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 some of the promising research in the treatments for relapsing indolent or slow-growing non-Hodgkin's lymphoma.
Joining me 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.
This session of our discussion is really going to focus on new therapies for patients with relapsing indolent lymphoma, and there are a variety of different new drugs and types of drugs that are in development, in studies and clinical trials and starting to make their way into clinical practice. And it's important to note that many of these treatments not -- are not yet approved and not yet fully evaluated, but are still very promising, and so we want to touch on some of them today.
As many patients with indolent lymphoma know, rituximab, or Rituxan, a monoclonal antibody which works by activating the immune system or by directly having effects on the lymphoma cells, is very important.
So, Dr. O'Connor, what are some of the approaches that you're familiar with and working with to try to make rituximab work better? Because, as we know, that's a good, good agent, but we want to make it better.
OWEN O'CONNOR, MD: Well, this is a particularly exciting area of lymphoma research and drug development, and using the same rationale that pioneers in cancer chemotherapy have used years ago by trying to combine different kinds of chemotherapy drugs, we now have a lot of new tools, new biologic drugs like rituximab, and a lot of new molecules and drugs that are coming out related to rituximab. And so now some of the new strategies, whether it's trying to combine biological drugs in the same way that we combined chemotherapy drugs in the past to try to produce even better results.
JOHN LEONARD, MD: So, Dr. Coleman, what is your take on some of the new other monoclonal antibodies? In particular, they target all of these CDs, which can be very confusing to patients to keep track of.
MORTON COLEMAN, MD: Well, I think maybe it's important for us to sort of define what we mean by antibodies and CD20s and CD80s and so forth. An antibody should be viewed as really a guided missile directed toward the lymphoma cell. But the monoclonal antibody does not go directly to the cell in general. It goes to a specific target on the lymphoma cell, and that specific target is called an antigen.
The antigen identifies the lymphoma cell, very much like the Golden Gate Bridge would identify San Francisco and the Empire State Building would identify New York City. Well, that Golden Gate Bridge or the Empire State Building would be considered the antigen, and that's located on the surface of the lymphoma cell. It's also located on regular lymphocytes, normal lymphocytes that we see, that we normally have.
Well, these antibodies are directed toward these antigens, and there are multiple antigens, multiple neon signs, multiple -- multiple identifying structures on the cell. Those identifying structures, the antigens, are multiple. Some -- One of them is called CD20, which is very prevalent on most lymphoma cells, but there are other antigens -- CD22, CD40, CD80.
Those antibodies hit the antigen and induce a whole host of events, biologic events, which ultimately result in the death of the cell. We're now exploring ways to make these antibodies more effective, to make the antigens more presentable, if you would, or to make the antibody kill the cell more effectively. One of the techniques, harkening back to chemotherapy, is to use a combination of antibodies, and hopefully this is a very, very promising area.
JOHN LEONARD, MD: So we have lots of different antibodies that target -- go after different targets. They can work differently to interact with the immune system. They can flick switches in the cell differently to make the cell die, and now we're looking at combining them much as we combine chemotherapy.
Another area that is very important in B cell lymphoma is the idea of the radioactive antibodies, and we have Zevalin and Bexxar, radioactive antibodies, also against that CD20 target, but have a radioactive particle attached to them and allow the radi -- radioactive energy to be delivered to the tumor cells and less to the normal cells.
And we know that these drugs can be useful in patients with disease that's resistant to rituximab or resistant to chemotherapy. But now we're starting in clinical trials to see them used in a variety of different other settings, including earlier in the course of the disease and after chemotherapy. So how do you see -- You know, our group has done a lot of work with these agents. How do you see the most promising areas of pursuing and potentially using these radioactive antibodies for this group of patients?
MORTON COLEMAN, MD: I might add that we can not only attach a radioisotope to monoclonal antibodies, but we can attach toxins and drugs to the antibody, as well, for direct delivery to the tumor cell. But the idea of using radioimmunotherapy up front is very, very appealing. As you know, John, we've done studies at Cornell and studies have been done elsewhere using radioimmunotherapy up front. There have been studies both with Zevalin as well as Bexxar showing that if you use this particular modality at the outset of treatment that the results are rather pleasing, to say the least. We get virtually 100% responses, with many of these responses, at least three quarters of them, being complete responses, and these responses are extraordinarily durable.
So with the concept of using radioimmunotherapy up early is very, very appealing. Also, the concept of using radioimmunotherapy as consolidation for a previous chemo or chemo-Rituxan therapy also has a great deal of appeal. There are studies ongoing now to see whether the use of the radioimmunotherapy as opposed to the cold antibody itself is more effective, have been ongoing now for a number of years, and it would be interesting to see what the final results are. Hopefully, we'll be able to get a bigger cell kill and a greater degree of cure for those potentially curable lymphomas, and a greater degree of remission for those that aren't curable.
JOHN LEONARD, MD: So the point of consolidation that you alluded to is really the idea of kind of a one-two punch, where you give the chemotherapy first or some treatment first to try to knock it down, and then the radioimmunotherapy is kind of a second punch or a second wave to try to knock it out. And I think that's -- While that's not a standard way of using radioimmunotherapy, at this point there are lots of exciting data that are looking at it in that capacity. And I think that holds a great deal of promise. We're still studying it in clinical trials, and some of these are randomized trials to answer the question of the role of radioimmunotherapy, but I think it's a very exciting approach.
