Cancer Answers: New Updates on Lymphoma, September 21, 2008

Dr. Francine Foss, New Updates on
Lymphoma September 21, 2008Welcome to Yale Cancer Center Answers with Dr. Ed Chu and
Dr. Ken Miller.  I am Bruce Barber.  Dr. Chu is Deputy
Director and Chief of Medical Oncology at Yale Cancer Center and
Dr. Miller is a Medical Oncologist specializing in pain and
palliative care, and he also serves as Director of the Connecticut
Challenge Survivorship Clinic.  If you would like to join the
discussion, you can contact the doctors directly at canceranswers@yale.edu
or1-888-234-4YCC.  This evening we welcome Dr.
Francine Foss.  Dr. Foss is a Professor of Medical Oncology at
Yale Cancer Center and an internationally known expert in the
treatment of lymphoma.Foss
 Most lymphomas are divided into Hodgkin and non-Hodgkin. 
There are about 8,500 Hodgkin lymphoma cases per year in the United
States, as opposed to non-Hodgkin lymphomas, which are the majority
of cases.  Most of those are B-Cell lymphomas. If you look at
all non-Hodgkin lymphomas, 85% of them are of the B-cell type, and
only a small minority, 15 %, are T-cell lymphomas.  However,
if you look overall at the number of lymphomas in the United
States, T-cell lymphomas are about 9000 cases as opposed to
Hodgkin, which is 8500 cases. You hear more about Hodgkin disease
than you do about T-Cell lymphoma.Miller
 I am really glad you brought up the numbers because we think of
Hodgkin's in a very prominent way, perhaps because this was one of
the first types of lymphoma that was cured.Foss
 That is right, Hodgkin's disease was cured in Stanford with
radiation and chemotherapy, called MOPP. There have been a lot of
therapies directed at Hodgkin lymphoma and now at non-Hodgkin
B-cell lymphomas.  There are a lot of new therapies that
target B-cells, however, T-cells have only recently been recognized
and only recently have we had good therapies for these
patients.Miller
 Because T-cell is less common than B-cell lymphoma, how did you
get involved?Foss
 I guess because I like to study rare and unusual things. I got
involved when I was back at the National Cancer Institute where we
had one of the first programs in T-cell lymphoma, and in fact, it
was at that program, at the NCI, that we first discovered the
HTLV-I virus, which is the virus that causes acute T-cell leukemia.
That was done by Dr. Bob Gallo, and at the time, we were looking at
other T-cell lymphomas to see if they had a virus as well, and so I
got involved very early on in those projects.Miller
 Along those lines, this issue of the viral cause of some cancers
is very important. What is your finding, are T-cell lymphomas
caused by a virus, what causes them?2:38 into mp3file 
http://www.yalecancercenter.org/podcast/Answers_Sept-21-08.mp3Foss
 We know that viruses can contribute to B-cell lymphoma, the EBV
virus being the most common type, but we can also see EBV virus in
various T-cell lymphomas as well.  We know that patients who
have hepatitis, for instance, can have a higher incidence of
lymphoma. We do find this HTLV-1 virus in T-cell lymphoma, but that
is fairly rare in the United States.  Other than that, we
really do not have any close connection between viruses and T-cell
lymphoma.Miller
 Lymphocytes, which are a form of white blood cells, have a certain
appearance under the microscope, can you tell the difference
between what is a T-cell and what is a B cell under the microscope,
how do you know the difference?Foss
 It is very difficult to tell and the only way that we can really
know the difference is using surface markers. These are proteins on
the surface of the cells that we have antibodies for.  We can
look under the microscope and we can tell whether the patient has a
T- or B-cell based on looking not only at one, but a whole panel of
markers. The other way we can do it is by looking at the genes
themselves.  We look for the T-cell receptor, T-cell
lymphomas, or the immunoglobulin heavy chain for B-cell
lymphomas.Miller
 With T-cell lymphoma, there is a wide spectrum of how it presents,
