Medically Reviewed On: July 16, 2008

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 the options faced by a patient when indolent or slow-growing non-Hodgkin's lymphoma returns or relapses.

Joining me today is my Cornell colleague, Dr. Morton Coleman. He's a clinical professor of medicine at the Weill Medical College of Cornell University. Rounding out our group today is Dr. Owen O'Connor. He's an oncologist with the Memorial Sloan-Kettering Cancer Center.

We're going today to talk about indolent lymphoma. Indolent lymphoma accounts for about a third of patients with lymphoma. The most common type of indolent lymphoma is follicular lymphoma. Patients often get their initial treatment, their disease response to treatment, and then at some point in time later the disease recurs or relapses.

And so the first question that comes up is the difference or the issue of relapse disease versus refractory disease. Dr. Coleman, how do we define that from the standpoint of classifying patients and their approach?

MORTON COLEMAN, MD: John, we usually refer to relapse as a term connoting a return of disease after the initial response. Refractory disease usually connotes a term which means that the disease never fully responded, either it progressed-and we call that progressive disease-or that the disease did not respond fully.

Very often, patients will respond in a complete manner. that's known as a complete remission. Those patients who come out of that sort of response is considered a relapse, whereas patients who don't fully respond, or where the disease continues to grow, those patients are considered to have refractory disease.

JOHN LEONARD, MD: So why is that an important distinction for a patient, as far as sorting out whether they responded and relapsed or whether the disease didn't respond at all?

MORTON COLEMAN, MD: It may have great relevance with regard to the sensitivity to therapy. Those patients who relapse tend to, from a complete remission, tend to be more sensitive to the subsequent therapy. It's more difficult to treat patients who have not fully responded or who have progressive disease. It probably connotes some form of resistance to treatment.

JOHN LEONARD, MD: One of the unusual things about indolent lymphoma as compared to other sorts of tumors is the fact that patients often don't need treatment, either at the time of diagnosis or at the time of relapse. And that can be a very complicated decision, as to deciding whether or not to initiate treatment or not.

Dr. O'Connor, how do you, as you approach your patients, how do you make that decision? What are some of the factors that you think about in deciding whether or not you need to start treatment for an individual patient?

OWEN O'CONNOR, MD: Well, typically it requires a close interaction with the patient and getting a sense from them on the kind of symptoms they have that might be disease related. So probably one of the first decision points would be to try to decipher what symptoms the patient may be experiencing that are disease-related.

In addition, there are other features of the disease that one might take into consideration, including the size of the disease. So, for example, patients that have bulky disease might be patients you'd want to treat sooner rather than later. And certainly, patients who have a trend toward slowly progressive disease might be patients in whom you'd rather treat when the disease volumes are typically a little bit smaller.

The other important reason for treating patients would pertain to vital organ compromise. So if patients had, for example, a lot of disease in the bone marrow with low hemoglobin counts and low blood cell counts, that might be a good reason to try to treat the disease to allow the normal blood cells to recover.

MORTON COLEMAN, MD: I would like to add that while we try to be very scientific about making a decision on when to initiate therapy, clearly judgment is called for, and the physician has to put together all of these various factors which Dr. O'Connor had mentioned in deciding when to initiate treatment.

JOHN LEONARD, MD: One of the things that I like to do is to try to monitor the patient over time, because I think the pace of the disease or the . . .so you can get a sense of whether it's rapidly progressive or whether it's slowly progressive, in which case you might be more comfortable watching for a while.

Patients often ask, is there a size cutoff when my disease . . . when a lymph node gets to a certain number value of centimeters in size? Is that an absolute determinant of when you would treat me? Do you all use any kind of size cutoff in that, or is it just part of the whole picture of when you see a patient? Mort?

MORTON COLEMAN, MD: Yeah, I think it's really part of the whole picture. Clearly, there is a judgment call here, and knowing your patient is very important. When you sense the pace of the disease getting more aggressive, when you decide that the bulk is more than the patient should be carrying around, those are the factors that go into knowing your patient and making the right judgment call.

