JOHN LEONARD, MD: Hello, I'm Dr. John Leonard. I'm the Clinical Director of the Cornell Center for Lymphoma and Myeloma. We're going to talk today about how a patient with indolent or slow-growing non-Hodgkin's lymphoma decides among treatment options when the disease returns or relapses.
Joining me today is my Cornell colleague, Dr. Morton Coleman. Dr. Coleman is a clinical professor of medicine at the Weil Medical College of Cornell University. Also joining me is Dr. Owen O'Connor. He's an oncologist with the Memorial Sloan-Kettering Cancer Center.
Let's start today with a brief review of the treatment options. Patients with indolent lymphoma, which is about a third of patients with non-Hodgkin's lymphoma overall, often have disease that off -- that can recur. And there are a whole array of treatment options, and it can be very complicated, choosing between chemotherapy, rituximab, radioactive antibodies like Zevalin and Bexxar, stem cell transplant
Dr. Coleman, you've seen over the years kind of the major impact that rituximab has made in these diseases, and traditionally patients were treated with chemotherapy. Now we use rituximab with chemotherapy. Now there's a whole group of patients that are getting treated with rituximab alone. So what sorts of patients do you see as appropriate for just treatment with rituximab alone, and how do you like to give it in that sort of scenario?
MORTON COLEMAN, MD: Patients really tolerate Rituxan remarkably well. One of the particularly good properties of Rituxan is that it does not impact bone marrow function, and sometimes we can just get away, or get by, if you would, with using Rituxan by itself. It's simple. You take it once a week for four weeks, and it's given in the office, and thereafter there's very little to contend with.
The big debate now in medical circles is whether patients who respond to Rituxan -- those patients in particular who have just slowly progressive disease -- whether these patients should be maintained with Rituxan or not. I think the current trend is tilting toward maintaining these patients, although the jury is still out.
JOHN LEONARD, MD: And so the advantages, Dr. O'Connor, of maintenance rituximab in your view, obviously, the patient has to come back to get more treatment. What's the tradeoff there? Are there downsides in your experience as far as the convenience of it? Do you think it works well? What about side effects?
OWEN O'CONNOR, MD: Well, as Mort suggested, there's a lot of controversy in the medical community today about the merits of using rituximab on a maintenance schedule versus using it on an as-needed basis. And the current data seems to suggest that using it on a maintenance-type schedule on a very well-prescribed regimen -- for example, every six months -- may afford patients longer duration of benefit. But there's still a lot of clinical trials ongoing exploring this question in more -- more detail.
JOHN LEONARD, MD: Yeah, I think -- I think this is a very complicated area, and one that's in flux, that patients should know about and speak about with their physician, but I don't think there's a clear-cut answer.
One of the other major areas that's come out is radioimmunotherapy, with two FDA-approved drugs, Zevalin and Bexxar. There are a number of scenarios that those agents can be very useful for. Dr. Coleman, what's been your experience with these drugs? Particularly, we'll now focus again on those patients with slowly progressive disease and maybe not a lot of therapy in the past. How do you look at radioimmunotherapy as an option for that group of patients?
MORTON COLEMAN, MD: If there's one plea that I make to my fellow physicians, is that if you're going to use radioimmunotherapy, to use it earlier rather than later. The chances of being successful with this particular therapy is far greater if you use it early on in the treatment schema, rather than waiting until the patient has had multiple therapies.
The nice thing about radioimmunotherapy is that it's therapy that's really completed within a couple of weeks, so it's extremely convenient for the patient. Also, we find that patients who respond to radioimmunotherapy -- and again, the chances of responding very well are greater when used early on, that these responses are very durable and long-lasting so that it's a very convenient way to treat people. The total duration of therapy, as I said, is short, and very often the remissions are prolonged, measured in many, many, many, many years.