MORTON COLEMAN, MD: It's a triple -- It's a triple punch, if you would. Chemotherapy, immunotherapy and radiation.
JOHN LEONARD, MD: There's a whole other area, and that is really other new drugs that aren't related to antibodies. These can be new chemotherapy drugs, they can be other drugs that work in different ways that are different from chemotherapy and different from the antibodies. And Dr. O'Connor, you've done a lot of work in these areas in developing these other groups of drugs. Can you give us some sense of some of the most exciting and promising new drugs that you see in this area?
OWEN O'CONNOR, MD: Sure, John. I mean, in my mind there's never been a more exciting time to be involved in cancer research and drug development for the treatment of lymphoma, and there's no doubt that our new agents that we're developing for these diseases directly comes from decades of research into understanding cancer biology and what makes a lymphoma cell a lymphoma and not a regular lymphocyte.
All of these new molecules seem to target relatively discrete pathways in the cancer cell. And as you know well, cancer cells are basically defined by their ability to grow when they shouldn't and their ability to resist cell death when they're supposed to die.
And so now, having these new tools that allow us to compromise those abilities, to get cancer cells to stop growing, to get -- to lower the threshold to help cancer cells to die, have become part of the new armamentaria of agents. So it's a relatively exciting era as we begin to understand these new drugs and now begin to think about integrating them with conventional chemotherapy drugs, monoclonal antibodies and radioimmunotherapies. They really provide an exciting new opportunity to change the natural history of these diseases.
JOHN LEONARD, MD: Many of these agents are really almost like flicking switches in the cell to get the cell to stop doing what it's -- what it's causing problems with, trying to flick switches in the cell to tell it to grow like it's supposed to or die off like it's supposed to, rather than the characteristics of the normal cancer cell. And I agree. The challenge is really combining these new agents with the standard treatments so that we can get the most bang for the buck, so to speak.
Another very interesting area to patients, more so in the initial treatment setting, but also a little bit in the relapse setting, is the issue of vaccines. And vaccines for lymphoma, the idea is to train the immune system to fight the lymphoma cell, much as we train our immune systems to fight the flu when we get a flu shot.
Dr. Coleman, you've been having patients receive vaccines for decades, and you've seen this area progress and evolve. What's your take on the vaccine approach? It's one that many patients are interested in. Where do you think that could potentially play a role for patients?
MORTON COLEMAN, MD: Yeah, it's an exciting new approach to the treatment of lymphoma, primarily used in patients who have had very little treatment. The difference between a vaccine and monoclonal antibody therapy is the difference between what we call active and passive immunization. When you're giving a monoclonal antibody, in fact what you are doing is you're passively immunizing the patient. The antibody has been created elsewhere, and you're using it against the tumor.
In the case of vaccines, we're actually having the patient himself create antibodies, or even cellular immunity, which is a different form of immunity, toward the tumor itself. So here the patient himself is fighting the disease, as opposed to having some product from the outside fight the disease.
The -- But to be sure, and to be absolutely certain that vaccines do have utility, it's important to enroll patients in clinical trials. And if I could make a plea to the audience and to the public, is please enter clinical trials. The number of patients we have are limited to study, and every new clinical trial just gets us that much closer to the ultimate cure of lymphoma.
JOHN LEONARD, MD: I think, Dr. O'Connor, you feel strongly about that issue, as well. I think in reality, everything that a doctor tells a patient as to what to expect out of their disease, what's the prognosis, what's the best treatment, comes out of clinical trials. And certainly, many of the new agents and approaches we've talked about today are available as potential options for patients, mainly through -- through clinical trials, and really, those trials are going to tell us what are the best agents that patients should consider, and how best to combine them with standard treatment.
So I think that's a good message to end up with, is that there are many new options out there, many exciting therapies, and certainly participation, or at least learning about clinical trials, which sometimes can take some effort, should be a priority for patients. Any time they make a treatment decision, they should at least ask their doctor and think about that as a potential option that may open some doors to them.
Thank you both very much for joining us today. Clearly, there's a great deal of promising research going on, as you've heard about, and in particular, lots of interesting options in the group of patients with relapsing indolent non-Hodgkin's lymphoma.
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 being with us today, please stay tuned now for a live question and answer session.
Q&A Session
MORTON COLEMAN, MD: Welcome to the question and answer portion of the program. I'm Dr. Morton Coleman. I am a Professor of Medicine at Weill Medical College of Cornell University and Director of the Center for Lymphoma and Myeloma at New York Presbyterian Hospital, Weill Cornell Campus.
Joining me today is Dr. Morton Diamond, who is living with lymphoma and is the moderator of the patient blog at lymphomainnovations.com. Mort and I, Mort, will be answering your questions for the next 20 minutes. You can submit a question online, or if you have joined us by phone, press *0. Now let's start with our first question.
I had indolent non-Hodgkin's lymphoma that transformed into aggressive non-Hodgkin's lymphoma, as a result I've had R-CHOP treatment. What's next for me now?
Well, there is a small portion, but a large -- but a -- but a large minority of patients who in fact will transform from an indolent lymphoma into an aggressive lymphoma. If the patient had never been treated, what we do is we give them R-CHOP generally, and sometimes consider them for an autologous transplant.
If the patient has already received R-CHOP, we very often will consider them for transplantation, but there are some data now showing that the radioimmunotherapies may also be effective in transformed lymphoma. Not every low-grade lymphoma, however, transforms, and many people go for many, many years -- in fact, decades -- staying in their low-grade state.