JOHN LEONARD, MD: I think another major issue is symptoms, and certainly, if patients are symptomatic from their disease, that would be a reason to initiate treatment. Owen, what are the some of the symptoms that you look at, or typically tell your patients to watch out for, as a potential sign of their disease progressing and potentially needing treatment?

OWEN O'CONNOR, MD: Well, probably the most important is pain, and especially pain in areas where there is growing disease would be a very important feature for patient comfort, and also without allowing the disease to get too big.

Other symptoms that would be concerning would revolve around fevers, chills, sometimes sweating at night. We call these constitutional symptoms, or B symptoms. And many times patients with lymphoma will develop these other kinds of symptoms that may signal a need for treatment.

JOHN LEONARD, MD: So once you go through the issue and the discussion with the patient and assessment of symptoms, you have a patient that's in a scenario where you say, "Okay, it's time to do treatment," what are some of the options that are available, Dr. O'Connor, as far as approaching a patient? There's a long list of options to choose from. What are some of the things that are available for most patients as potential treatments?

OWEN O'CONNOR, MD: Well, this is the good news and the bad news in follicular lymphoma therapy. As you know, there's a very long list of biological agents like rituximab, radioimmunotherapeutic agents like Bexxar and Zevalin, and a host of different chemotherapies. That can include single-agent chemotherapy drugs, like fludarabine, all the way to combination chemotherapy drugs like CHOP or CVP.

Making the decision about which treatment to choose oftentimes is guided by how the physician interprets the aggressiveness of that patient's disease and how the patient interprets that patient's health in general in terms of trying to select a therapy that might be the least noxious toward that particular patient.

JOHN LEONARD, MD: So we have a number of different options. The picture has clearly changed over the last several years, Dr. Coleman. How do you think that that's changed the approach to patients, to some degree?

MORTON COLEMAN, MD: Well, it allows us to really tailor the therapy to suit the patient, if I may say. Very often you find out what's necessary for the patient to live as full a lifestyle as they wish to live, and sometimes you may make a treatment decision based on those necessities.

On the other hand, certainly, there are clinical parameters that we use to make certain decisions. If the disease is not particularly aggressive, when they just want to select using something fairly simple, such as radio-either immunotherapy - that is, Rituxan monoclonal antibody therapy, or maybe even want to consider radioimmunotherapy. They have really very little in the way of long-term side effects, and allow the patient to lead a very full life with very little toxicity.

On the other hand, there may be reasons why one may want to select chemotherapy or chemotherapy with immunotherapy, whether that be Rituxan or radioimmunotherapy consolidation. Again, a lot of it depends on the clinical presentation, the needs of the patient, and also the desire of the patient. But again, a lot of clinical judgment goes into making a specific decision.

JOHN LEONARD, MD: So I think to, really, to some degree, summarize this, one of the nice things about having so many different treatment options is the fact that, perhaps because we have treatments that are less toxic -some of the novel agents, some of the antibody and radioimmunotherapy-based agents-that we might treat patients because we're not as worried about some of the toxicities, it might offer them options to get treatment that are going to have less side effects. And in reality, that may allow us to not necessarily wait until the disease is very resistant to treat patients.

It might make the decision as to whether or not to start therapy a little bit easier because we can . . . we have choices that aren't going to be as toxic, potentially, as some of the more traditional agents. And certainly, the idea that patients can get treatment without losing their hair, without missing time from work necessarily, things of that nature, certainly, I think, adds some value. So I think there's certainly reason to be encouraged for patients, and I think the challenge is really to continue to sort out these issues as to when we -- when to initiate therapy and what treatment to pick.

So I'd like to thank you both very much. I think this has been a very nice overview of the situation that patients face, deciding when to get treatment, and also what treatments to get with indolent non-Hodgkin's lymphoma when the disease relapses.

Joining me today have been my colleagues Dr. Morton Coleman and Dr. Owen O'Connor. I'm Dr. John Leonard. Thank you very much for joining us.

QUESTION AND ANSWER SESSION

JOHN P. LEONARD, MD: Good afternoon. This is Dr. John Leonard. Welcome to the question and answer portion of the program. Again, I'm John Leonard. I'm the clinical director of the Cornell Center for Lymphoma and Myeloma. And joining me today is Betsy de Parry, who has written about her personal experience with lymphoma. And for the next 20 minutes or so, Betsy and I will be online answering some of your questions, and you can go ahead and either submit your question online, or if you've joined us by phone, please press the number 1, and your question will come in to us.

