Presented at the Radioimmunotherapy of Non-Hodgkin's Lymphoma symposium held at the American Society of Hematology 42nd Annual Meeting, December 1, 2000, in San Francisco, California.

Question: Dr. Gordon: Brian, I noticed on one of your slides that the response rate to Rituxan was higher in patients that had had a previous transplant. Do you have any thoughts about why that may be the case, or does that give you some ideas about what to do post-transplant with Rituxan?

Answer: Dr. Link: In the so-called large Phase II pivotal study, there were 23 patients who had previously had autologous bone marrow transplant for their relapsed lymphoma. In that subset of patients, 78% achieved overall response. We assumed it was a quirk of observation. However, it has been noted by other series of investigations as well, so it appears to be a consistent observation. But the short answer to your questions is: I have not heard any satisfying explanation, and I'm not even sure I've heard very many satisfying hypotheses as to why it may be.

Answer: Dr. Cheson: I'm not sure it's specific for the antibody either. In the experience at our institution in patients with Hodgkin's disease who failed autologous stem cell transplant, they had an amazingly high response to vinblastine, much higher than you would have expected in any other setting, like 50-60%.

Answer: Dr. Gordon: I think Tom raised the issue of secondary leukemia in the Zevalin studies, and also in the Bexxar studies. Since the one patient that you described was ours, I think I can give you a little bit more data which are interesting. This is someone who had had a couple of other therapies and developed an 11Q2.3 acute leukemia within a year following Zevalin therapy. Since we had bone marrow prior to the Zevalin, we had the opportunity to look for the 11Q2.3, and it wasn't there. These are data I think we're going to have to pay attention to as we start introducing new therapies into the treatment of lymphoma.

Answer: Dr. Cheson: If you look at the Bexxar data that Kaminski just updated a few months ago, many of the patients who developed a secondary MDS/AML did have prior cytogenetic abnormalities. So, I think it's not an all or nothing. I think some will and some won't.

Question: Audience Member: Are there any hypotheses about the mechanism of resistance to the radioimmunoconjugates?

Answer: Dr. Wiseman: Some of these patients may have had prior radiotherapy, and so that may have induced some resistance, but I think that most of the patients we see in these trials have not. They have been patients with more advanced stage disease that had prior chemotherapy, and I think it's more of a problem of delivery of the radioisotope. I think that if you can get enough of the radioisotope there that you can see a response. But there are times when, in larger masses, the antibody is not getting into the center of the tumor.

Question: Audience Member: Are there any antibody therapies being developed for Hodgkin's disease?

Answer: Dr. Cheson: Yes, there are a number of antibodies being developed for Hodgkin's disease. There is a radioimmunoconjugate, the anti-ferritin, which has had sort of a checkered history. There was also a bi-specific monoclonal. Now there's a HEFA, which is an anti-CD30 monoclonal that has been on the shelf at the NCI for a number of years and is now being humanized in anticipation of clinical trials. And rituximab has a significant response rate in those patients with Hodgkin's disease who are CD20+.

Question: Audience Member: Conceptually, there is a potential advantage for having a moderate amount of tumor available to have a clustering of the radioisotope effect to maximize your advantage for the crossfire. I was curious if there were any good models that would predict what an optimal size tumor might be to take advantage of the added radioimmunoconjugate. I was also curious to know if you have gone back and looked at the difference in patients who had large tumors vs. the patients who had small tumor burden. Was the difference between the radioimmunoconjugate and the unlabeled antibody more evident in one group over another?

Answer: Dr. Wiseman: Theoretically, you're getting a better response if you have a larger tumor, especially with the longer pathlength of beta-emitters on the mathematical model. If there's just a single cell binding the antibody, much of the radiation that would be delivered by that antibody would not be received by the cell to which it was bound.

Question: Audience Member: So then, how would we reconcile that with our instincts to use immunotherapy as mop-up or adjuvant after maximum de-bulking with chemotherapy?

Answer: Dr. Cheson: That was the initial instinct we had – minimal residual disease and then clean it up. I think we're learning more and more that the antibody sensitizes tumor cells to chemotherapy. In a number of studies that aren't published yet, there appear to be higher response rates when the antibody is given first, followed by the chemotherapy. You can infer that, for example, from the Czuczman CHOP-rituximab study. I expect you'll get much higher results with that than you would with CHOP first and antibody later. Therefore, the way to do these may be to have one antibody there first and then to do clean-up with another kind of antibody. But we have to learn which is best in each one of those indications; maybe better to have rituximab there first and then clean it up with a radioimmunoconjugate. Those are the kind of trials that need to be done.

