Understanding Lymphoma

Dr. Francine Foss, Understanding Lymphoma
 March 21, 2010Welcome to Yale Cancer Center Answers with Drs. Ed Chu and
Francine Foss, I am Bruce Barber.  Dr. Chu is Deputy Director
and Chief of Medical Oncology at Yale Cancer Center and Dr. Foss is
a Professor of Medical Oncology and Dermatology specializing in the
treatment of lymphomas.  If you would like to join the
conversation you can contact the doctors directly.  The
address is canceranswers@yale.edu
andthe phone number is 1888-234-4YCC.  This evening
Ed welcomes his co-host Dr. Foss for a conversation about lymphoma.
 Here is Ed Chu.Chu
Francine, thanks so much for being on the other side of the
microphone this evening and being here to talk about your favorite
subject, which is lymphoma.Foss
 Thank you Ed, it's a pleasure to be able to talk about lymphoma,
particularly today when we have had a flurry of new drugs and a lot
of activity in terms of understanding the molecular basis of these
diseases.Chu
Absolutely and we certainly will get into that, but for our
listeners out there, let's start off with a general definition of
what lymphoma is.Foss
 Lymphoma is a malignancy of the white blood cells that comprise
the lymph nodes.  Lymph nodes, as you know, are part of our
immune system in our body.  There are multiple lymph nodes in
different parts of the body and in those lymph nodes there are
different types of cells, particularly T cells and B cells, and
then there are some other cells as well. There are three different
types of lymphomas all arising from these cells.  There are T
cell lymphomas, B cell lymphomas, and then Hodgkin's disease.Chu
In a show that we did, I think just a week ago, the topic was
colorectal cancer and you asked me how I got involved.  Let me
turn that question around to you and ask how you got involved, what
interested you about going into this field of lymphoma
research?Foss
 Well, I have always been interested in blood and diseases
involving the blood cells, and when I was back at the National
Cancer Institute I got very interested in the T cell lymphoma
program.  At that time that was one of two or three programs
in the Untied States that was focusing on T cell lymphoma and in
fact a lot of work that was done in the laboratory that I worked in
led to the development of a number of cell lines and led indirectly
to the identification of HIV and HTLV-1 in addition, so I got very
involved particularly in the potential viral origin of lymphomas at
that time.Chu
For some background information for our listeners, what age group
is typically at risk for developing lymphoma, how common is it?2:45 into mp3 file 
http://www.yalecancercenter.org/podcast/mar2110-cancer-answers-foss.mp3Foss             
 It's interesting, and I don't think most people out there are
aware of this, but if you look at the SEER data looking at the
incidence of cancers in the United States, non-Hodgkin's lymphoma
actually is the fifth most common cancer behind the solid tumors
like lung, colon, and bladder and the number of new cases in the
United States is actually increasing.  It's 74,490 cases as of
last year and that's gone up at least 10,000 from 2009.  In
addition, about a quarter of these patients, or 20,000 patients,
will go on to die every year of non-Hodgkin's lymphoma.  The
median age is 67, although the disease certainly does occur in very
young people, in children all the way up to the elderly.Chu
Francine, what do we know about the risk factors for developing
lymphoma?Foss
 That's an interesting question Ed, and it really requires a fairly
long answer, but I can summarize it by telling you that for many
patients the risk is unknown.  Most cases of non-Hodgkin's
lymphoma occur sporadically, however, we do know that certain
populations are at high risk and that includes people who are
immuno compromised for some reason, particularly because they have
had an organ transplant, like kidney transplant or liver transplant
and they have auto-immune diseases that require them to take immuno
suppressive medications. Also people who are infected with HIV or
who have the HTLV-1 virus and we now know that people who have
hepatitis C virus are also at an increased risk.  In addition,
we have the EBV virus that causes Mono that we are
all exposed to as young children and that can be a risk. Recently
we found an increased incidence of gastric cancers, lymphomas of
the stomach, in people who have H. pylori, which is essentially an
infection involving the stomach lining.  And then finally, we
always worry about occupational exposures because there has been a
connection between benzene, or chemicals, and Leukemia, and we also
have seen with the Agent Orange exposure during the Vietnam War, an
increase in the incidence of lymphomas in these populations. 