So thank you for joining us. We have lots of questions, and we're not going to, unfortunately, in the relatively short time that we have today, we're not going to be able to get all of them. But I do want to also remind you that a nice venue to get more information and have some of your questions answered if we don't get to them today is through the blog at lymphomainnovations.com.

So why don't we go ahead and get right into it? One of the questions that's come up-and I'm just going to try to summarize in our short time some of the main topics that people have asked about-one of the issues is the issue of maintenance rituximab. And as many of you know, there is evidence after either getting chemotherapy, after getting rituximab, that the idea of maintenance treatment or giving additional treatment with rituximab while the patient is in remission after rituximab can potentially benefit patients. So there's a lot of interest these days on the issue of maintenance rituximab.

And there are a number of studies that show that if a patient gets chemotherapy alone or gets rituximab alone, usually given in a four-dose, one dose per week over four weeks regimen, that by giving additional rituximab in the indolent lymphomas-now, this has been less well established and is less useful in the aggressive lymphomas-but in the indolent lymphomas, that giving maintenance rituximab can keep people in remission longer.

Whether or not that translates into a better long-term outlook with respect to keeping people living longer versus giving rituximab, again, not while someone's in remission but when they need it, at the time of the progression of their disease, remains to be seen. So I think the issue of rituximab maintenance has potential benefits. We don't know all the answers. It seems to be very well tolerated. The long-term potential benefit of that, particularly in the indolent lymphoma, we're still working on.

So that's something that I would certainly encourage people to speak with their doctors about because there aren't absolute, clear answers there. But that is a very reasonable option for some people to consider. And again, depending on the individual situation, may be something very reasonable to think about.

The other area that comes up and that a number of people have asked online about is the issue of watch and wait and the idea that we could potentially not treat patients at diagnosis with -- again, with indolent lymphoma, but the idea being not to do immediate treatment but to potentially wait and withhold therapy in patients who are feeling well and are asymptomatic until the time that the disease progresses. And so that is another option that is reasonable for many people at the time of diagnosis, or at various times at relapse. You don't necessarily benefit by early treatment if patients are feeling well with indolent lymphoma.

This is a very, for many people, a stressful thing, and in a second we'll get Betsy's input on this, because I think that the issue of watch and wait is one that takes a lot of adjustment for patients to get used to from the standpoint of what many people would call watch and worry, because you don't often have to . . . you're often able to watch and just monitor the disease. And that's nice, because many patients are not on therapy at the time. But on the flip side, patients do worry about their disease, and it's something that's very different than many other tumors that patients are dealing with. For instance, breast cancer, lung cancer, colon cancer, diseases of that nature, we don't often watch. We, you know, go ahead and treat, usually. So this is a special thing about the indolent lymphomas. And Betsy, do you have any thoughts or insights on the watch-and-wait scenario?

BETSY DE PARRY: Well, I absolutely agree with you. I think that watch and wait can be great for some people, and other people like to take a more proactive approach to getting treated. And I think it's something that's a very personal decision that should be made with your doctor, and of course nobody -- nobody knows your own lifestyle better than you, and you just have to really weigh all of the facts that come into play and decide what's best for you individually.

JOHN P. LEONARD, MD: I think that that is one of the scenarios. Certain types of lymphoma, for instance, the aggressive lymphomas, patients need treatment basically immediately. And for the aggressive forms of lymphoma, CHOP and rituximab is usually the standard therapy.

And I will mention that one of our questions came in, is there a difference between rituximab and Rituxan? Sometimes the names are used interchangeably. Rituximab is the generic name. Rituxan is kind of the brand name. So they're basically the same name, for people who sometimes get confused by the two different nomenclatures.