JOHN LEONARD, MD: The radioimmunotherapy is one option, and the challenge is among the different treatment options that we have for this particular group of patients with disease that's relatively sensitive, relatively early in the course. There are some issues of potential long-term side effects as far as effects on the bone marrow, but in general I think these are not a major issue for most patients, but something that patients need to keep in mind and speak about with their doctors.
MORTON COLEMAN, MD: Yeah, one of the extraordinarily nice things about radioimmunotherapy is that we've seen patients responding to radioimmunotherapy when they did not respond previously to plain, ordinary, what we call monoclonal Rituxan therapy. And also that we've seen excellent responses in patients who seem to be resistant to chemotherapy. So this represents a whole new modality of treatment for these patients. Again, it's something that we need -- we need more experience with, but at least the current experience is, is that it is a very useful and very simple treatment to give.
JOHN LEONARD, MD: So that's a good segue to our other kind of major category of patients, and that's the group of patients that maybe has had a number of prior treatments, maybe they worked at the beginning pretty well but are no longer working as well. Maybe the patient has some response, but it doesn't last very long.
And one strategy in some cases is to do autologous stem cell transplant. Dr. Coleman, what sorts of patients with more resistant disease or multiply relapsed disease, I guess, where the disease has been back several times, where do you think about autologous stem cell transplant?
MORTON COLEMAN, MD: Well, I do use autologous stem cell transplant, usually, when I get the sense that the pace of disease is beginning to increase, that the disease is becoming more aggressive. I have had very good experience with using autologous transplantation in patients where I sense the disease is transforming into a more aggressive form of disease, which very often indolent or follicular lymphoma may do. In those instances, I feel that autologous transplant could be also -- really almost virtually life-giving.
But in addition, the radioimmunotherapy has been used now in cases of refractory disease where the patient is not responding to chemotherapy. I think that perhaps maybe we ought to define for the audience what we mean by monoclonal antibody therapy and what we mean by radioimmunotherapy. When we talk about Rituxan, we're talking about a monoclonal antibody, that is, a biologic agent that's directed specifically to the lymphocyte so that it spares other tissues.
In the case of radioimmunotherapy, we also have a monoclonal antibody directed against the lymphocyte or the lymphoma cell, as the case may be. But in this case, we're carrying a warhead -- that is, a radioisotope -- and we have a double means of killing the tumor. That is, we can kill it by the monoclonal antibody itself, or we can kill the tumor by the use of radiation. And the nice thing about it is, is that the radiation will hit cells that have not necessarily been hit by the monoclonal antibody itself, what we refer to as a crossfire effect.
So we do have options for patients whose disease is picking up, whose pace is picking up, who seems to be developing a certain amount of refractoriness to chemotherapy or simple monoclonal Rituxan therapy. And those two options in particular are radioimmunotherapy and autologous stem cell transplant.
There's also an option, of course, of allogenic transplant, which -- and we now have what we call the mini-transplant, the so-called mini-transplant, where we don't hit the patient so heavily with chemo, but depend on the graft-versus-tumor reaction. Again, that does carry with it greater risks. So we have new options now for patients who have resistant disease.
JOHN LEONARD, MD: I think that's a very good summary. I think that patients, you often find that patients are considering those two options, the more intensive stem cell transplant or the radioimmunotherapy option, in the resistant setting, and certainly, having something like radioimmunotherapy with Zevalin or Bexxar that has a lot less toxicity than the intensive regimen certainly makes it appealing to many patients, particularly the elderly.
Thank you. I think that this discussion hopefully has helped people better understand their treatment options, if they have relapsing disease, in the -- in particular in these indolent forms of lymphoma.
Joining me today are my colleagues. Again, thank you, Dr. Morton Coleman and Dr. Owen O'Connor. I'm Dr. John Leonard. Thank you very much for joining us.