We then extrapolated that to look at people say in the Midwest
where they are exposed to a lot of herbicides and pesticides on
farms and we have seen an increased risk in that population as
well.Chu
There really are a wide number of different risks factors.Foss
 And one of the interesting things that Yale Cancer Center has been
pursuing over the last 10 or 15 years is looking at these
epidemiologic factors, and in fact, we have a very active group
here that performs studies looking at all of these different
factors and one of the things that actually came up, as you may
remember, is the connection between hair dye and the incidence of B
cell lymphomas.Chu
Francine, you mentioned a moment ago that we are seeing an
increased incidence of lymphoma, do we know why that's
happening?5:49 into mp3 file 
http://www.yalecancercenter.org/podcast/mar2110-cancer-answers-foss.mp3Foss 
            
 I think there are a number of reasons for that, one of which is
that we are using more of these immuno suppressive medications, we
are doing more organ transplant nowadays.  In addition, there
are a lot of people out there that are infected with Hepatitis C,
and with respect to the occupational exposures it's really hard to
get your hands around that.  Many people when you question
them don't really know what they are exposed to at work, but I
think obviously with increased pollution levels in the environment
in general, certainly we are all exposed to more chemicals that we
don't even know about.Chu
Lymphomas are a very broad term, there are obviously specific
subsets of lymphoma.  Can you tell us a little bit about
that?Foss
 There are different subsets based on the cell types, so I said B
cell, T cell, and Hodgkin's. That's a broad way to categorizes
lymphomas, but then within each of those different subsets there
are different subsets, so within the B cell lymphomas there are a
group of patients that have what we call low grade or indolent
lymphoma that can do very well for a long period of time, often
times without treatment, or if they do get treatments, it is very
low level, nontoxic types of approaches. On the flip side, there
are lymphomas that are very aggressive.  In the T-cell group
there are the cutaneous lymphomas that are indolent, again low
grade and slowly progressive, and then there are more aggressive T
cell lymphomas. And then within Hodgkin's disease there are a
number of different subtypes that have different outcomes. 
Primarily with Hodgkin's there are very early stage patients that
do very well with localized therapy or short course chemotherapy,
and then there are the more advanced stage patients that require
more aggressive approaches.Chu
How can one differentiate between these different subtypes of
lymphomas?Foss
 The histology and the pathology is critical in the diagnosis of
lymphoma. All the action is really under the microscope and we
depend on our colleagues in hematopathology to look at this tissue
and do a number of different special stains looking at specific
markers.  Over the last 5 or 6 years we have come a long way
in identifying and subtyping lymphomas based on the identification
of specific markers that identify a specific type, such as mantle
cell lymphoma, which is identified by the expression of the Cyclin
D1 gene.  In addition, we have various chromosomal
abnormalities that we can detect that help us to subtype these
different types of lymphomas.Chu
Are there any blood tests that can help the diagnosis of a
particular type of lymphoma?Foss
 The blood test does not necessarily help us in the diagnosis, but
it can actually detect the presence of lymphoma cells in the
blood.  So, while you think about lymphoma as occurring in the
lymph nodes primarily, these cells travel around from one lymph
node to other so they essentially all get in the blood at one point
or another, and using very sensitive techniques like flow cytometry
and8:53 into mp3 file 
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 gene rearrangement studies we can detect these small populations
of cells.  In certain types of lymphoma, as they become more
advanced, we see more of these lymphoma cells in the blood and I
will also mention that they can get into the liver, spleen, and the
bone marrow and the other parts of the body as well.Chu
All of us at some time or another have felt swollen lymph glands
that get tender.  When does one have to begin to worry that
this is more than an infection and something more serious?Foss
 That's one of the more common problems that the primary care
doctor faces, is patients coming in with swollen lymph nodes who
may or may not have symptoms.  Clearly if you have a runny
nose or a sore throat and you have lymph nodes in your neck, or if
you have a rash on your foot and you have a groin lymph node, it is
easy to explain why that lymph node is there.  In many cases
there will be a history, however, there are patients that do show
up with a lymph node without any evidence of an infection, and in
some of those cases there could have been an occult infection that
was missed and the lymph node will resolve over time, but in other
cases one has to worry about that node and so generally what I tell
people is if you have a lymph node that's been there for a month
and it's not getting any better, at least get it checked out.Chu
Are there any other symptoms that are typically associated with
lymphoma?Foss
 Just like with other kinds of cancers, many of our patients with
lymphoma come in without symptoms, particularly patients with low
grade lymphomas; however, when patients do get sick with lymphoma
the kind of symptoms that they experience could be things like
fevers and night sweats, which are drenching sweats at night. 