But in the aggressive lymphomas, basically we treat people generally immediately, and generally CHOP and Rituxan is the standard treatment. But in the indolent lymphomas, it's really a lot more of a negotiation, a lot more of, I like to say, a partnership between the patient and the doctor and, obviously, the patient's family, where you think about the goals of therapy. You decide, do you need to do treatment, and if so, what treatment do you pick based on the goals and the situation that one faces? Some patients often will want to do a more attentive therapy so that they potentially will have a longer remission. Other patients will often want to do a less aggressive therapy to try to avoid side effects and toxicity.

So it's really something that is very individualized and can be very balanced, and the whole issue that we alluded to earlier about maintenance treatment is one of those that comes in -- comes up very often in that because I think patients are, you know, figuring out the idea of maintenance and how that helps them meet their goals, depending on their individual situation.

The other -- another question that came up was the role of radioimmunotherapy and the radioactive monoclonal antibody. The idea of a monoclonal antibody, as we talked about a little bit in the video, was the issue that antibodies are proteins that bind to the tumor cell and can stimulate an immune response against a lymphoma cell. A second step in dealing with a monoclonal antibody and trying to make it work better is to attach a radioactive particle to it. And so there are two of these agents approved, Zevalin and Bexxar. They have the added potential benefit of adding another way to get after the tumor cell, mainly by carrying radiation toward the tumor cell.

On the flip side, they -- So they can work better. On the flip side, they do have some extra side effects, mainly on the bone marrow and the blood count. And so we tend to use radioimmunotherapy from inpatient, where the disease has been resistant to Rituxan, resistant to chemotherapy, particularly in the indolent lymphomas. But there's a lot of interest in using the radioactive antibodies such as Zevalin and Bexxar as part of initial treatment. And this is, I think, something that's being evaluated in clinical trials and something that is under a great deal of interest among the scientific community, the idea that by using these very effective treatments earlier in the course of the disease . . . that we may actually be making patients live longer by using these very effective treatments, not saving them until the disease is resistant to other things, but using them earlier in the course of the disease.

And that brings us to a question that one of our audience members sent in, and that is the prospects for a cure in the indolent lymphomas. Indolent lymphomas are typically not curable, meaning that we don't typically expect that we're going to get rid of the disease, and we're going to get to a point where we're going to say, "Hey, it's gone, and it's not coming back." Although, we would certainly like for that to happen, and short of that, we would like these to be diseases that people can live a relatively normal life with, but manage, such as . . . we all have friends and family, and even ourselves, with diabetes and high blood pressure and diseases of that nature. So it really results in kind of a different mindset with respect to what you're expecting out of the disease.

And so the issue of cure comes up. One of the challenges with cure in these diseases is you have to wait a long time, because patients can be in remission for 10 years or 20 years, and you think, "Wow, maybe we've hit upon the cure here," and then the disease can come back late. So it's not something we talk about a lot, but it's something that certainly we all are hopeful about, and I think we're making progress.

Betsy, your thoughts on cure and indolent lymphoma, or at least how one deals with thinking about that in the face of these complicated diseases? BETSY DE PARRY: Well, I think that "cure" is a word that we would all love to hear from our doctors. And we as patients put a lot of emphasis on that word. And for myself, I've been in remission now for four years after radioimmunotherapy. That's been the last treatment that I've had. I am healthy. I do all the things that normal people do, just as I did before I was ever ill.

In my own mind, I am cured, and I will never hear that from a doctor. It certainly will take a generation or more to prove that these newer treatments work. However, I actually went to the dictionary and looked up the word "cure," and it says, "Restored to health." It doesn't give you a time frame. And so psychologically, I think that today I am cured. I am . . . there's no evidence of disease in my body. That's how emotionally I deal with it.

And I've shared that with a number of other patients who have thought of it in that light and seem to be able to deal with their remissions, quote and unquote, just a little bit better.

JOHN P. LEONARD, MD: There are a couple of other questions on the line, and I think we want to spend a little bit of time, and we'll go a little bit longer today because we started late, and part of that was my fault with some technical issues on my end, so I apologize for those of you that had to wait a little bit. One area that a number of our audience members were interested in is the issue of aggressive lymphomas. We've talked a little bit more about the indolent lymphomas. The aggressive lymphomas are generally treated with CHOP and Rituxan chemotherapy, and a percentage of patients can be cured with those diseases. And again, it all, to some degree, depends on your definition of cure. But in many situations, with the aggressive lymphomas, the disease goes away and doesn't come back. So that, to some degree, is the good part of the aggressive lymphomas.