Q & A Session
OWEN O'CONNOR, MD: Welcome to the question and answer portion of the program. I'm Dr. Owen O'Connor. I'm a medical oncologist at Memorial Sloan-Kettering Cancer Center in New York. Joining me today is Mort Diamond a non-Hodgkin's lymphoma survivor and moderator of the patient blog at lymphomainnovations.com. Mort and I will be answering your questions for the next 20 minutes or so. You can submit a question online, or if you have joined us by phone, please press the *0 on your phone and submit your question.
Let's start now with our first question. We have a lot of questions today, but the first -- and many of them seem to revolve around a specific theme. The first is, does any treatment interfere with another that does not allow you in the future to use any current treatments or new treatments?
And that's actually a fairly good question that goes to an important point, which is that many of these indolent lymphomas are chronic diseases, and I have seen a host of other questions regarding the curability of these diseases. In general, most of the indolent lymphomas we consider to be incurable diseases. They're diseases that are very slow-growing and typically tend to respond to a lot of different types of treatment.
There is one situation where indolent lymphomas may be curable, and that's in the case of very, very limited, localized disease -- say, one lymph node in the neck where radiation therapy alone can cure some patients. But for the most part, we really think about these diseases as chronic diseases, and we try to find strategies to help patients live with these diseases for long periods of time.
There are certain therapies that will preclude some future options. For example, allogeneic stem cell transplant, which is not a therapy most doctors are likely to recommend early. But many new drug trials and many times conventional cytotoxic chemotherapy can be more toxic or can -- the past exposure to an allogeneic stem cell transplant may limit your ability to get other treatment.
I think many clinical trials looking at new drugs will also have limitations on enrolling patients that have allogeneic stem cell transplant, and a lot of this goes to the point of cumulative bone marrow toxicity. So it is something to keep in mind as you embark down the road of discussing new treatment options with your doctor, trying to identify meaningful, efficient therapies that don't preclude future treatments.
Another question goes to the issue of, does low-grade lymphoma always come back, and is there any time limit? And really, that's a question that relates to the first one, which is that, again, these are chronic diseases, and except for very rare situations, these diseases will almost always come back in time. And so again, the management emphasis is on trying to help patients with -- live with these diseases for as long as possible.
And I think this is a good juncture to try to get some insight from our colleague, Mort Diamond, on his perspectives about the management of indolent lymphomas. Mort?
MORTON DIAMOND: Thank you, Dr. O'Connor. First, I emphasize that while I am a ... physician, I speak as Mort Diamond, non-Hodgkin's lymphoma patient. And I was keenly interested in Dr. O'Connor's earlier statement that non-Hodgkin's lymphoma is generally considered an incurable disease. Therefore, I personally opted to apply for and happily was accepted into a clinical experimental trial with radioimmunotherapy.
The point I wish to make from a patient's point of view is that each patient should feel comfortable with the treatment plan that he or she accepts. In my own case, I reverted to my basic values, which I call my creed, and I wanted to hit or attack this disease as early and as hard as I could. And following my creed, I chose a clinical trial.
OWEN O'CONNOR, MD: I think that's a very good entrÃ©e to one of the -- another question, and there are several questions asking what's new? And that's sort of what I do for a living, is developing new drugs for the treatment of lymphoma. And regrettably, we don't have another four hours to talk about this, but that would be the amount of time I would need to address that question with any -- with any credibility. But suffice it to say there are a lot of new treatments coming down the road for the management of these diseases.
And as we begin to better understand the biology behind what makes a lymphoma cell a lymphoma cell, we're beginning to identify completely new targets in various types of cancer, targets that we now have drugs for that will allow us to attack lymphoma and a host of other cancers right at the root.
For example, there's a new class of drugs known as proteosome inhibitors, and some important work from our group has established that one of those proteosome inhibitors, bortezomib, can produce very meaningful responses in patients with follicular lymphoma, with more than 50% of patients with relatively drug-resistant follicular lymphoma having a very nice and very meaningful duration of response to that drug. We've had several patients who have maintained their remissions for years.