Patients could be fatigued related to the lymphoma or to anemia
that can develop from the lymphoma.  Patients can have bone
pain, they can have pain in their organs, and they can just feel
over all run down and sick, but like I said, many of our patients
come in asymptomatic because they noticed a lymph node that did not
go away.Chu
If anyone should experience any of these symptoms that you just
mentioned, what should they then do?Foss
 That's kind of a grey area again for the primary care doctor
because many of those symptoms could be seen in other
conditions.  Patients who are fatigued, run down, or have
other illnesses for instance, could have those symptoms.  And
so what needs to be done I think is a good physical exam and a
blood test.  A blood test does not always pick up lymphoma,
but there can be some hints there, for instance if the CBC, the
white count, the red count, or the platelets show abnormalities
that can certainly be an indicator, and if you look at the
chemistries, sometimes a marker called LDH is elevated in people
who have lymphoma, but I just want to let our listeners11:47 into mp3 file 
http://www.yalecancercenter.org/podcast/mar2110-cancer-answers-foss.mp3know that a number of patients with early stage lymphoma come in
with a completely normal set of blood tests.Chu
Should individuals seek out medical attention with their primary
care physician, general internist, when would they come to see a
specialist like yourself?Foss
            
 We are really depending on the general internist and the primary
care doctors to pick up these lymph nodes or symptoms that might be
suggestive of lymphoma, and often times patients will get sent to a
surgeon or a needle biopsy of the lymph node or a blood test will
show something abnormal before they come to see us, however, as a
lymphoma doctor, I will get patients directly sent to me by a
primary care doctor who has found a lymph node and will send the
patient to us to pursue the workup to make the decisions about what
kind of test needs to be done, for instance a needle biopsies
versus excisional biopsy of that node.Chu
We have talked about all of the different risk factors and there
are many, but what do you know about the genetics of lymphomas?Foss
 There are certain family syndromes where lymphomas can occur, and
interestingly in some of these families lymphomas occur with other
solid tumors, and that's primarily the situation that we have seen
in our patients.  There are very few patients that have a
genetic predisposition.  There are some families or ethnic
groups that have a higher instance of lymphoma and that includes
people from Japan or the Caribbean, primarily because they may be
infected with HTLV-1.Chu
At this point we are going to take a short break for a medical
minute.  Please stay tuned to learn more information about the
evaluation and treatment of lymphoma with my co-host and guest Dr.
Francine Foss.Chu
Welcome back to Yale Cancer Center Answers.  This is Dr. Ed
Chu and I am here in the studio14:32 into mp3 file 
http://www.yalecancercenter.org/podcast/mar2110-cancer-answers-foss.mp3
 this evening with my co-host and friend Dr. Francine Foss who this
evening is our guest expert discussing the evaluation and treatment
of lymphomas.  Francine, let's talk a little bit about once an
individual is given the diagnosis of lymphoma, how does one
evaluate to see what the extent of the disease is?Foss
 The first thing we would like to do is to know whether the
lymphoma is localized or has spread to other areas of the
body.  There are a couple of ways to do that.  One of
which is to get a CAT scan, which is the traditional test, but more
recently we have started using PET scans because PET scans are a
different kind of imaging that actually is enhanced in areas that
are metabolically active and lymphomas are particularly sensitive
to this technology. So, if we can get a PET scan along with the CAT
scan, which is called a CT PET scan, that's our preferred method of
imaging.  In addition, we would like to, in most of our
patients, also get a bone marrow biopsy just to see whether the
lymphoma involves the bone marrow, and that sounds pretty scary to
patients but it's actually a very simple procedure.  We do it
right in the office.  We now mark the area that we are going
to put the needle in and then we put small needles in and we take a
sample of the bone marrow.Chu
I am curious, how often does lymphoma spread to the bone marrow? Or
does it depend on the particular subset of lymphoma that we are
dealing with?Foss
 That really depends on the subtype of lymphoma and for patients
with say limited stage Hodgkin's disease, it's very rare, whereas
for patients with follicular lymphoma, it's very common.Chu
Once a patient has been staged, then how do you go through the
treatment planning and recommendation for the particular type of
treatment?Foss
 The treatment planing is highly dependent obviously on the type of
lymphoma; however, we can generalize to some degree. If we look at
say low grade lymphomas, there are about 7 or 8 different subtypes
within that category, but essentially we treat them all the same
way and likewise with the diffuse large B cell lymphoma, it depends