The down part, the downside, or one of the potential downsides of the aggressive lymphomas is that they always need treatment. So the idea of watch and wait is not one that we typically think of with the aggressive lymphomas, and that they can be more problematic if they don't respond to treatment. And so patients who have disease that relapses or comes back after CHOP and rituximab, or doesn't have a good response to the CHOP and rituximab, often go on to further chemotherapy-based regimens, and in some situations will go on to receive a fancy way of giving higher doses of chemotherapy, something called high-dose chemotherapy, and a stem cell transplant.

And so they can be more complicated diseases. Stem cell transplants for some people in some situations, particularly with the aggressive lymphomas, have been shown to increase cure rates and extend survival. So there are the reasons, and the importance of stem cell transplants are a little bit more well established in the aggressive lymphomas. They're also sometimes in the indolent lymphomas performed. But it's a little bit less clear how important that they . . . that the stem cell transplant issue is, and it's a little bit less clear how . . . when exactly to use it in the course of the disease.

We've had a few questions here relating to Zevalin and Bexxar, and I want to come back to that. These agents are generally pretty well tolerated agents. They do affect the blood count. They generally don't have a lot of side effects, such as nausea, vomiting, hair loss and some of the other things that we tend to see with chemotherapy. And so for many people, these are good treatment options and can control the disease, but with less in the way of side effects with respect to some of the things that we have seen typically with chemotherapy. Betsy, do you have any comments on radioimmunotherapy?

BETSY DE PARRY: Well, radioimmunotherapy rescued me when all else failed. And I think the great part about radioimmunotherapy, as you said, is that it really doesn't have any of the side effects. The treatment is given in two doses a week apart. It enables the patients to get back to work relatively quickly. You're not going through months of treatment and debilitating side effects, and I think the good news is, too, that so many of us who have taken it really have had good, long remissions. In fact, I just talked to somebody the other day who has had a remission of ten years.

So I think that this treatment really gives many lymphoma patients a chance to look forward to bright futures instead of frequent relapses and more chemotherapy. So I think they're just great. I'm so glad that doctors have stuck with them and developed these treatments and are using them effectively.

JOHN P. LEONARD, MD: Now, I think so. It is important, and I agree. We've treated a number of patients at our center with these agents. They can be very, very useful. They do, like any treatment such as radiation or chemotherapy, have the potential for long-term side effects. The chances of that is very small -- are very small. One of our questions relates to that issue. They are very small, but any patient with lymphoma getting just about any form of therapy has, unfortunately, a low but greater than kind of the average person risk of a long-term problem relating to the radiation. In some cases, these can relate to other cancers. The chance of these are very small, but it needs to be figured into the equation. And if you're considering radioimmunotherapy, it's something that needs to be discussed, but I can tell you that there are lots of patients out there-and we have a number at our center-that have a very similar story, where other treatments weren't working well, and this allowed people to have a very good response, even when the standard treatments weren't working.

We've had a few questions about T-cell lymphomas. T-cell lymphomas tend to be much less common, and they tend to get less attention in various programs because they're less common diseases. I just want to mention them briefly, because we do have some audience members who are interested in them.

T-cell lymphomas in some cases can be more prone to involve the skin, and that's one whole group of typically more indolent or slow-growing lymphomas that can involve the skin and often, at least at the beginning, can be treated locally with topical treatments or radiation. Sometimes they need more systemic treatments. On the other hand, other types of T-cell lymphomas can be more aggressive and often need to be treated like the aggressive lymphomas. Like with the CHOP chemotherapy, we don't use rituximab in the T-cell lymphomas because it doesn't bind to those cells as a target. But they do certainly -because they are less common-they can be more complicated to treat because many doctors are less familiar with them and because the clinical trials that we have are less extensive, because they're less common disease.

And so I would certainly, with the T-cell lymphomas, one of the scenarios . . . one of the pieces of advice I have for patients is to get a good pathology opinion because they can be confusing to diagnose, and you may want to particularly think in those situations about a lymphoma specialist, because they are much less common and less frequently encountered by doctors out in practice.