So there are a lot of new things coming in terms of new drugs attacking this disease. And as we just heard from Mort, enrollment in a novel clinical trial looking at the combination of some other new drugs appears to have benefitted him well, and our recommendation routinely is that once patients developed relapse disease, looking for promising clinical trials is a very meaningful way to try and treat these diseases long into the future.
There's another question here regarding a patient who received CHOP-XR, which sounds similar to Mort's experience, as first-line treatment. They apparently finished this therapy in January of this year, and have just felt several lumps recently under the skin, and they want to know what are their next options for treatment.
Well, this is a very, very important question, and it goes to what the patient and the doctor should do next. There's no question that this case requires a critical evaluation by a specialist in medical oncology, because the first step is to actually prove that you have the disease back, and oftentimes failure to biopsy patients to actually establish the fact that the disease is back is something that we see often.
Should the disease be back, it would suggest that this is a disease that's resisted two very effective lines of treatment, namely a systemic chemotherapy in the form of CHOP and a novel effective therapy in the form of a radioimmunotherapy approach, like Bexxar.
I think there is no single answer on what the next best treatment is, but should you establish that the disease is back, clearly you're going to need to discuss all of the options. And there are issues that enter this equation that include your age, the presence of other comorbidities and evaluation of what toxicities we think certain patients are likely to tolerate.
In some cases, there are other lines of conventional chemotherapy that include purine analogs, like fludarabine. There are investigational trials. And in cases like this, depending on the patient and how healthy the patient is, even consideration of various types of transplant, including autologous or allogeneic stem cell transplant offer meaningful treatment options for these sorts of scenarios.
But again, I need to emphasize that this is a complicated discussion that requires a full disclosure of all the different issues and comorbidities so that you can pick the next best therapy that's going to be most effective and least toxic.
There are a number of questions here revolving around lifespan and how long will various therapies last. And it's really fair -- it's pretty difficult to try and comment how long patients will live with various kinds of cancers, and in particular with the indolent lymphomas. These diseases, as I've been saying, are really chronic diseases that do respond to lots of different treatments. And the most important point to emphasize is that since we've entered this era of Rituxan and the use of monoclonal antibodies directed against the CD20 protein on the surface of these cells and we've now got a whole battery of other new drugs, like Zevalin and Bexxar, we are beginning to see that patients with these diseases do seem to fare better in terms of the duration of benefit that they get from these treatments and most likely overall survival.
So it's not an easy question to answer. Again, it requires a full assessment of what other comorbidities the patients bring into the diagnosis of lymphoma. Do they carry issues related to heart disease or pulmonology disease? All of these things will enter that more global assessment of how patients are likely to do. Mort, do you have any --
MORTON DIAMOND: Yes, sir. As I listen to a renowned researcher like Dr. O'Connor speaking and mentioning how many unanswered questions there remain in lymphoma, I am thinking that while we, the patient, need the brilliant researchers, the researchers continue to need us, the patients. And therefore, I again affirm what I think is still very important, namely that patients inquire of their oncologists about clinical trials, because we can help the researchers, who then can further help us.
OWEN O'CONNOR, MD: And I think that's a very important point that you'll hear again and again. You heard it with Dr. Leonard, and I think clinical trials with some -- represent a very important venue to try to advance the standard of care for patients with all sorts of diseases.
I'm going to apologize in advance, because the questions are rolling in here faster than I can keep up with. And regrettably, I won't be able to answer all of them. But what I'm trying to do is find general themes to help address the greatest number of questions possible.
There is, germane to the point Mort just made, is there a website that lists current treatments and/or clinical trials? And I think the answer to that is yes. There is a lot of information on the Internet, and I caution all of my patients to be careful as they surf the net regarding issues related or personal experiences relayed from patients with lymphoma. The National Cancer Institute has a very large website that has patient education-related information and gives general concepts and principles for treatment. There are major foundations, like the Lymphoma Research Foundation, and the Leukemia and Lymphoma Society also have significant -- have made a significant investment in various patient education activities. So I think personally speaking, those are the three websites I would go to. I really wouldn't venture off into too many other areas for information.