sometimes it sounds like it is a skin disease, other times a blood
disease, can you lay that out for us a little bit?Foss
 T-cell lymphomas are what I call, the promiscuous lymphoma,
because they can occur in a number of different parts of the body
and they can also masquerade as other diseases.  It is not
uncommon for us to see patients that have been misdiagnosed with
autoimmune diseases like arthritis or lupus. Some patients have had
hemolytic anemia of unclear etiology, and some patients come in
with a fever that they have had for weeks or months.  Often
times it is difficult for the primary care doctor to diagnose
T-cell lymphoma because in its earliest stages, it can be very
difficult to find. It is only after these symptoms have manifested
themselves for weeks or months that we are actually able to make
that diagnosis. In cases that I see sometimes the pathologist will
tell me that the diagnosis is very tricky. I think that is an
important thing for patients to remember because if you do have one
of these lymphomas and you have had these symptoms for weeks or
months, it is not necessarily that your doctors made a
mistake.  The disease itself likes to masquerade itself as
other things.Miller
 If you have a patient with T-cell lymphoma affecting the skin,
what might you see when you examine that patient?5:14 into mp3file 
http://www.yalecancercenter.org/podcast/Answers_Sept-21-08.mp3Foss
 A lot of T-cell lymphomas like the skin because of the
characteristics of the cells that make them like to live in the
skin, but it is important to remember that even though they are in
the skin, they are also possibly in other areas of your body. You
cannot trick yourself into thinking that just by treating that skin
nodule you are going to get rid of the disease.  We do not
understand why they like to go the skin, but if you look at all
lymphomas that present in the skin, about 80% of them are T-cell
lymphomas.  There are some B-cell lymphomas that can also do
this, and it is important to remember that.Miller
 Is it a rash?Foss
 Well, usually they present as nodules or lumps, but they also can
present as a rash.  They can look like eczema, psoriasis, or
an insect bite.  In some cases, we have people that come in
with a rash that looks like Lyme disease, but it was biopsied and
it was shown to be lymphoma.Miller
 Interesting, you said two points which I think are really
fascinating, one is, promiscuous lymphoma, and the second is that
it masquerades.  Those are important things to remember. 
We had an e-mail question from Marsha who lives in Longmeadow,
Massachusetts.  She writes, "My father had non- Hodgkin
disease, and then T-cell lymphoma, is this genetic and do I have to
worry about my children?"Foss
 We do not have a lot of good information to support that these
lymphomas are genetic, and in fact, we do have some evidence to
support the fact that there are environmental factors that
contribute to getting these lymphomas.  The only hint we have
about a potential genetic predilection is that there has been work
done here at Yale as part of an international effort to look at
various genes in patients to see whether any of those genes predict
whether the patient is ever going to develop a lymphoma in their
life. We have actually picked out a panel of genes that predicts
for T-cell lymphoma.  This work is being done by Dr. Yawei
Zhang in the Epidemiology Department at Yale, and in fact, by
looking at these panels of genes, we can start looking at family
members to see if there might potentially be a risk in the family,
but at this point we really do not feel that these lymphomas by and
large are genetic.Miller
 If we have project 10-20 years into the future, if you know what
genes may predict, how might that help you and help patients,
eventually?Foss
 There are two factors here, there is the biological factor and
then there is the environment that we all encounter everyday with
all of the various chemicals, toxins, and radiation. Many of us in
the lymphoma field feel that there is a contribution of
environmental toxins and the way the body responds to those. 