The other -- another area that's come up is . . . and people have issues in, and I think one of my pet areas, is the development of new drugs and new treatments, and there are a variety of new drugs coming out in lymphoma being studied. We've had several questions about Velcade. Velcade is a drug that is what we call a proteosome inhibitor. It's not a chemotherapy drug. It is a drug that has been developed in multiple myeloma, a different type of tumor, a tumor of the bone marrow and the cells of the bone marrow that can affect the bones, so it's a related disease to lymphoma, but not -- not the same and very different in certain ways.

But Velcade is a drug-it's also called bortezomib. It's a drug that's used in multiple myeloma and is FDA-approved there. It turns out that Velcade has some activity, meaning it can be useful to shrink tumors in mantle-cell lymphoma, a less common subtype of lymphoma. It can also be useful and have activity in some of the indolent forms of lymphoma, and it's a drug that we're studying right now in combination with the standard CHOP and rituximab in the large-cell lymphomas, the more aggressive lymphomas, as well as mantle-cell lymphoma. So Velcade is a drug that's been around for a while in other diseases.

We're studying it in lymphoma, and it seems to be very useful. It's given intravenously, usually two times a week, two out of every three weeks, so it does involve a lot of trips to the doctor, though they tend to be short trips. It can affect the blood counts. It can give people some fatigue, low blood counts, also some of the neuropathy. Numbness and tingling of the fingers and toes can sometimes happen.

But I think Velcade is a very interesting new drug that has a lot of potential, and it's being studied in clinical trials, and one of our challenges is how to sort out where best to use it, how to combine it with our standard treatments.

There are lots and lots of other drugs that are coming along in clinical trials, new antibodies like Rituxan that go against other targets in lymphoma, other agents that can stimulate the immune system to fight the lymphoma, and a number of other different agents, some of which are chemotherapies, some of which work in different ways. And I would encourage you all, if you're at a point in your disease or your family member's disease where you're potentially needing treatment, to look at clinical trials, because there are a wide variety of clinical trials out there.

Betsy, I don't know. Did you receive your Bexxar treatment or your radioimmunotherapy treatment as part of a clinical trial, or did you receive it afterwards?

BETSY DE PARRY: Actually, I took Zevalin . . .

JOHN P. LEONARD, MD: Or Zevalin. I'm sorry.

BETSY DE PARRY: ... shortly after it had been approved. I was very lucky that it became available literally in the nick of time.

JOHN P. LEONARD, MD: Well, I think that is a very . . . and Zevalin and Bexxar, people ask, they're very similar. There are some differences. But they're more alike than they are different, and both are relatively overlapping in how they work, their side effects and where they use them. But I think it's a great example of the fact that those drugs, as well as all of the drugs, and really any time a patient goes into an examination room and talks to a doctor, and the doctor tells the patient what to expect out of the disease, what's the best treatment, it's all based on clinical trials. So I think it's very important that patients take the opportunity to at least learn more about clinical trials, because that's where a lot of these new approaches are coming along.

That's where we can tell you what to expect out of the disease and what . . . how best to treat it, and in many cases can make available new treatment options that patients might not otherwise have. And, as you alluded to, Betsy, there are times when patients maybe have their backs against the wall. Maybe the standard treatments or the treatments they have available aren't working well, and a clinical trial or some of these new agents that are just coming along really may offer a very nice potential alternative. So I think it's very important to keep in mind.

I think we're about at the end of our time. I'd like to thank everyone for joining us. And again, there were many questions that we couldn't go to. We tried to summarize them to some degree, but I would encourage you to look at the blog atlymphomainnovations.com, and that's an excellent source of more information and may be able to give you an opportunity to have more specific answers to your questions and to potentially cover some of the topics that we didn't have time to get to.

I would remind you that this is just the first webcast in this series, and there will be two more events later in the fall with my colleagues that will be available to take additional questions and provide additional perspectives. And again, you can visit lymphomainnovations.com for updates on that. Thanks very much for joining us. Again, I'm Dr. John Leonard from Cornell Medical College. Thank you.