And also, be cautious when you read information off the Internet. A lot of this information is generic. It's really directed toward populations of patients and really is not geared or tailored to an individual, specific scenario. So many patients are inclined to personalize a lot of that information as they read it, and that sometimes creates more anxiety than is necessary.
Mort, do you have any input about the Internet? I'm sure.
MORTON DIAMOND: Yes, sir, I -- I found the National Cancer Institute website to be superb not only in describing succinctly the actual study, but assisting the prospective patient by defining the geographic areas in the country where these studies were taking place. So I found that to be extremely helpful.
While my principal investigator was in Nashville, Tennessee, the same time I found that the closest treatment facility or participating facility was in Orlando, Florida, approximately 200 miles from my home in Fort Lauderdale. So I think the NCI, National Cancer Institute website was superlative, Dr. O'Connor.
OWEN O'CONNOR, MD: Good, good. So there's a lot of questions about rituximab, and let's try to touch on Rituxan a little bit. And certainly, there seem to be a number of questions about using Rituxan as a maintenance schedule, with one specific question asking, "Is there a danger in building up immunity to rituximab and adhering to a maintenance schedule?"
I think immunity is not the concern that we have when we think about using rituximab, or even using a lot of rituximab. Rituximab, as many of you know -- and you heard Mort Coleman [SIC] say on the video -- is a monoclonal antibody. So it's a protein that is specifically designed to recognize other proteins. And in this particular case, the binding of Rituxan to its target protein, called CD20, which is universally expressed in all B cell lymphomas, helps mediate and facilitate the death of that lymphocyte.
Now, Rituxan, while being relatively selective for lymphoma, also can impact normal lymphocytes in the body that express CD20. So one of the common side effects of the drug is something called lymphopenia. "Lympho" means lymphocyte, "penia" typically means small numbers of. So we can cause a -- it can cause a reduction in your normal lymphocytes, as well. But the good news is that that does not appear to be associated with any significant clinical problems like increased infections.
The issue that we have with Rituxan is the concept of building up resistance to treatment with Rituxan. It is a drug that actually does work fairly well when we use it, again. But of course, those patients who develop disease that grows on Rituxan or grows shortly after we use it do acquire resistance to Rituxan.
Now, this is true regardless of what therapy we talk about, whether it's a monoclonal antibody or it's a radioimmunotherapeutic, or even conventional chemotherapy. One of the bizarre and unfortunate biological features of all cancers is that they have the genetic plasticity to become resistant to no matter what you throw at them.
And the frustrating paradox is, normal cells in the body don't become resistant. If anything, normal cells in the body, like your normal bone marrow cells, over time become increasingly more sensitive to chemotherapy, and patients then with a lot of therapy can have -- suffer a lot of cumulative toxicity of those prior treatments. So we don't typically worry about immunity. We do worry about resistance, which can happen with Rituxan and other treatments.
I don't know of any data that says patients getting maintenance Rituxan are more likely to become resistant to Rituxan than other patients. And the concept of using maintenance Rituxan is an attractive one, but at the moment it's a highly controversial one.
What the data seem to be telling us so far is that for patients who seem to have -- who have B cell malignancies -- in particular, follicular lymphoma -- that using Rituxan on a maintenance schedule can help increase the duration of benefit. So if you keep getting the drug on a roughly every six month basis, the time before your disease comes backs actually increases.
But recognize that there's another way to use the drug. Rather than giving it to you preventively, we can just give you the drug when your disease comes back, when you need it, so we treat you on an as-needed basis.
It looks like -- and it's very early -- but it looks like when you use Rituxan on a maintenance schedule versus treating it when the disease comes back, in both of those cases, the overall survival of patients seems to be identical. So it doesn't impact your overall survival. What it seems to impact is the duration of benefit of that -- is the duration of benefit. So giving Rituxan on a regular basis seems to enhance that duration of benefit.