Mort, do you have anything to add?
MORTON DIAMOND: No, sir. That's an area far beyond my expertise, Dr. Coleman.
MORTON COLEMAN, MD: Thank you very much. Are there any questions over the phone?
Well, if not, I would like to summarize a number of questions that I see coming up on the board here, and one of them is when to use radioimmunotherapy. There are several questions here pertaining to that particular issue.
Radioimmunotherapy is a new and very effective form of treatment for low-grade lymphoma. It is my plea to patients and doctors both that the radioimmunotherapy used as early as possible, currently it is not indicated to give radioimmunotherapy as initial treatment, although there are a number of experimental protocols, one of which we had engaged in at Cornell, which showed that the remissions to radioimmunotherapy are excellent. The remission rate is about 35 -- 75% complete remissions, and that these remissions are really quite durable. However, most insurance companies will not pay for it as initial therapy. What they will do is they will pay for it as the next therapy following the first relapse.
Now, very often there's a tendency among physicians to hold off on the radioimmunotherapy and wait until the patient's received three or four different types of therapy. Usually, if you wait that long, the chances for getting the kind of response that we really like, which is a complete remission, and that that complete remission translates into a long and durable remission, is best if you use it early on. That's usually after the first relapse or the second relapse. So if I have to make a plea, if we're going to use radioimmunotherapy, the best place to use it is early on, not wait until the patients receive multiple therapies.
Do you have anything to add, Mort?
MORTON DIAMOND: Yes, Dr. Coleman. First, I wish to affirm what was said by yourself and your colleagues in the video. I participated in a clinical trial in which I received radioimmunotherapy as first-line or front-line therapy. Happily, I've had a wonderful result, so please, lymphoma patients, speak to your physician about entering into a clinical trial. Additionally, speaking as a patient, not as a physician, I urge lymphoma patients to obtain a consultation with a physician who's an expert in radioimmunotherapy before the patient enters a cycle of recurrent chemotherapy or even cyclic serial Rituxan therapy.
While they may be appropriate, my plea is for the patients to obtain that consultation to find out if radioimmunotherapy, as Dr. Coleman indicated, would be appropriate earlier in the course of this disease.
MORTON COLEMAN, MD: Let me just add to Mort's remarks. Not only will the chemo -- will the radioimmunotherapy work better if used early on, but you're less apt to run into toxicity if you use the radioimmunotherapy after the first or second relapse. What happens is if you receive multiple courses of chemotherapy, you tend to damage the bone marrow to some degree -- sometimes slight, sometimes more so -- and it makes it much more difficult for the radiotherapy to be able to work without creating a whole lot of damage to the patient.
Now, radioimmunotherapy is not a free ride in that it does have bone marrow toxicity, and that toxicity can last for a while. But again, that toxicity is less apt to occur if you in fact receive it earlier on.
Now, I have another question here, which is, how is the vaccine for follicular lymphoma working?
We do not have data yet for the vaccine therapy of follicular lymphoma. Vaccine therapy is different than Rituxan or radioimmunotherapy. Vaccine therapy represents what we call active immunity. That is, your own body is making an antibody to the tumor as opposed to receiving the therapy from the outside. That is known as passive immunotherapy. And when you receive therapy from the outside, you're receiving something like Rituxan. You don't actually enhance the body's own ability to ward off the disease.
So vaccine therapy has a great deal of appeal. There have been a number of studies that have been undertaken. The data are still not in, and it is usually used at this time as an initial therapy. There are not very many protocols that are now available for patients who have been previously treated.
Mort, have you had any experience, or have you been offered vaccine trials at any time?
MORTON DIAMOND: No. No, sir, I've had no experience, nor has that been suggested to me.
MORTON COLEMAN, MD: Well, most of the trials now are almost ending accrual, so that hopefully we'll have some answers on the vaccines probably within the next year or two. And we're all hoping that they will in fact prove to be effective, because in that way you will have continuous antibody to your -- to your tumor.
I'm looking here at several other questions regarding Rituxan and Rituxan maintenance. Rituxan maintenance is a very controversial area in oncology at this time. Rituxan has been used as initial therapy, and then patients are not maintained, whereas in other instances Rituxan is used on a repeated basis.
One very common way of giving it is to give four doses of Rituxan every six months for a total of four doses, although there are other regimens, as well. Frankly, we don't know which maintenance regimen is better, and in fact there is some controversy over whether maintenance should be done at all.
One of the new toxicities that we've encountered with Rituxan maintenance is that the immunoglobulins of patients tends to fall, and as a result some patients may be more predisposed to infection. In fact, we've encountered a number of patients who have developed chronic sinusitis after having received Rituxan maintenance, and it is sometimes very difficult to clear the sinusitis unless we give gammaglobulin. So no treatment is actually a free ride, although I will say that Rituxan has very, very little toxicity associated with it.
Whether to give maintenance, how to give maintenance is still very, very controversial. There are some instances, though, where I think Rituxan maintenance is in fact very worthwhile, and that is when you have a condition which is ongoing, such as immune thrombocytopenia, or in the instance where you may have very, very high proteins, and you don't want these proteins to come back, then a very, very good case could be made for Rituxan maintenance. Again, the jury is out, and I suspect many of the listeners today have either had Rituxan maintenance offered or suggested and others have not.
Are there any phone questions that we have?
Mort, do you have any comment about Rituxan maintenance?