For instance, if we know that you have a pattern of genes that
makes it harder7:58 into mp3file 
http://www.yalecancercenter.org/podcast/Answers_Sept-21-08.mp3
 for you to repair DNA damage by these chemicals, for instance,
then one might think about a prophylactic or preventive program,
using antioxidants or other substances that might help to protect
your DNA.  The same way that we think about patients with
familial colon cancer and familial breast cancer, we know that we
need to look in other target organs for other cancers that are
associated with those family cancers.Miller
 Let me ask you, along those lines, one of my cousins has Celiac
disease, or sprue, which is a bowel disorder. In that case,
does a careful diet reduce his risk of developing lymphoma?Foss
 It is unclear, but I think most of us feel that because the
disease is stimulated by the gluten in the diet, the more of that
gluten that your body is exposed to, the more of those T-cells are
going to be reacting against it and eventually, if you have
lymphocytes, be they T- or B cells that continue to react against a
foreign toxin or an antigen, then eventually you are going to
select out a clone of cells that will develop into a
lymphoma.  So, I think the answer is yes.  If we are
careful about exposure, perhaps we can prevent some of these
cancers.Miller
 Let me ask, this is not quite T-cells as much as maybe, B-cell,
but the bacteria in the stomach, H pylori, is a fascinating
story.  How is that associated with non-Hodgkin lymphoma and
can you cure lymphoma by giving antibiotics?Foss
 Well, that has been a really interesting story for those of us in
the lymphoma field because what we have learned is that this
bacteria infection in the stomach essentially acts like a foreign
antigen and it stimulates an immune response, in this case, of the
B-cells, and what happens with that infection sitting there for
weeks, months, or years, is that the body develops a very brisk
reaction and you develop a clonal proliferation of B cells, which
is our definition of B-cell lymphoma.  We know that treating
that infection with antibiotics and medications that suppress the
acid in the stomach actually can cure patients without giving them
chemotherapy or radiation.  That is really fascinating and has
got us thinking a lot about some other things that we are exposed
to in our environment. In fact, you can extrapolate from that to
look at some of these lymphomas that actually spontaneously
regress.  We have seen T-cell and B cell lymphomas that go
away without us doing anything, and perhaps that represents taking
away some stimulus for the lymphoma that we do not even know about
yet.Miller
 Along those lines, you see so many patients with this unusual,
maybe not unusual, but with this specific type of lymphoma. Any
stories that you can remember in terms of patients where you saw
regression, without chemotherapy?10:44 into mp3file 
http://www.yalecancercenter.org/podcast/Answers_Sept-21-08.mp3Foss  
              
 There was a very interesting story about an elderly Italian
gentleman who came in with this huge mass on his scalp.  It
started as a little tiny nodule and got bigger and bigger over
about 4 to 5 months, such that it almost covered the entire
scalp.  He came in to see us and he had a biopsy that showed
aggressive T-cell lymphoma, a very aggressive form under the
microscope, and so we quickly rushed him to get his CAT scans and
his bone marrow biopsy and get ready to give him
chemotherapy.  Well, low and behold, two weeks later when he
came in after getting all these scans done, the lesion looked like
it had shrunk down by about 50% and he had done absolutely nothing.
We decided to do the conservative thing, which is to wait another
couple of weeks to see what happened and low and behold, the lesion
completely disappeared and it has never come back again.Miller
 Wow.Foss
 That is an important lesson for us as doctors; we need to
carefully look at the whole situation and the whole patient before
we launch into any therapy.Miller
 That reminds me of one of my mentors years ago who used to say,
"Do you know why they call it the practice of medicine, because
we're just practicing."  Does that apply to you and what you
have learned?Foss
 I think that certainly applies to lymphoma, because with the
exception of the diffuse large B-cell lymphomas, there really is
not any specific treatment paradigm for these diseases.  If
you look at the low-grade B-cell lymphomas, there are five possible
treatments.  In fact, the NCCN guidelines, which are national
practice guidelines for cancer, do not give us a specific
recommendation. They tell us that there are five or six things that
you can do and which one you do for a patient really depends on the
patient and the doctor and a number of other factors that are
intangible. Miller
 We are going to come back to that in a couple of minutes. 
For now, we are going to take a break.  We encourage you to
please e-mail us if you have questions at www.canceranswers@yale.edu.Miller
 Francine, before we talk about the specific treatments, when you
see a new patient with a T-cell lymphoma, how do you make decisions
in terms of who needs to be treated, who does not, and what kind of
treatment to give, what is the process?Foss
 What we do is we carefully review the history, and of course the
biopsies, and in many cases we will ask for additional tissue so
that we can determine the subtype of T-cell lymphoma.  That is
very important because if you look at the new lymphoma
classification system, they have broken T-cell lymphoma up into
about 15 or 16 different subtypes, and all of those have slightly
different treatments.  The first important thing is making the
right diagnosis.  The second thing is looking at the overall
patient and how far the lymphoma has spread. We look in the blood
and in bone marrow, and we usually do CAT scans or PET scans. 
