This coverage is supported by an educational grant from
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
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
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
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
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
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