MORTON DIAMOND: Yes, sir. Yes, sir. I think an important element from the patient point of view is that the patient should feel comfortable with his or her plan of treatment. For myself, my personal creed is that I wanted to attack my lymphoma as early and as hard as I could. So personally, I was very much attracted to radioimmunotherapy up front. My personal creed is that I would not feel comfortable being placed on a conveyer belt of cyclic or serial Rituxan, and that's why, Dr. Coleman, I return to my earlier plea suggesting that the lymphoma patient -- certainly the one who has a recurrence -- talk to a physician who is experienced in radioimmunotherapy.
MORTON COLEMAN, MD: Yes, but let us be very clear that we really still do not know what is the very best way to treat low-grade lymphoma. We're blessed by having many, many options. We can -- We have a bevy of choices. But we still don't know what is really the absolute correct sequence for treating low-grade lymphoma. And while I am also what I call a hawk when it comes to treating low-grade lymphoma, there are many doctors who would argue quite vehemently that watching and waiting and taking a more benign, if you would, approach to lymphoma is a perfectly reasonable and good thing to do. We just don't have the data.
And one of the reasons that we don't have the data is that we're blessed that people with low-grade lymphoma are simply living a long time, and that's a wonderful new development. Many years ago, statistics were gleaned on patients with low-grade lymphoma, particularly follicular lymphoma, which is by far the largest number of patients, and the median survival was between seven and ten years. None of the people who are in lymphoma therapy today -- the cognoscenti, if you would -- would even venture to say that ten years is a reasonable median survival. We just don't see people dying from low-grade lymphoma like we used to. And I'm sure that's because of the advent of Rituxan biologic therapy.
And I'm hopeful, with more of the newer developments that are coming down the pike, that the median survival will continue to increase even greater. I simply don't see people dying from follicular lymphoma like I used to ten and 20 years ago.
Now, I see a lot of questions about other types of low-grade lymphoma. Certainly, follicular lymphoma is the predominant low-grade lymphoma, and in fact, follicular lymphoma comprises about a quarter of all lymphomas. But I see questions about other low-grade lymphomas, and I thought it would be best to comment about them.
There is small lymphocytic lymphoma, which is very much like chronic lymphatic leukemia. There is marginal zone lymphoma, which includes the MALT lymphomas, which are very often lymphomas of organs. And some people will include Waldenström's macroglobulinemia as another low-grade lymphoma.
Whether you have small lymphocytic lymphoma, whether you have Waldenström's macroglobulinemia, whether you have marginal zone lymphoma or follicular lymphoma, one can anticipate having relapses. Again, we hope that these newer therapies, such as radioimmunotherapy, perhaps maintenance Rituxan, perhaps vaccine therapy will prolong these remissions so that patients won't require a great deal of therapy.
But I do want to emphasize that all of these low-grade lymphomas are still not considered curable, and that patients should anticipate getting a relapse. If so, it's not the end of the world, as we have multiple options, as I have mentioned.
Mort, do you have any comment to make?
MORTON DIAMOND: No, sir, I don't.
MORTON COLEMAN, MD: Okay. There are some other questions here pertaining to the combination of chemotherapy with Rituxan, and some have asked which types of chemotherapy to give. The most common choice for most of the doctors these days is to use CHOP-Rituxan. However, there are other choices, and again, many of the choices of what chemotherapy to give is based on what we've hoped to accomplish and what the patient himself or herself is like.
For instance, if we have an elderly patient, we may not want to use CHOP, because CHOP includes Adriamycin, which has cardiac toxicity. On the other hand, if you're a young patient and you may want to go for a transplant, we might want to avoid a drug like fludarabine, which is commonly used in low-grade lymphomas, because fludarabine may impact the bone marrow stem cells, which may make it more difficult to do an autotransplant.
So again, we need to choose our therapy based on what the patient wants and what the needs of the patient in fact are. One of the nice things about radioimmunotherapy, if someone wants to go about leading -- leading their life and not being impacted by having to receive a lot of treatment, one could take radioimmunotherapy and be done with their therapy within two weeks. So that may be a choice that someone may want to make.
Some people may want to use drugs that don't create hair loss because they have a job and they don't want to be seen in a wig, although wigs today are very, very fine, and you can hardly tell the difference. So we select the particular type of chemotherapy regimen we give based on what we hope to accomplish and what the patient wants.
Mort, would you care to comment on your own therapy and how you went about choosing what you wanted -- how you wanted to be treated?
MORTON DIAMOND: Yes, sir, Dr. Coleman. Again, my personal creed or feeling were that I wanted to attack this disease as early and as hard, so therefore I participated in a clinical trial in which I received radioimmunotherapy as first-line treatment. I did not lose a single day of work, Dr. Coleman, from this therapy.
MORTON COLEMAN, MD: I think that's just -- that's a fantastic endorsement. But again, let me make clear that there is still great controversy over what represents the best form of therapy, and that taking a more benign approach is certainly very reasonable in someone who's totally asymptomatic.
But regardless, I want to leave the listeners with a real upbeat note. We are making progress in low-grade lymphoma. The cup is no longer just half full, it's three quarters full, and I'm hopeful that we'll have a cure very shortly in the very near future.
That's about all the time we have. I'd like to thank Mort Diamond for such an interesting discussion. This is the finally webcast and chat in our non-Hodgkin's lymphoma series. For more information on non-Hodgkin's lymphoma and to watch the previous videos in this series, please visit lymphomainnovations.com. Thank you for joining us today. I'm Dr. Morton Coleman.
