Dr. Gopal, are you encouraged in the direction of where research is headed and its benefit for patients?

Targeting the Tumor in Lymphoma July 8, 2009 Ajay Gopal Please remember the opinions expressed on Patient Power are not necessarily the views of Seattle Cancer Care Alliance, its medical staff or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That s how you ll get care that s most appropriate for you. Introduction There's exciting news for people who are suffering from lymphoma, many types of lymphoma, and there's a lot of research going on at the Seattle Cancer Care Alliance. A leading expert will help us understand it, next on Patient Power. Hello and welcome to Patient Power. I am Andrew Schorr, and this program like so many others is sponsored by the Seattle Cancer Care Alliance. Today we're talking about lymphoma. Now, lymphoma strikes typically when people are aging, and cancer is increasing as our population ages, and the hope is we can cure lymphoma, and in some cases now we can and hopefully that will happen much more often. But if we can't, then we can control it and allow people to lead relatively normal lives and do that with medicines that are not particularly toxic, that there are few if any side effects. Well, there's a lot of research going on, and one of the people who is very much involved in it at the Seattle Cancer Care Alliance is Ajay Gopal. He is associate professor at the University of Washington. He's an associate member of the Fred Hutchinson Cancer Research Center and a lymphoma specialist at the Seattle Cancer Care Alliance. Dr. Gopal, are you encouraged in the direction of where research is headed and its benefit for patients? Latest Therapies for Lymphoma I'm very excited. This is a very exciting time for new therapies and improving outcomes for patients with lymphomas, both Hodgkin's and non-hodgkin's lymphomas. And before I go further I would just like to thank you, Andrew, for the invitation to speak with you today. Thank you so much, sir. So let's talk about it. Related to cancer, it's often trying to figure out how different approaches or different medicines can work together. Now, you've done a lot of work on that lately. For instance one of the drugs for non-hodgkin's lymphoma now for a number of years, and I received it as a leukemia patient too, was Rituxan or rituximab. Are we finding ways in your 1

research that maybe there can be improved results layered on top of rituximab, and, if so, with what? A number of investigators including those at our center have tried to find ways to improve how well Rituxan works. One advantage of Rituxan is that the side effects are very mild, but unfortunately not everybody who receives rituximab goes into a complete remission, and the remissions may not last indefinitely. So one hope we have in the long run is that for those that have the slow-growing lymphomas that are often very difficult to cure with chemotherapy maybe we can rethink our strategy in treating these lymphomas, and think about a way to control them over the long term with minimal side effects. Along those lines we looked at a number of drugs that were related to vitamin A, and one particular drug that we showed in the laboratory to have significant antilymphoma activity is a drug called fenretinide. This is a drug that actually is provided by the National Cancer Institute, and when we looked at it in combination with rituximab in the laboratory we found that it dramatically enhanced the antitumor activity of rituximab. All right. Let me see if I can understand that. So this is what you call a synergistic effect, right? That's what it appears to be. Combining Drugs for Better Outcomes So this is common in medical oncology, isn't it, and that is you have drug A and drug B, sometimes--as I received--drug C, and they try to target the cell in different ways, and that produces more of a cancer cell kill, I guess? Well, that's what we hoped would happen with sort of one plus one equals three, that you get more out of putting drugs together than you would giving them by themselves, and that's what we appear to see in the laboratory with these drugs, fenretinide and Rituxan. All right. Where are we with that research? So for instance if somebody comes to the Seattle Cancer Care Alliance might they be part of a non-hodgkin's lymphoma trial where that synergistic combination might be offered to them? That trial is currently open. We actually have a clinical trial using fenretinide, which is a pill, and it really has very moderate toxicities, combined with rituximab, which 2