We put all of that information together and we take the general
health of the patient into consideration and then we decide whether
the patient should be treated with conventional chemotherapy,
radiation therapy, or whether they might be a candidate for one of
our investigational studies looking at new ways to approach T-cell
lymphoma.Miller
 Let me throw out a couple of case scenarios.  You do all the
tests, you do a thorough evaluation, and lastly, you find out of
there is a relatively young person, let's say 50 because I am
around that age, or little bit older, with early stage single
nodule on an area of the skin, how do you approach that?Foss
 If that is an aggressive T-cell lymphoma, then we may approach
that just by radiating the area, but we keep in the back of our
minds that these lymphomas do come back, and in many cases with
T-cell lymphoma they are not really curable, so we have to be very
careful about watching what is going to happen next.Miller
 And on the other side of the spectrum, a patient let's say who
presents with very advanced T-cell lymphoma with symptoms and with
enlarged lymph nodes, what is the general approach there?Foss
 We know that those patients need aggressive chemotherapy and in
many cases they need to have 4 or 5 chemotherapy drugs given at the
same time.  We also know that although half of those patients
will go into remission, many of them will relapse, so that is when
we start thinking about more aggressive approaches to potentially
cure these patients. That includes bone marrow15:42 into mp3file 
http://www.yalecancercenter.org/podcast/Answers_Sept-21-08.mp3transplantation, be it from you or from another donor. We like
to start thinking about that earlier rather than later in a disease
that we know is going to recur.  If we in fact have a family
donor, that would be the preferred approach for many of our
patients, but there are patients who are older, who have other
medical problems, or who do not have an identically matched donor,
and in that case, we need to think of more creative strategies for
them.Miller
 For those that are able to have a bone marrow transplant, what is
the advantage of that, what is the mechanism by which it works?Foss
 There are two types of bone marrow transplant. The autologous
transplant is where you give yourself back the cells, and the
allogeneic transplant is where you get the cells from somebody
else.  In the autologous transplant, we would like to take the
cells from you at a point where we think your disease is completely
in remission, and then we give you very high dose chemotherapy to
try to eradicate any residual tumor cells that are still hiding out
in the body. Then we give you your own stem cells back to
reconstitute your immune system. An autologous transplant is
super-duper chemotherapy, whereas the allogeneic transplant has a
completely different mechanism. With the allogeneic transplant we
are essentially getting rid of your own immune system using our
conditioning therapies, and then we are giving you back a new
immune system. We are giving you cells from somebody else and those
cells hopefully will be able to recognize your tumor cells and any
residual tumor cells left in your body and kill them. The
allogeneic transplant is really immunotherapy as opposed to the
autologous, which as I mentioned, is really super-duper
chemotherapy.Miller
 What are some antibodies for T-cell lymphoma?Foss
 Antibodies are very interesting and have completely changed the
way we treat lymphomas.  An antibody is a molecule that is
directed against a protein on the surface of a tumor cell.  In
the case of rituximab, for instance, rituximab for B-cell lymphoma
targets the CD20 protein, which is expressed on just about every
B-cell lymphoma.  These antibodies are part of the body's own
immune system and by binding these antibodies to the tumor cells,
it helps our immune system get rid of those tumor cells.  So,
we have rituximab for B-cell lymphoma and now we have got a number
of antibodies for T-cell lymphoma as well; including Campath which
is good not only for T-cell but also for other types of lymphoma.
