
Here's another one of those survival curves, and this, as you can see, is kind of an old one, but it is, I think, very instructive, and it's a study done by the National Cancer Institute comparing watchful waiting in indolent lymphoma, asymptomatic patients, to a very aggressive treatment program which consisted of combination chemotherapy and radiation to all lymph node regions at low dose. And you can see, with long-term followup, there does not appear to be a survival advantage of aggressively treating this type of lymphoma at the time of diagnosis. This summer was a meeting, an international lymphoma meeting, and two European trials were presented. Exactly the same results.
Slide #11
Then we need something new, and along comes immunotherapy, and the rituximab and the CD20 antibody that Dr. Stabler mentioned. Now I don't really know why Dr. Stabler is having this cheese craving, because the real success of this is the fact that it's a chimeric antibody and that it has a human component that makes it more effective for the immune system, and it also changes the pharmacology in a desirable fashion, and it makes it less immunogenic so that you won't make an antibody to that antibody. And of course the CD20 antigen is a particularly good target because it's limited to B cells and expressed in more than 90% of B cell non-Hodgkin's lymphoma, of which indolent lymphoma is a subtype.
Slide #12
And the studies with rituximab in indolent lymphoma began in patients who had recurrent disease, and this was the pivotal trial, the trial that was used for approval, with 162 patients with recurrent disease, and you can see the response rate to four treatments with rituximab given weekly times four.
Subsequently there was a trial, a small trial, in which patients were treated with eight weeks, and at first glance it looks like the results are better. This is another one of those issues with the interpretation of clinical trials. Actually, there's no statistical difference between these two, and it may very well be a patient selection issue.
However, as you can imagine, what our real interest was to begin in clinical trials to look at rituximab in previously untreated patients. And here we see that rituximab does have a higher response rate, and this is an area now of active investigation. This was a group of patients who were watchful waiting candidates that received this treatment.
Another important fact about rituximab is that patients could be re-treated. This is kind of a good news/bad news phenomenon. The good news is that there's a 40% response rate for patients who originally responded to rituximab, and in this particular trial, it was interesting that the duration of response was actually longer than the first time around. However, the response rate dropped from 100% to 40%, and that indicates to us that there is some mechanism of resistance, and it also indicates to us that it's very, very important to study this in the context of clinical trials so we know when best to use this agent, a theme that we'll be going over throughout the meeting.
Slide #13
The next excitement in the area, particularly with regard to approved drugs, is the entrée of radioimmunotherapy into our armamentarium, and that is basically taking the antibody, hooking it up with a radioisotope, and then selectively irradiating lymphoma. And recently, in the past year, the Zevalin radioimmunoconjugate, which is an yttrium anti-CD20 combination, has been approved for use, and the excitement there is that the response rate was 70%, even among patients who had regrown or failed to respond to rituximab.
Slide #14
So as you can imagine, we've got our work cut out for us. We need to figure out how to use these and other new therapeutics. Our current model has been that chemotherapy would be the first treatment, followed by antibody treatment, which is the approved indication for rituximab, and then perhaps followed by another treatment down the road upon relapse, perhaps it's radioimmunotherapy.
But what we really don't know is a combination of chemotherapy and antibody therapy given together, given sequentially, might be better than using it in this way, where patients relapse, and then a longer period of time, better quality of life, until another treatment is needed. Or perhaps it's better to do it, as originally thought, in the approved method. We don't know this. That's why clinical trials are so important.
Slide #15
There are other targets on B cells that are available for new therapeutics, and this is a very active area of investigation. I know many of you in the audience are participants or interested in the vaccine approaches for follicular lymphoma, and this relates to the fact that each follicular lymphoma has a specific immunoglobulin that marks that as a unique B cell lymphoma for which originally specific antibodies were made by Dr. Ron Levy and colleagues, and then more recently as an active immunization, that is, identifying this surface immunoglobulin and making it immunogenic in the form of a vaccine.
Slide #16
This has the advantage that the patient can then make his own antiidiotypic antibody, and also harness the T cells to do cell killing as well. This is something that we're really excited about in that we now have a randomized phase III clinical trial ongoing, and we're really going to find out what this approach can do.
Slide #17
Other types of indolent lymphoma include the small, mature B cell non-Hodgkin's lymphoma, small lymphocytic lymphoma, which is related to chronic lymphocytic leukemia. This is treated very much in the same way as follicular lymphoma, with a few differences in therapeutic choices, as well as lymphoplasmacytoid lymphoma, which tends to occur in older patients with a male predominance and overlaps with Waldenström's.
Slide #18
Marginal zone lymphoma is an interesting disorder that occurs most commonly in extranodal sites, and for each of these extranodal sites, the approach is one that's individualized. Often, patients have a history of autoimmunity, and as I mentioned, H. pylori is the culprit in gastric lymphoma, and treatment with antibiotics may be sufficient to eradicate or control this form of lymphoma. It does transform as follicular lymphoma over time, and that needs to be monitored.
There are also two other subtypes of marginal zone lymphoma, one that occurs primarily in lymph nodes and another in the spleen. I know there are some questions that have come up about these disorders, and in the breakout groups, they're going to be under the other indolent B cell lymphomas.
Slide #19
I want to move on to diffuse large-cell lymphoma, or aggressive lymphoma. This is very different. This is for patients who are often presenting with a nodal or extranodal site, more commonly symptomatic. It occurs at all ages in children, middle age, older age, with frequently extranodal sites of involvement and can be limited or advanced in stage. That has importance with regard to whether chemotherapy alone is used or some combination with radiation, and this disorder does have curative potential with current combination chemotherapy based upon features at diagnosis.
Slide #20
The features, in addition to stage, include the age of the patient; LDH, which is something we measure in the blood; performance status, which is just how well you are doing in your activities of daily living, as well as whether there are multiple extranodal sites. And there is also an age-adjusted that uses three of these five parameters.