is given intermittently. And that trial is open to patients with relapsed non-hodgkin's lymphoma, and the idea is can we control this lymphoma for the long term by simply taking pills, which have very moderate side effects and intermittent doses of rituximab. At the present time we certainly have folks that have been on this therapy without disease progression now for beyond two years, but I must just cautiously say that it's early on, and we are looking hopefully towards the future to see the results from this study. Now, I know your dream as a researcher is if you can't cure it could somebody take a simple oral medicine with low side effects and just go on with their life. That's right. For example, for more common diseases like hypertension we don't actually cure hypertension but we can treat it. Or high cholesterol is easily treated by taking a medication, and if it's adequately treated then it doesn't cause anyone any long-term problems. We can envision that for some lymphomas and for some cancers in general that maybe this chronic approach of controlling the cancer and not making the patient sick and not having the cancer impact their quality or quantity of life could be achieved. Doctor, we've mentioned Rituxan, and I received it for my leukemia treatment, so it's widely used and it's been used by tens of thousands, hundreds of thousands of patients. When we're talking about treating lymphoma now, is there anything about Rituxan where there's new thinking going on that if it continues to circulate in the blood besides the cancer it's killed it makes it more difficult to kill other cells? That's a very good point, Andrew. Rituxan, as you know, is a monoclonal antibody, which is essentially an immune protein that targets a specific target on the surface of lymphoma cells called CD20. And this drug has shown that it's improved survival in many different kinds of lymphomas. But unfortunately not everybody stays in remission indefinitely after Rituxan therapy, and there are many other therapies that are either approved or in development that also target CD20. One question that we raised was that if there's lots of this Rituxan around would it cover up the target of other anti-cd20 antibodies, and I must say even though this is a controversial topic data from our laboratory does suggest that there is some competition between Rituxan blocking the target of other antibodies that we would want to go and stick on and kill lymphoma cells. Let me see if I understand that. So there are these proteins on the cells' surface and unique, let's say, to lymphoma cells, so that's what you want to home in on. That's right. 3

All right. So Rituxan targets CD20, and there are other drugs I believe that do that too, and then it's also circulating in the body. So you're saying that at some point if somebody relapsed that kind of circulating effect could get in the way of treatment? It could. At least in the preclinical studies that we have performed in the laboratory it looks like if there's lots of rituximab around and then you again try to treat a lymphoma with an antibody that targets that same CD20 that Rituxan targets it's not as effective as if you did not have Rituxan around. All right. So are you coming up with any kind of medicine that maybe can get around that? There are probably a lot of different ways to deal with this, but one approach that we have looked at here is to simply look for another target, a target that's not interfered with by Rituxan. And that target that we're focusing on in our studies is a protein on the surface of cells called CD45. And we do have a clinical trial that targets this CD45 and uses the antibody to target the radiation preferentially to tumor cells. Radioimmunotherapy for Treating Lymphoma Let's talk about radiation. So you all have been very involved, and I've spoken with your colleague Oliver Press there about it, radioimmunotherapy, or RIT. Tell us about what radioimmunotherapy is and some of your recent research in it as it could be helpful in lymphoma. Radioimmunotherapy is a way to target radiation to many sites of lymphoma in the body. What we know about radiation is that actually radiation is probably the single most effective therapy for treating lymphoma and actually many other cancers. The trouble is it's not safe to give radiation in sufficient doses if there are many sites in the body where lymphoma is located. Radioimmunotherapy allows us to get around that problem by attaching radioactivity to an antibody, much like Rituxan, which is given intravenously and then circulates around the body and specifically targets and attaches to tumor cells and radiates to tumor cells. All right. So tell me how this might be helpful and particularly for some populations where maybe more aggressive treatment hasn't been offered. 4