Answer: Dr. Gordon: If you look at radioimmunotherapy as a mop-up, there is some concern about toxicity to normal organs if you don't have a tumor sink there to take up the radioimmunoconjugate. So, I think that needs to be looked at as we design new trials.

Answer: Dr. Cheson: The Europeans are embarking on a study of chemotherapy for indolent lymphomas, and whether you get a maximum response randomizing to a radioimmunoconjugate, I guess it would have to be Zevalin over there, vs. no further therapy. So, we may find out how toxic it is, by letting the Europeans find out for us.

Answer: Dr. Wiseman: I think you're potentially going to have a different bio-distribution; that you're going to have less taken up by the tumor if there is a smaller amount of tumor present. That's going to allow a longer time in circulation, which may give more radiation to bone marrow. On the other hand, part of the dose to the bone marrow comes from the marrow being involved by lymphoma, and if you had a minimal residual disease you would end up with less radiation. So, I think it's something that requires a careful look, and maybe even a different dosing scheme compared to patients with bulkier disease.

Question: Audience Member: There are data with Bexxar on re-treatment. Are we going to see some data using re-treatment with Zevalin?

Answer: Dr. Witzig: There are no data yet. We have a trial that is going to give patients two sequential doses about four months apart. We're going to be doing the indium imaging, so I think we'll be able to answer the question of how they image the second time, and what the toxicity is.

Question: Audience Member: Do you think it would be an advantage to combine different modalities in a single molecule? For example, to have the human FC to give complement fixation and ADCC along with the radioimmunoconjugate? Are there any plans to use radiolabelled rituximab? You said that the reason you'd shied away from it initially was its long half-life, but is that still something you see as a problem after these Phase I and II studies?

Answer: Dr. Gordon: I think it's unlikely that we'll see a change in the molecule. I think that if we were using the Rituxan, the chimeric antibody linked to the yttrium, it would not be as much of a problem as people thought it was going to be several years ago. But I doubt that we're going to go back to that.

Answer: Dr. Wiseman: The one difference between the unlabeled antibody and the labeled antibody was that you're really using the labeled antibody to deliver the radiation to the cell. I think the FC portion becomes less important in that situation, unless you're going to have the radiation be delivered and then have the FC portion there to somehow be involved in the ADCC. What is best for the unlabeled antibody would be a long circulation and active immunoglobulin for the antibody molecule. For the radioimmunotherapy, you prefer a shorter circulation time to avoid the radiation to the marrow and you're looking at the best molecule to penetrate and bring that radiation into the tumor. I think they are two different strategies and, although combining them may be interesting, you might run into the problem that one strategy might be in opposition to the other.

Answer: Dr. Link: And it's also important to recognize that the unlabeled chimeric protein is given along with the murine labeled protein. So, in theory, you could take advantage of both biologic effects, if in fact they exist clinically.

Question: Audience Member: I have a question about the second malignancies, myelodysplasias, and so on. I wonder, with a low dose of radiation, whether that would be responsible or if the patients had had prior alkylating agents or etoposide.

Answer: Dr. Gordon: No, actually that's what is interesting. That patient had only chlorambucil on two separate occasions; no adriamycin, no etoposide, no growth factor, and no transplant.

Question: Audience Member: Was the response rate higher with Zevalin or Rituxan after transplant?

Answer: Dr. Cheson: Rituxan.

Question: Audience Member: There seems to be a growing body of evidence that there's a benefit conveyed by radioimmunotherapy relative to, say, naked antibody. What will it take before radioimmunotherapy is considered an alternative to Rituxan as opposed to a follow-up, assuming that you get better responses and better response durations, particularly in younger patients whose immune systems may be able to tolerate the radioimmunotherapy better?

Answer: Dr. Cheson: Well, since you don't get a longer response duration in Tom's study, it's going to take a lot more than response rate. You know, we've been fooled for decades getting higher response rates in follicular lymphomas and then not translating into prolonged survival. I think it's going to be hard not to use rituximab first, because you get a year with virtually no toxicity. You can give it over and over again; you can give chemotherapy after that. I think that for all intents and purposes, I'd probably use it after I used an unconjugated antibody.

Question: Audience Member: If I had a patient where I really felt I needed a response now, and Tom's data holds up, it would certainly seem to me logical to consider the more potent antibody, recognizing that we may or may not get more duration from it.

Answer: Dr. Witzig: The other thing that is interesting to remember is that the best responses that have been seen with these radiolabelled antibodies are in the context of a transplant. That's why I think we need to know whether people can get a second dose, because if you play the Zevalin card in a younger patient up front and then you can't give it to them later, that's going to also influence how you sequence things. If a person is 80 years old and you're not considering a transplant, you could give the Zevalin now. Those are the questions that need to be answered. But I think that, in the end, the best response rate may be in the context with transplant.