Joining me 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.
This session of our discussion is really going to focus on new therapies for patients with relapsing indolent lymphoma, and there are a variety of different new drugs and types of drugs that are in development, in studies and clinical trials and starting to make their way into clinical practice. And it's important to note that many of these treatments not -- are not yet approved and not yet fully evaluated, but are still very promising, and so we want to touch on some of them today.
As many patients with indolent lymphoma know, rituximab, or Rituxan, a monoclonal antibody which works by activating the immune system or by directly having effects on the lymphoma cells, is very important.
So, Dr. O'Connor, what are some of the approaches that you're familiar with and working with to try to make rituximab work better? Because, as we know, that's a good, good agent, but we want to make it better.
OWEN O'CONNOR, MD: Well, this is a particularly exciting area of lymphoma research and drug development, and using the same rationale that pioneers in cancer chemotherapy have used years ago by trying to combine different kinds of chemotherapy drugs, we now have a lot of new tools, new biologic drugs like rituximab, and a lot of new molecules and drugs that are coming out related to rituximab. And so now some of the new strategies, whether it's trying to combine biological drugs in the same way that we combined chemotherapy drugs in the past to try to produce even better results.
JOHN LEONARD, MD: So, Dr. Coleman, what is your take on some of the new other monoclonal antibodies? In particular, they target all of these CDs, which can be very confusing to patients to keep track of.
MORTON COLEMAN, MD: Well, I think maybe it's important for us to sort of define what we mean by antibodies and CD20s and CD80s and so forth. An antibody should be viewed as really a guided missile directed toward the lymphoma cell. But the monoclonal antibody does not go directly to the cell in general. It goes to a specific target on the lymphoma cell, and that specific target is called an antigen.
The antigen identifies the lymphoma cell, very much like the Golden Gate Bridge would identify San Francisco and the Empire State Building would identify New York City. Well, that Golden Gate Bridge or the Empire State Building would be considered the antigen, and that's located on the surface of the lymphoma cell. It's also located on regular lymphocytes, normal lymphocytes that we see, that we normally have.
Well, these antibodies are directed toward these antigens, and there are multiple antigens, multiple neon signs, multiple -- multiple identifying structures on the cell. Those identifying structures, the antigens, are multiple. Some -- One of them is called CD20, which is very prevalent on most lymphoma cells, but there are other antigens -- CD22, CD40, CD80.
Those antibodies hit the antigen and induce a whole host of events, biologic events, which ultimately result in the death of the cell. We're now exploring ways to make these antibodies more effective, to make the antigens more presentable, if you would, or to make the antibody kill the cell more effectively. One of the techniques, harkening back to chemotherapy, is to use a combination of antibodies, and hopefully this is a very, very promising area.
JOHN LEONARD, MD: So we have lots of different antibodies that target -- go after different targets. They can work differently to interact with the immune system. They can flick switches in the cell differently to make the cell die, and now we're looking at combining them much as we combine chemotherapy.
Another area that is very important in B cell lymphoma is the idea of the radioactive antibodies, and we have Zevalin and Bexxar, radioactive antibodies, also against that CD20 target, but have a radioactive particle attached to them and allow the radi -- radioactive energy to be delivered to the tumor cells and less to the normal cells.
And we know that these drugs can be useful in patients with disease that's resistant to rituximab or resistant to chemotherapy. But now we're starting in clinical trials to see them used in a variety of different other settings, including earlier in the course of the disease and after chemotherapy. So how do you see -- You know, our group has done a lot of work with these agents. How do you see the most promising areas of pursuing and potentially using these radioactive antibodies for this group of patients?
MORTON COLEMAN, MD: I might add that we can not only attach a radioisotope to monoclonal antibodies, but we can attach toxins and drugs to the antibody, as well, for direct delivery to the tumor cell. But the idea of using radioimmunotherapy up front is very, very appealing. As you know, John, we've done studies at Cornell and studies have been done elsewhere using radioimmunotherapy up front. There have been studies both with Zevalin as well as Bexxar showing that if you use this particular modality at the outset of treatment that the results are rather pleasing, to say the least. We get virtually 100% responses, with many of these responses, at least three quarters of them, being complete responses, and these responses are extraordinarily durable.
So with the concept of using radioimmunotherapy up early is very, very appealing. Also, the concept of using radioimmunotherapy as consolidation for a previous chemo or chemo-Rituxan therapy also has a great deal of appeal. There are studies ongoing now to see whether the use of the radioimmunotherapy as opposed to the cold antibody itself is more effective, have been ongoing now for a number of years, and it would be interesting to see what the final results are. Hopefully, we'll be able to get a bigger cell kill and a greater degree of cure for those potentially curable lymphomas, and a greater degree of remission for those that aren't curable.
JOHN LEONARD, MD: So the point of consolidation that you alluded to is really the idea of kind of a one-two punch, where you give the chemotherapy first or some treatment first to try to knock it down, and then the radioimmunotherapy is kind of a second punch or a second wave to try to knock it out. And I think that's -- While that's not a standard way of using radioimmunotherapy, at this point there are lots of exciting data that are looking at it in that capacity. And I think that holds a great deal of promise. We're still studying it in clinical trials, and some of these are randomized trials to answer the question of the role of radioimmunotherapy, but I think it's a very exciting approach.
MORTON COLEMAN, MD: It's a triple -- It's a triple punch, if you would. Chemotherapy, immunotherapy and radiation.