Well, you bring up a good point. Our particular focus with radioimmunotherapy has been the use in stem cell transplants. Stem cell transplants we know for many lymphomas can be curative for those who have had relapse after their initial therapy, and historically these therapies have been denied for adults over the age of 60 or 65 because there is a concern that it may be too toxic to give high-dose chemotherapy. Unfortunately, by excluding adults over the age of 60 or 65 we're excluding about half of the people with lymphoma. So that means that half of the people that need this therapy historically have not been able to get it. So what we have tried to do with radioimmunotherapy is because it's targeted, because it delivers radiation to the tumor sites more than the normal organs it is much lower toxicity. And we've recently published a study showing that we can safely give this in very high doses to adults over the age of 60 with really no treatment-related deaths, much lower toxicity even than in the chemotherapy they had as part of their earlier therapy for lymphoma, and we've treated patients well into their 70s with this strategy. So the idea is that the radioimmunotherapy helps very effectively prepare someone for transplant? Well, the radioimmunotherapy actually is the antitumor part of the therapy, so the very high doses of radiation that we can focus on tumor sites with radioimmunotherapy allows patients to go into prolonged remissions. Now, we do have to give a transplant because the main side effect of high doses of radiation is that the blood counts are low and the bone marrow is ablated, so we have to give them their own stem cells back to rescue them from the radioimmunotherapy. It's still a stem cell transplant. It's just that all the other toxicities like lung toxicity, liver toxicity, sore mouth, known as mucositis, doesn't typically occur when we use high doses of radioimmunotherapy. Is that what's happening now is that transplant with these different approaches is being made available to a wider age group of people and maybe people in poor health? That's true. I think as the population ages, as we recognize that this is a group of patients that we have denied therapy, many groups, including our own, have focused on ways to safely provide transplant to adults in their 60s and 70s and sometimes even beyond. Well, we have a lot more to talk about. We're going to continue our discussion on really targeting the tumor in lymphoma for better results and the tools that are available in the lab emerging, and standard therapy too, as we continue our 5

discussion in just a minute with Dr. Ajay Gopal from the Seattle Cancer Care Alliance. We'll be right back with much more on Patient Power. Welcome back to Patient Power. I'm Andrew Schorr. We're visiting with Dr. Ajay Gopal, who is a lymphoma specialist at the Seattle Cancer Care Alliance. We've been hearing about exciting research and really state-of-the-art care for lymphoma at the Seattle Cancer Care Alliance. So, Doctor, we talked about the expanding availability of treatments like transplant for people who need it and ways of preparing people for that that can spare them some of the toxicities and side effects of that. So you talked about you being very hopeful. Let's talk about other kinds of lymphoma beyond non-hodgkin's lymphoma. Some people, I know it's much less common, end up with T-cell lymphoma. What can you do there now that may be encouraging? There are a number of new drugs for T-cell lymphoma. Studies carried out at our center, participated by at our center including actually one of my colleagues here, Dr. Andrei Stustov, is our local T-cell specialist. T-cell lymphomas are really somewhat of a rare type of lymphoma, and they are particularly hard to treat. Unfortunately, individuals with T-cell lymphomas are much less likely to get into remission and to have long-term cures as compared to those with B-cell lymphomas. One of the problems maybe is that there are less targeted therapies developed for T-cell lymphomas, and we're trying to address that somewhat in terms of transplant approaches for T-cell lymphomas. All right. Now, related to Hodgkin's disease, that's different from, or Hodgkin's lymphoma, that's different, and I know not very common, often curable but sometimes it comes back for people. Where are we with that? Are there any new medications and trials or new approaches there? Again, there are a variety of new approaches for Hodgkin's lymphoma. I think one of the most exciting is a drug that is also an antibody therapy, and I think you'll see a theme here that many of these targeted therapies are really what's making a huge difference in treatments for lymphomas across the board. This particular one, we are one of several sites participating in a study of an anti-cd30877, this is a protein on Hodgkin's cell877, immunotherapy which targets an immunotoxin, which is actually something that's derived from a mollusk or related to something that's derived from a mollusk, specifically to the Hodgkin's cell, again with the idea that we could put somebody in remission with a targeted therapy that has low toxicity. So that's study is ongoing. It's actually an international study, and we're all very encouraged by the preliminary results from the prior studies. 6