Slide #21
The excitement in our field over the last year has really been palpable with the publication of this study from France comparing CHOP versus rituximab-CHOP in older patients with diffuse large B cell lymphoma. All patients were between the ages of 60 and 80, and they participated in a randomized trial, and the results of this trial published in the last year showed a significantly improved response rate, significantly improved event-free survival and overall survival with the combination. This is the most significant non-Hodgkin's lymphoma study that we have seen in the last decade.
Slide #22
There are two other studies that have either been completed or are looking at this question. This is the U.S. study comparing CHOP versus rituximab-CHOP in a slightly different fashion, and it also has a secondary piece, a secondary randomization to maintenance or not. So this will hopefully confirm the findings in the French study and add the issue of maintenance.
Slide #23
There is also a European-Canadian study that's being done in younger patients comparing CHOP and r-CHOP. And what we'd like to see is that all of these trials confirm one another.
Slide #24
In addition, there's tremendous excitement in the research arena regarding large-cell lymphoma, and now extending across multiple subtypes of lymphoma, and that is to use new techniques looking at the molecular attributes or molecular signatures of non-Hodgkin's lymphoma, in this case, diffuse large-cell lymphoma. And by looking at the expression of individual genes, in fact, thousands of genes, subtypes could be determined that had a different overall survival. This helps us in thinking about prognostic groups, about treatment decisions, but most importantly, it helps us to identify new targets, targets that can then evolve into new therapies.
Slide #25
My last two subtypes will be mantle cell and peripheral T cell lymphoma. Mantle cell lymphoma is a disorder that involves lymph nodes, spleen, liver, often the GI tract, as well Waldeyer's ring, which is this area in the mouth, the tonsils, the neck, and sometimes circulating lymphoma cells, tends to be advanced in stage and present in middle-aged to older males. There are variants that can be important with regard to the treatment, and the diagnosis is critically important, to make that diagnosis of mantle cell lymphoma, because of its unique behavior.
Slide #26
With regard to therapy, I think it's fair to say there's no standard approach for mantle cell lymphoma. The use of transplantation in first remission prolongs remission, but we are seeing late relapses at several years. The role of more aggressive chemotherapy is uncertain. You'll hear a little bit more about this from Dr. Khouri in his session. And this is a disorder where we desperately need investigational approaches to be pursued. Again, an uncommon subtype of non-Hodgkin's lymphoma, but a lot of promise out there with new approaches, like some subtypes of allotransplantation that are called mini, or less toxic, combining chemo and immunotherapy, using radioimmunotherapy in this disorder, perhaps in the context of transplantation.
Slide #27
Finally, T cell non-Hodgkin's lymphoma, if you look at all the NHL, about 80, 85% in this country are B cell, the remainder being T cell, and they are even further subtyped. And it's very difficult to get a handle on the best management for this disorder, which is usually managed like other large-cell lymphoma. The most common subtype is peripheral T cell lymphoma, which tends to have a propensity for skin and be advanced in stage.
Anaplastic T cell lymphoma is an important subtype. It can be identified reliably by the pathologist. It occurs in children and young patients, and it has a very high cure rate. Important to distinguish. Something called angioimmunoblastic lymphadenopathy T cell lymphoma, or we like to say AILD, is a very rare but significant disorder that can be often managed by perturbing the immune system. And then we have the more rare T cell lymphomas, again, which tend to be managed as for diffuse large-cell lymphoma.
Slide #28
I'll finish by talking about Hodgkin's disease, and I think we owe a great debt of gratitude to this gentleman, Sir Thomas Hodgkin, who identified Hodgkin's disease in 1832 simply by the patients that he saw in his practice. It wasn't until many years later that the lymph nodes removed from those patients that were archived were actually evaluated and shown to in fact be what we currently call Hodgkin's disease.
Slide #29
Hodgkin's disease is important because it really led the way for the treatments we now receive for non-Hodgkin's lymphoma. Radiation therapy and the extent of radiation therapy developed at our institution by Dr. Henry Kaplan, and then the first use, the first curative use of combination chemotherapy in adults was MOP chemotherapy for lymphoma, which directly led to CMOP for non-Hodgkin's lymphoma and then to CHOP chemotherapy, which we know about.
Slide #30
In Hodgkin's disease, we use the same staging system, but we tend to group patients now rather than using a pure staging system. For patients with low-bulk, early stage disease, the rate of cure currently with very brief therapy, chemotherapy and limited radiation, should be well above 90%. For those patients who are limited but have bulky disease, we use more chemotherapy, a little higher dose of radiation, about an 80, 85% cure rate. And even for patients with advanced stage disease, depending on the study, cure rates that range from 70 to 85%.
Slide #31
We're still learning from Hodgkin's disease. It's still paving the way and allowing us to address questions about how best to use radiation, how best to use chemotherapy. Very importantly, looking at late effects for patients who live many years. The average age of our patients is 25. And we now follow patients more than 30 years, and we're learning about late effects. They're important. We want to know about the genetic predisposition to these, and the environmental influences that relate to them, and they're also leading the way into new imaging techniques which can be applied to non-Hodgkin's lymphoma, as well.
Slide #32
So lymphoma is many diseases, and we have many options. I couldn't discuss all of them today. I've made a list of them. They're all areas of tremendous promise, tremendous hope, but areas in which we also need to put in a lot of work, and the way that we do this, the way that we study these different treatments, find out if they work or if they don't or how to make them work, how to do it best, how to get new drugs out there for all people, is to participate in clinical trials.
I'm very happy to have had this opportunity to introduce the lymphoma biology, and we'll go on to our next speaker, Dr. Jonathan Said. Thank you.
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