Now we have some new unique and interesting ones that are still in
investigation; such as the antiCD4 antibody.Miller
 Along those lines, a lot of your research has been on a fusion
toxin that was8:23 into mp3file 
http://www.yalecancercenter.org/podcast/Answers_Sept-21-08.mp3one of the first FDA approved biological drugs for the treatment
of lymphoma.  Can you tell us the history of that and what it
is?Foss
 Just like an antibody would bind to a protein on the surface of a
tumor cell, a fusion toxin essentially does the same thing, but the
fusion toxin is armed with an element such as a toxin that can get
into that tumor cell and kill it; whereas the antibody by itself
really depends on the immune system to kill the cell.  Ontak
is a molecule that consists of interleukin 2, which binds to the
interleukin 2 receptor combined with diphtheria toxin, so that once
that molecule binds to the cell, the diphtheria toxin gets into
that tumor cell and it kills the cell.  So the IL-2 part of it
is a carrier; a way of delivery in that molecule specifically to
tumor cells that have the IL-2 receptor.Miller
 When the diphtheria toxin is, in a sense, delivered, almost like a
Trojan horse to the cancer cells, what happens then?Foss
 The diphtheria toxin is a very potent toxin and if you just get
one molecule into a cancer cell, it will kill that cell.  So,
it is a very, very effective way of killing cancer cells.Miller
 Is the diphtheria toxin delivered in normal cells?Foss
 The delivery of diphtheria toxin is very selective based on the
IL-2 part of that molecule. The IL-2 part will deliver it only to
cancer cells or cells that have the IL-2 receptor. In our body
there are only a few circulating T lymphocytes, normal ones, that
have the IL-2 receptor, otherwise, our normal tissues do not. Even
though those few normal T cells are targeted by the molecule, they
reconstitute themselves very quickly, so it really does not have
any major impact.Miller
 It sounds like a wonderful approach to treatment to be able to be
that selective.  We have an e-mail from Michael who lives in
Groton who is on the other side of the spectrum from the very
intense therapy. He said, "My uncle was just diagnosed with a
T-cell lymphoma and his doctors are recommending a watch and wait
approach. Is there a role for careful observation?"Foss
 I think there is definitely a role in B-cell lymphoma for watch
and wait; for the low-grade B-cell lymphomas.  In T-cell
lymphoma it really depends on the subtype.  Many of these
patients do need to go on to therapy, and the nice thing about
T-cell lymphoma is that we have a number of oral drugs that are
available now. For instance, we have an oral retinoid molecule
called Tagretin that is a derivative of vitamin A. We now have oral
HDAC inhibitors, and the one that was recently approved by the FDA
is called vorinostat, which is a biomodulator, and it works by
effecting the transcription of genes. So both21:08 into mp3file 
http://www.yalecancercenter.org/podcast/Answers_Sept-21-08.mp3Tagretin and Zolinza are biological oral therapies that do not
have a lot of side effects for patients. These are very nice drugs
to use in an early stage patient.Miller
 How does Tagretin, which is a form of vitamin A, work?Foss
 It is a form of vitamin A that is modified slightly, chemically,
so that it binds to cells. It affects the transcription of various
genes such as genes that turn on cancer cells, so if you can turn
off these genes that are driving those cancer cells to divide, then
you can essentially put the cancer in remission.Miller
 Francine, you are very active as an investigator, what clinical
trials are you working on?Foss
 We are working on a number of different clinical trials for T-cell
lymphoma.  One of the interests in our group is trying to
develop a new therapy for patients when they first come in. What we
have done is we have taken the conventional chemotherapy called
CHOP, and we have added the Ontak molecule to that.  So, we
are giving combined therapy with the biological agent in
chemotherapy when patients first come in, and we know that by doing
that about 90% of our patients will have a complete response, or a
very good response, to their chemotherapy.  We are also
working on a number of drugs that are important for patients who
fail chemotherapy, second line agents, and we have a couple of new
histone deacetylase inhibitors.  One of them is romidepsin,
and the other one is Belinostat, and these are slightly different
from each other but they both have very significant activity. 
In addition, we have worked with a couple of other new drugs such
as pralatrexate, which is a new derivative of methotrexate, a very
old drug.  Pralatrexate has a very high activity in T-cell
lymphoma and hopefully that drug will be FDA approved this
year.
  We are also looking at some new drugs that we think might be
active in T-cell lymphoma.  One of these drugs is called
chlofarabine and another one is called Treanda.