JOHN LEONARD, MD: There's a whole other area, and that is really other new drugs that aren't related to antibodies. These can be new chemotherapy drugs, they can be other drugs that work in different ways that are different from chemotherapy and different from the antibodies. And Dr. O'Connor, you've done a lot of work in these areas in developing these other groups of drugs. Can you give us some sense of some of the most exciting and promising new drugs that you see in this area?
OWEN O'CONNOR, MD: Sure, John. I mean, in my mind there's never been a more exciting time to be involved in cancer research and drug development for the treatment of lymphoma, and there's no doubt that our new agents that we're developing for these diseases directly comes from decades of research into understanding cancer biology and what makes a lymphoma cell a lymphoma and not a regular lymphocyte.
All of these new molecules seem to target relatively discrete pathways in the cancer cell. And as you know well, cancer cells are basically defined by their ability to grow when they shouldn't and their ability to resist cell death when they're supposed to die.
And so now, having these new tools that allow us to compromise those abilities, to get cancer cells to stop growing, to get -- to lower the threshold to help cancer cells to die, have become part of the new armamentaria of agents. So it's a relatively exciting era as we begin to understand these new drugs and now begin to think about integrating them with conventional chemotherapy drugs, monoclonal antibodies and radioimmunotherapies. They really provide an exciting new opportunity to change the natural history of these diseases.
JOHN LEONARD, MD: Many of these agents are really almost like flicking switches in the cell to get the cell to stop doing what it's -- what it's causing problems with, trying to flick switches in the cell to tell it to grow like it's supposed to or die off like it's supposed to, rather than the characteristics of the normal cancer cell. And I agree. The challenge is really combining these new agents with the standard treatments so that we can get the most bang for the buck, so to speak.
Another very interesting area to patients, more so in the initial treatment setting, but also a little bit in the relapse setting, is the issue of vaccines. And vaccines for lymphoma, the idea is to train the immune system to fight the lymphoma cell, much as we train our immune systems to fight the flu when we get a flu shot.
Dr. Coleman, you've been having patients receive vaccines for decades, and you've seen this area progress and evolve. What's your take on the vaccine approach? It's one that many patients are interested in. Where do you think that could potentially play a role for patients?
MORTON COLEMAN, MD: Yeah, it's an exciting new approach to the treatment of lymphoma, primarily used in patients who have had very little treatment. The difference between a vaccine and monoclonal antibody therapy is the difference between what we call active and passive immunization. When you're giving a monoclonal antibody, in fact what you are doing is you're passively immunizing the patient. The antibody has been created elsewhere, and you're using it against the tumor.
In the case of vaccines, we're actually having the patient himself create antibodies, or even cellular immunity, which is a different form of immunity, toward the tumor itself. So here the patient himself is fighting the disease, as opposed to having some product from the outside fight the disease.
The -- But to be sure, and to be absolutely certain that vaccines do have utility, it's important to enroll patients in clinical trials. And if I could make a plea to the audience and to the public, is please enter clinical trials. The number of patients we have are limited to study, and every new clinical trial just gets us that much closer to the ultimate cure of lymphoma.
JOHN LEONARD, MD: I think, Dr. O'Connor, you feel strongly about that issue, as well. I think in reality, everything that a doctor tells a patient as to what to expect out of their disease, what's the prognosis, what's the best treatment, comes out of clinical trials. And certainly, many of the new agents and approaches we've talked about today are available as potential options for patients, mainly through -- through clinical trials, and really, those trials are going to tell us what are the best agents that patients should consider, and how best to combine them with standard treatment.
So I think that's a good message to end up with, is that there are many new options out there, many exciting therapies, and certainly participation, or at least learning about clinical trials, which sometimes can take some effort, should be a priority for patients. Any time they make a treatment decision, they should at least ask their doctor and think about that as a potential option that may open some doors to them.
Thank you both very much for joining us today. Clearly, there's a great deal of promising research going on, as you've heard about, and in particular, lots of interesting options in the group of patients with relapsing indolent non-Hodgkin's lymphoma.
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 being with us today, please stay tuned now for a live question and answer session.
Q&A Session
MORTON COLEMAN, MD: Welcome to the question and answer portion of the program. I'm Dr. Morton Coleman. I am a Professor of Medicine at Weill Medical College of Cornell University and Director of the Center for Lymphoma and Myeloma at New York Presbyterian Hospital, Weill Cornell Campus.
Joining me today is Dr. Morton Diamond, who is living with lymphoma and is the moderator of the patient blog at lymphomainnovations.com. Mort and I, Mort, will be answering your questions for the next 20 minutes. You can submit a question online, or if you have joined us by phone, press *0. Now let's start with our first question.
I had indolent non-Hodgkin's lymphoma that transformed into aggressive non-Hodgkin's lymphoma, as a result I've had R-CHOP treatment. What's next for me now?
Well, there is a small portion, but a large -- but a -- but a large minority of patients who in fact will transform from an indolent lymphoma into an aggressive lymphoma. If the patient had never been treated, what we do is we give them R-CHOP generally, and sometimes consider them for an autologous transplant.
If the patient has already received R-CHOP, we very often will consider them for transplantation, but there are some data now showing that the radioimmunotherapies may also be effective in transformed lymphoma. Not every low-grade lymphoma, however, transforms, and many people go for many, many years -- in fact, decades -- staying in their low-grade state.
Mort, do you have anything to add?