Mort, have you had any --
MORTON DIAMOND: Dr. O'Connor, may I interject a plea from a patient's point of view?
OWEN O'CONNOR, MD: Sure.
MORTON DIAMOND: I have had the opportunity over the years, since my radioimmunotherapy treatment, to speak with many estimable oncologists, and the comment made to me over and over again, affirmed by the video preceding this question and answer period, is that radioimmunotherapy appears to be more valuable when used earlier in the course of lymphoma. Therefore, as a patient, I would make a plea to other patients that before subjecting oneself to serial or repeated cycles of chemotherapy, and perhaps even Rituxan, that you, the patient, insist on a consultation with a physician who is experienced in administering radioimmunotherapy. Only after that consultation, then could you, the patient, decide what is the best option for your recurrent disease.
So my plea, succinctly, is patients should insist on a consultation with a physician experienced in radioimmunotherapy before treating -- before deciding upon a personal treatment plan.
OWEN O'CONNOR, MD: Absolutely. And I think Mort points out another point. I mean, whether we're talking about radioimmunotherapies like Zevalin or Bexxar, or we're talking about CHOP or CVP or fludarabine, most therapies -- all therapies work best in patients who have been exposed to the least amount of therapy. And so as disease tends to progress, it's pretty clear that subsequent therapies may have merit, but the duration of those merits seems to go down.
And drugs like Zevalin and Bexxar -- and there's some new data that's published by Dr. Press and his colleagues out in Seattle that seems to suggest that the use of early radioimmunotherapy type approaches, as Mort mentioned, seem to be associated with some significant therapeutic benefits.
I now in the closing minutes here am going to try and find one or two questions that might help us conclude this. I think we've touched on a lot of issues. But there are a number of issues relating to, "What can I do now that I've finished my therapy in terms of diet, antioxidants, vitamins and all these sorts of things?" And these are great questions.
Unfortunately, there's no piece of information that I can put my hand on that says becoming a vegetarian or taking vitamin C or taking some other multivitamin changes the natural history of your disease. I think that it is common sense, and probably fairly obvious, that maintaining as healthy a lifestyle as you can -- that includes not just eating well, but it also includes good exercise and includes alleviating stress -- I think these are really important for patients dealing with all sorts of cancers.
We know that there seems to be some relationship, for example, in patients who are overweight and trying to maintain active programs of relatively more calore-restricted diets with good exercise and low stress is probably something that's going to help you deal with it in terms of coping. Whether those things translate to have significant impact in the natural history of these diseases is something science will have to help us sort out in the years to come.
So again, these are great questions. There is really no data to point to any of these alternative therapies -- and that includes a host of new herbal therapies -- as changing the natural history of these diseases. I think adopting a well -- a good diet with exercise and low stress, lots of good vacation, is one valuable way to approach this disease.
MORTON DIAMOND: Dr. O'Connor, I must interject, sir, the importance of a positive attitude.
OWEN O'CONNOR, MD: Yeah.
MORTON DIAMOND: That is so overwhelmingly important, the sense of well-being, and perhaps even in the course -- modifying the course of the disease.
OWEN O'CONNOR, MD: Yeah, I couldn't -- I couldn't agree more. I saw my own father go through a battle with kidney cancer, and he defied every doctor's prognosis, living with the disease for over five years, when his first physician saw him and said, "You only have a few months." And he was the example of a positive viewpoint.
So with that, I want to think Mort Diamond, our guest today.
MORTON DIAMOND: ... Thank you Dr. O'Connor.
OWEN O'CONNOR, MD: Unfortunately, this is all the time we have. These are a lot of great questions, and I want to think you for your time. This is the second webcast and chat in our NHL series, with one more event on Friday, December 15th. I'd encourage everybody to try and visit the lymphomainnovations.com website for more information. And I want to thank you for joining us today. I'm Dr. Owen O'Connor. Thank you.