Treanda was another drug that was approved this
year for B-cell lymphoma and ultimately what we would like to do is
to develop an immunotherapy for T-cell lymphoma.  We are
working with some of the basic science groups at Yale to try to
hook up various kinds of immune effector genes to targeting genes
so that we can selectively get to those lymphomas cells and make
the immune system work in our favor.Miller
 One of the things you talked about was called HDAC, or histone
deacetylase inhibitors. On a very basic level, for me and for the
listeners as well, can you explain what histones and deacetylase
are?Foss
 Basically, if you look at our chromosomes, our genes are in
chromosomes and23:51 into mp3file 
http://www.yalecancercenter.org/podcast/Answers_Sept-21-08.mp3the chromosome consists not only of DNA, but also of proteins
called histones that keep that wound up in a tight coil.  We
want that DNA to be wound up in a coil most of the time because
coiling it up prevents the genes from being transcribed. We do not
want our chromosomes making all kinds of genes all the time that we
do not need, so the histones are kind of a protection to
essentially silence some of those genes. We can modify those
histones by acetylation and deacetylation, and that process
basically allows them to fall off the DNA and allows it to open up
so the genes can be transcribed.  We know if we look at tumor
cells versus normal cells there is a different pattern of
acetylation of those histones. If we actually treat tumor cells
with these histone deacetylase inhibitors, or HDAC inhibitors, we
can cause those histones to fall off the DNA and allow various
genes to be transcribed, and some of those genes are genes that are
going to turn off the tumor cell.  This is an important
process that we only recently learned about and I view this as a
biological therapy because we are modifying proteins that are
responsible for gene transcription in the cells.Miller
 I am going to ask you to make long-term predictions. What do you
see in oncology, 20-50 years from now? Will these diseases be
treated with chemotherapy as we know it now, or do you think there
will be more of these biologic approaches?Foss
 The field is really moving toward biological approaches and
targeted therapies. If you think about chemotherapies, by and
large, they kill all dividing cells, they are not specific. We have
learned from years and years of giving chemotherapy that is very
difficult to cure more patients this way.  We can put patients
in remission, but do we really cure more patients? There was
recently a summit where this was discussed on national TV, and a
Newsweek article followed up. The point that was made in that
article is that going down the same road with more chemotherapies
that look the same, is not really going to help us. Most people
feel that the future is in some of these novel agents like
antibodies, like the HDAC inhibitors, and some of these other new
targeted therapies that are targeting specific proteins or enzymes
that we know are important for tumor cells.Miller
 I read that Newsweek article as well and you know what, it was
sort of sobering and solemn in a way.  You are experienced
with treating non-Hodgkin lymphoma, do you feel pessimistic about
it or more optimistic? Where have we been and where we are
going?Foss
 I have been treating non-Hodgkin lymphoma now for almost 20 years.
I started out at the National Cancer Institute when we thought that
giving more chemotherapy was better.  We have evolved
considerably from that point and26:45 into mp3file 
http://www.yalecancercenter.org/podcast/Answers_Sept-21-08.mp3now what we are doing is taking a more holistic approach to the
whole disease.  We are looking at patients, and even if we
know that we may not be curing those patients, we have very good
drugs and very good strategies to keep their disease in remission
and improve their quality of life. That is one major direction that
we are going in.  Another direction is focusing more on
immunotherapies and thinking more about transplant and other
immunotherapy approaches for patients. Even though the initial
vaccine studies with B-cell lymphoma did not prove to be
successful, I think we learned a lot about giving vaccine therapy.
The next set of studies is hopefully going in a different direction
and will allow us to use immunotherapy more broadly.  I feel
very, very optimistic about the future.Miller
 I have to say, listening to you, I feel the same way.  As we
wrap it up, what is available for patients in terms of support
groups at Yale and other programs in the community?Foss
 Yale has a number of support groups for patients.  We have
lots of information available through our cancer line where
patients can get information about diseases, how to obtain a second
opinion, and also how to participate in our support groups.
Specifically for lymphoma and leukemia patients, there are a couple
of resources that you should know about.  The Leukemia and
Lymphoma Foundation has a website and a Connecticut office, and the
Lymphoma Foundation does as well. It is important to use these
resources.Miller
 Thank you Francine. This has been a wonderful session. 
Thanks for being with me.  For now, I would like to wish all
of you a safe and healthy week.If you have question for the doctors or would like to share
your comments, go to www.yalecancercenter.org,
where you can also subscribe to our podcast and find written
transcripts of past programs. Next week Ken Miller speaks with
Lucinda Hogarty, the program director for the Connecticut Cancer
Partnership.  I am Bruce Barber, and you are listening to the
WNPR Health Forum from Connecticut Public Radio.