MORTON DIAMOND: No, sir. That's an area far beyond my expertise, Dr. Coleman.
MORTON COLEMAN, MD: Thank you very much. Are there any questions over the phone?
Well, if not, I would like to summarize a number of questions that I see coming up on the board here, and one of them is when to use radioimmunotherapy. There are several questions here pertaining to that particular issue.
Radioimmunotherapy is a new and very effective form of treatment for low-grade lymphoma. It is my plea to patients and doctors both that the radioimmunotherapy used as early as possible, currently it is not indicated to give radioimmunotherapy as initial treatment, although there are a number of experimental protocols, one of which we had engaged in at Cornell, which showed that the remissions to radioimmunotherapy are excellent. The remission rate is about 35 -- 75% complete remissions, and that these remissions are really quite durable. However, most insurance companies will not pay for it as initial therapy. What they will do is they will pay for it as the next therapy following the first relapse.
Now, very often there's a tendency among physicians to hold off on the radioimmunotherapy and wait until the patient's received three or four different types of therapy. Usually, if you wait that long, the chances for getting the kind of response that we really like, which is a complete remission, and that that complete remission translates into a long and durable remission, is best if you use it early on. That's usually after the first relapse or the second relapse. So if I have to make a plea, if we're going to use radioimmunotherapy, the best place to use it is early on, not wait until the patients receive multiple therapies.
Do you have anything to add, Mort?
MORTON DIAMOND: Yes, Dr. Coleman. First, I wish to affirm what was said by yourself and your colleagues in the video. I participated in a clinical trial in which I received radioimmunotherapy as first-line or front-line therapy. Happily, I've had a wonderful result, so please, lymphoma patients, speak to your physician about entering into a clinical trial. Additionally, speaking as a patient, not as a physician, I urge lymphoma patients to obtain a consultation with a physician who's an expert in radioimmunotherapy before the patient enters a cycle of recurrent chemotherapy or even cyclic serial Rituxan therapy.
While they may be appropriate, my plea is for the patients to obtain that consultation to find out if radioimmunotherapy, as Dr. Coleman indicated, would be appropriate earlier in the course of this disease.
MORTON COLEMAN, MD: Let me just add to Mort's remarks. Not only will the chemo -- will the radioimmunotherapy work better if used early on, but you're less apt to run into toxicity if you use the radioimmunotherapy after the first or second relapse. What happens is if you receive multiple courses of chemotherapy, you tend to damage the bone marrow to some degree -- sometimes slight, sometimes more so -- and it makes it much more difficult for the radiotherapy to be able to work without creating a whole lot of damage to the patient.
Now, radioimmunotherapy is not a free ride in that it does have bone marrow toxicity, and that toxicity can last for a while. But again, that toxicity is less apt to occur if you in fact receive it earlier on.
Now, I have another question here, which is, how is the vaccine for follicular lymphoma working?
We do not have data yet for the vaccine therapy of follicular lymphoma. Vaccine therapy is different than Rituxan or radioimmunotherapy. Vaccine therapy represents what we call active immunity. That is, your own body is making an antibody to the tumor as opposed to receiving the therapy from the outside. That is known as passive immunotherapy. And when you receive therapy from the outside, you're receiving something like Rituxan. You don't actually enhance the body's own ability to ward off the disease.
So vaccine therapy has a great deal of appeal. There have been a number of studies that have been undertaken. The data are still not in, and it is usually used at this time as an initial therapy. There are not very many protocols that are now available for patients who have been previously treated.
Mort, have you had any experience, or have you been offered vaccine trials at any time?
MORTON DIAMOND: No. No, sir, I've had no experience, nor has that been suggested to me.
MORTON COLEMAN, MD: Well, most of the trials now are almost ending accrual, so that hopefully we'll have some answers on the vaccines probably within the next year or two. And we're all hoping that they will in fact prove to be effective, because in that way you will have continuous antibody to your -- to your tumor.
I'm looking here at several other questions regarding Rituxan and Rituxan maintenance. Rituxan maintenance is a very controversial area in oncology at this time. Rituxan has been used as initial therapy, and then patients are not maintained, whereas in other instances Rituxan is used on a repeated basis.
One very common way of giving it is to give four doses of Rituxan every six months for a total of four doses, although there are other regimens, as well. Frankly, we don't know which maintenance regimen is better, and in fact there is some controversy over whether maintenance should be done at all.
One of the new toxicities that we've encountered with Rituxan maintenance is that the immunoglobulins of patients tends to fall, and as a result some patients may be more predisposed to infection. In fact, we've encountered a number of patients who have developed chronic sinusitis after having received Rituxan maintenance, and it is sometimes very difficult to clear the sinusitis unless we give gammaglobulin. So no treatment is actually a free ride, although I will say that Rituxan has very, very little toxicity associated with it.
Whether to give maintenance, how to give maintenance is still very, very controversial. There are some instances, though, where I think Rituxan maintenance is in fact very worthwhile, and that is when you have a condition which is ongoing, such as immune thrombocytopenia, or in the instance where you may have very, very high proteins, and you don't want these proteins to come back, then a very, very good case could be made for Rituxan maintenance. Again, the jury is out, and I suspect many of the listeners today have either had Rituxan maintenance offered or suggested and others have not.
Are there any phone questions that we have?
Mort, do you have any comment about Rituxan maintenance?