So we talked about three proteins, I think, on various cancer cells. We talked about CD20, CD45, CD30. So the idea is that in any of these cases developing targeted medicines that home in on these cancer cells and try to spare healthy tissue. That's exactly right. Standard Therapy and Clinical Trials So that's been a very exciting development, and you've also talked about using medicines together. Now, you have to as a starting point know what is a patient's specific situation, and that involves imaging and pathology. Tell us about how that's done at the Seattle Cancer Care Alliance so you really know what you're dealing with. What sort of work-up might a new patient go through, a lymphoma patient, to clearly understand what either standard therapy or a clinical trial might have the best chance for them? So this is obviously a multifaceted approach, and we have really a team approach here. Certainly one has to have expert hematopathologists who can look at the biopsy and be sure we know what kind of lymphoma we're dealing with. There are at least, and even with broad classification, 20 different kinds of lymphoma, and they are often addressed very differently, so it's important at the very beginning to make sure you have the right individuals to make the proper diagnosis. Beyond that patients will generally meet with a medical oncologist. We would discuss what we call staging, so, as you mentioned, usually CT scans, sometimes PET scans, bone marrow biopsies, sometimes even other tests like spinal taps or lumbar punctures, to really sort out where is the lymphoma located. And then we would sit down and review these tests and put together a treatment plan often proposing a clinical trial if the patient is interested. We try to have clinical trials that are available for most any situation, so if a patient is interested in participating in a new therapy and receiving something that's novel and promising they have that opportunity. Dr. Gopal, one of the things I'm sure you are asked about all the time, I know I ask my doctor, is there any way you can predict up front whether or not I'm going to be one of these people who receives a treatment but then relapses or it doesn't last long. Because some people, as you said, do very well for a long, long time, sometimes there are people where it almost appears they are cured and others where it comes back. 7

This is a major challenge, and I think it's a very important but often a difficult discussion to have. We have some bedside tools that we can use to give individuals an idea about whether they are more or less likely to go into long-term remission, and these are simple blood tests and staging and other factors that we can put into formulas to predict whether somebody has high-, low- or intermediate-risk disease. In fact some of this work has been done here in terms of applying these data to the transplant setting. I think in the future we are going to actually be much more sophisticated about this. We're going to know a lot more about the genes that are turned on or turned off in various tumors and be able to use those not only to predict how well folks will do in the long run but I think to design specific drugs to turn off the gene that might be causing a problem. There are pilot data looking at this and showing this can be done, but it's not quite ready for prime time yet. Transplants for Lymphomas Dr. Gopal, so transplant started in Seattle, and that remains part of the treatment options that are used in different cancers at Fred Hutchinson and Seattle Cancer Care Alliance. In lymphoma you have drug therapies but you've mentioned transplant along the way. How do you decide when transplant, which is877, even with the preparatory therapies you talked about that can make it available for older people and sicker people, it's still a big deal. How do you decide when that is appropriate in lymphoma? That's a very good question. Of course we wish that no one would ever need a transplant. We're really striving to cure people the first time around and not have a need for transplant. But if lymphoma comes back or if it doesn't respond to the initial therapy we sit down with patients, and we talk about the options, and in some lymphomas in some situations there's very strong data saying transplant is absolutely clearly the best thing. In other situations it becomes an option but it may not be the only option, and then we try to have these discussions to present the pros and cons of various approaches. But transplant, it's nice to know that that option is there when we get into difficult situations in treating lymphomas, and it can in even very difficult situations result in long-term remissions. Now, are these transplants in lymphoma typically when you're giving someone their own cells back, or would it be from a donor? More commonly transplants in lymphoma are done by giving someone one's own cells back, but we do do quite a few transplants, the so-called allogeneic transplants877, cells from someone else877, for lymphomas as well if lymphoma comes back after they get a transplant with their own cells. 8

So there could be a so-called double transplant. There could be. There could be another transplant if the transplant using one's own cells was not successful for the long term. There's one other therapeutic approach that we haven't talked about yet but has been talked about over a number of years but had been seen not ready for prime time yet, and that is so-called sort of anticancer vaccine or immunotherapy vaccine. Now, with one of your colleagues in prostate cancer we talked about encouraging results in advanced prostate cancer for a vaccine, and that was sort of the first time now some very positive news has been coming out. What about in lymphoma? Where does it stand? Vaccine therapy has really been a longstanding goal in lymphoma as well. In fact many years ago studies were done showing that patients who responded to a vaccine that was generated from their own tumor cells actually had longer remissions than those who didn't. But the question always was, did they have longer remissions because of the vaccine or did they have longer remissions because they just happened to have better immune systems that could respond to the vaccine. So to some degree this question has been answered at least in one recent clinical trial that was presented at the recent American Society of Clinical Oncology meeting, where patients where randomly assigned to either receive the vaccine or placebo after receiving their initial chemotherapy. And in this trial at least there did appear to be an improvement in remission for those that received the vaccine by about a year compared to those that did not receive the vaccine. So this is the first large study that has suggested in a clear benefit of receiving the vaccine as compared to those that did not. So does that mean maybe there will be another approach as well that can be added to these others you mentioned earlier? Right. I think what we need to find is the right cocktail, the right combination of therapies so we're not overtreating patients. We certainly don't want to say everyone should get a transplant off the bat, which would be probably clear-cut overtreatment, but we also don't want to under treat patients. And if we can understand the right sweet spot to give the best therapy to patients that has the minimum side effects and the best chance of long-term survival and remission, I think we will have achieved our goal. 9

When I talk to an oncology specialist such as yourself I always marvel that happily the increasing number of tools you have, the complexity of the illnesses, all these different subtypes as you've mentioned, and also the idea of combination therapy or even different therapeutic approaches used together or in sequence, the combinations are complex, and it really makes me think of this specialization and the art of medicine, how do you figure out who needs what, when, and what that range of treatments used together or one after another is. It's got to be quite a math problem, if you will. It can be quite complicated. I would like to think that we make most of our decisions based on data, based on studies that say therapy A is better than therapy B or A plus B is better than C plus D, but many times those data are lacking, and it really just comes down to one's interpretation of incomplete data and clinical experience. Consulting with your Doctor All right. Well, that brings me to people coming to the SCCA for treatment whether from near or from afar or coming for a second opinion because there may be a doctor closer to home who is not particularly a lymphoma specialist or not involved in some of the research. Are you open to people coming for consultations because of the complexity of the situation they may be facing? We see many patients for consultations, and we actually work with patients' local physicians, both as part of standard care but also as part of clinical trials. So we do have a broad network known as the Puget Sound Oncology Consortium, and more recently the Seattle Cancer Care Alliance network, where patients that want to be a part of clinical trials in many situations can actually be treated with their local oncologist on the clinical trial. So we see many patients for so-called second opinions, but we also can participate in their care even if they're getting much of their care at home. Now, you mention about lymphoma recurring or remission ending, relapsing, and that can be very discouraging to someone. But it sounds like it's not the point to give up hope. Absolutely not. There are so many therapies. Even just looking back over the last five years when I sit down with patients and I say five years ago I would have a list of three or four choices and now the list is ten, it gets to the point you made before that it can be confusing as to which choice to choose, but it's certainly better to have choices that one has to think about than to not have choices. There are many options now for lymphoma therapy. 10

Doctor, I know we clearly don't know what causes lymphoma, although I know in some areas of lymphoma there's a question whether certain chemical exposures were at work, but certainly in breast cancer, ovarian cancer and in some cases, for the minority of cases but still significant, there are genes that have been identified. Do we have any clue about any genetic connection and a family connection? There is some familiarity to lymphoma. There is a somewhat higher risk of having lymphoma if a family member has lymphoma, but as you mentioned it really is not as highly associated as in other cancers and certainly not at a level where we have identified a specific gene or genetic defect that can be passed along to other generations. The question that always comes up is does somebody have a higher rate of lymphoma within a family because of the genetics or is it because they grew up in the same area and had the same exposures, and I think that's still an unanswered question since there's data to suggest that exposures as you mentioned, pesticides, are associated with higher rates of lymphoma. So it's a little bit murkier in lymphoma than it is in other cancers. Well, to be sure, as the population ages, because one of the risk factors for lymphoma is aging, we may see more, but our hope is with your research, your colleagues here and around the world you can have a better way to cure it, and if not cure it control it. And I was delighted to hear you're optimistic, right? I'm very excited. It's really a very exciting time in lymphoma therapy. Certainly, the horizon is still far in the distance, but we have so many more options now that are less toxic and more effective than we had even just a few short years ago. All right. Well, we wish you well for your research and thank you so much for your dedication to lymphoma patients. Dr. Ajay Gopal, who is an associate professor at the University of Washington, a medical oncologist. He's an associate member at the Fred Hutchinson Cancer Research Center and a lymphoma specialist at the Seattle Cancer Care Alliance. You've been listening to Patient Power brought to you by the Seattle Cancer Care Alliance. I'm Andrew Schorr. Remember, knowledge can be the best medicine of all. Please remember the opinions expressed on Patient Power are not necessarily the views of Seattle Cancer Care Alliance, its medical staff or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That s how you ll get care that s most appropriate for you. 11