MORTON DIAMOND: Yes, sir. Yes, sir. I think an important element from the patient point of view is that the patient should feel comfortable with his or her plan of treatment. For myself, my personal creed is that I wanted to attack my lymphoma as early and as hard as I could. So personally, I was very much attracted to radioimmunotherapy up front. My personal creed is that I would not feel comfortable being placed on a conveyer belt of cyclic or serial Rituxan, and that's why, Dr. Coleman, I return to my earlier plea suggesting that the lymphoma patient -- certainly the one who has a recurrence -- talk to a physician who is experienced in radioimmunotherapy.
MORTON COLEMAN, MD: Yes, but let us be very clear that we really still do not know what is the very best way to treat low-grade lymphoma. We're blessed by having many, many options. We can -- We have a bevy of choices. But we still don't know what is really the absolute correct sequence for treating low-grade lymphoma. And while I am also what I call a hawk when it comes to treating low-grade lymphoma, there are many doctors who would argue quite vehemently that watching and waiting and taking a more benign, if you would, approach to lymphoma is a perfectly reasonable and good thing to do. We just don't have the data.
And one of the reasons that we don't have the data is that we're blessed that people with low-grade lymphoma are simply living a long time, and that's a wonderful new development. Many years ago, statistics were gleaned on patients with low-grade lymphoma, particularly follicular lymphoma, which is by far the largest number of patients, and the median survival was between seven and ten years. None of the people who are in lymphoma therapy today -- the cognoscenti, if you would -- would even venture to say that ten years is a reasonable median survival. We just don't see people dying from low-grade lymphoma like we used to. And I'm sure that's because of the advent of Rituxan biologic therapy.
And I'm hopeful, with more of the newer developments that are coming down the pike, that the median survival will continue to increase even greater. I simply don't see people dying from follicular lymphoma like I used to ten and 20 years ago.
Now, I see a lot of questions about other types of low-grade lymphoma. Certainly, follicular lymphoma is the predominant low-grade lymphoma, and in fact, follicular lymphoma comprises about a quarter of all lymphomas. But I see questions about other low-grade lymphomas, and I thought it would be best to comment about them.
There is small lymphocytic lymphoma, which is very much like chronic lymphatic leukemia. There is marginal zone lymphoma, which includes the MALT lymphomas, which are very often lymphomas of organs. And some people will include Waldenström's macroglobulinemia as another low-grade lymphoma.
Whether you have small lymphocytic lymphoma, whether you have Waldenström's macroglobulinemia, whether you have marginal zone lymphoma or follicular lymphoma, one can anticipate having relapses. Again, we hope that these newer therapies, such as radioimmunotherapy, perhaps maintenance Rituxan, perhaps vaccine therapy will prolong these remissions so that patients won't require a great deal of therapy.
But I do want to emphasize that all of these low-grade lymphomas are still not considered curable, and that patients should anticipate getting a relapse. If so, it's not the end of the world, as we have multiple options, as I have mentioned.
Mort, do you have any comment to make?
MORTON DIAMOND: No, sir, I don't.
MORTON COLEMAN, MD: Okay. There are some other questions here pertaining to the combination of chemotherapy with Rituxan, and some have asked which types of chemotherapy to give. The most common choice for most of the doctors these days is to use CHOP-Rituxan. However, there are other choices, and again, many of the choices of what chemotherapy to give is based on what we've hoped to accomplish and what the patient himself or herself is like.
For instance, if we have an elderly patient, we may not want to use CHOP, because CHOP includes Adriamycin, which has cardiac toxicity. On the other hand, if you're a young patient and you may want to go for a transplant, we might want to avoid a drug like fludarabine, which is commonly used in low-grade lymphomas, because fludarabine may impact the bone marrow stem cells, which may make it more difficult to do an autotransplant.
So again, we need to choose our therapy based on what the patient wants and what the needs of the patient in fact are. One of the nice things about radioimmunotherapy, if someone wants to go about leading -- leading their life and not being impacted by having to receive a lot of treatment, one could take radioimmunotherapy and be done with their therapy within two weeks. So that may be a choice that someone may want to make.
Some people may want to use drugs that don't create hair loss because they have a job and they don't want to be seen in a wig, although wigs today are very, very fine, and you can hardly tell the difference. So we select the particular type of chemotherapy regimen we give based on what we hope to accomplish and what the patient wants.
Mort, would you care to comment on your own therapy and how you went about choosing what you wanted -- how you wanted to be treated?
MORTON DIAMOND: Yes, sir, Dr. Coleman. Again, my personal creed or feeling were that I wanted to attack this disease as early and as hard, so therefore I participated in a clinical trial in which I received radioimmunotherapy as first-line treatment. I did not lose a single day of work, Dr. Coleman, from this therapy.
MORTON COLEMAN, MD: I think that's just -- that's a fantastic endorsement. But again, let me make clear that there is still great controversy over what represents the best form of therapy, and that taking a more benign approach is certainly very reasonable in someone who's totally asymptomatic.
But regardless, I want to leave the listeners with a real upbeat note. We are making progress in low-grade lymphoma. The cup is no longer just half full, it's three quarters full, and I'm hopeful that we'll have a cure very shortly in the very near future.
That's about all the time we have. I'd like to thank Mort Diamond for such an interesting discussion. This is the finally webcast and chat in our non-Hodgkin's lymphoma series. For more information on non-Hodgkin's lymphoma and to watch the previous videos in this series, please visit lymphomainnovations.com. Thank you for joining us today. I'm Dr. Morton Coleman.