on stage.  In a very small number of cases, patient may only
get radiation if they have localized lymph nodes and nothing
else.  But most of our patients now are getting systemic
therapy, and we are very fortunate, particularly in B cell
lymphomas, that we have the monoclonal antibody Rituximab, which is
a first-line therapy for pretty much all of our patients with B
cell lymphoma.  Some of those patients with more advanced
disease may get the antibody with chemotherapy, but many of our
early stage patients may get the antibody by itself as a
therapy.Chu
This antibody Rituximab, what is it targeting?Foss
 This antibody targets CD 20, which is a protein on the surface of
the B cell and is expressed pretty17:28 into mp3 file 
http://www.yalecancercenter.org/podcast/mar2110-cancer-answers-foss.mp3
 much on all B cell lymphomas, so it's a drug that we can use
across a wide range of different types of B cell lymphoma.Chu
What's pretty remarkable about this antibiotic treatment compared
to some other treatments in my own disease, colorectal cancer, is
it really is specific for this CD-20 positive lymphoma.Foss
            
 That's right.  One of the side effects of the antibody that
most patient don't even notice is that it does decrease the normal
B cells to some degree, but they pretty much rebound and for most
patients there is no sequela in terms of increase in infections, so
that is one thing you do need to watch out for.Chu
Now again, do you use this antibody alone or in combination with
more traditional chemotherapy? Foss
 There have been a lot of studies done in the United States and
other countries looking at large groups of patients with B cell
lymphoma showing that the combination of this antibody with
chemotherapy is superior to the use of chemotherapy alone. 
Whereas we used to give a combination called CVP for patients with
follicular lymphoma, now we are giving R-CVP and for patients with
the diffuse large B cell lymphoma we used to give just CHOP, and
now we are using Rituximab with the CHOP. The other role of this
antibody is in the maintenance settings, so patients who have had
chemotherapy may then just get an antibody to try to keep them in
remission.Chu
Are we really impacting then on the cure rates of patients with
lymphomas being treated with this antibody?Foss
 Ed that's a really interesting question and if you look say at
follicular lymphoma, we have very good data going back 30 or 40
years looking at the overall survival of patients with this
disease, and really we have not made much impact in that survival
until very recently, and when Rituximab was approved in the mid
1990s, we started to see a plateau on that survival curve, so it
looks like perhaps the use of Rituximab, and perhaps other new
drugs that we have for treating lymphoma, are now starting to make
an impact on the overall survival of these patients and that's
really the important thing for the patient to know is that we are
now using therapies that perhaps can cure their disease for the
long term.Chu
Let's talk about some of these newer drugs because it really is
remarkable, the advances that have been made just even within last
3-5 years, and you have been very actively involved in development
of many of these drugs, so take us through some of those newer
agents.Foss
 I mentioned Rituximab, the CD 20 antibody, and there has also been
the combination of that20:12 into mp3 file 
http://www.yalecancercenter.org/podcast/mar2110-cancer-answers-foss.mp3
 antibody with radioactivity, and those two drugs are called
Zevalin and Bexxar, radiolabeled antibodies, and those are also
being used extensively in patients with B cell lymphoma.  In
addition, we have another antibody directed at CD 20 ofatumumab and
that antibody was recently FDA approved for patients with CLL, but
is also being used in clinical trials for patients with B cell
lymphoma, and has activity in patients that have been refractory or
relapse after the Rituximab, so I think that's an important
addition.  If we look at some of the other kinds of lymphoma,
the T cell lymphomas, which are particularly difficult to treat and
generally have a worse prognosis, we have a number of drugs that
have been FDA approved. About 10 years ago the molecule ONTAK was
approved and that specifically targets the Interleukin 2 receptor,
which is expressed on many T cell lymphomas.  More recently,
this year we have been fortunate that the FDA approved two new
drugs for the treatment of T cell lymphoma, one of those drugs is
called Pralatrexate or Folotyn, and that drug is actually a
derivative of a very old drug that we had been using for a long
time called Methotrexate.  This drug is a drug that is
particularly active in patients with aggressive peripheral T cell
lymphoma, but importantly it is also now being looked at in other
kinds of lymphoma as well.  The other drug is a whole new
class of drugs called histone deacetylase inhibitors, so the drug
Romidepsin or Istodax was approved for patients with cutaneous T
cell lymphoma, however, this drug again is also being used in
patients with aggressive T cell lymphomas as well as multiple
myeloma and B cell lymphoma.  I think we are going to learn
more about these histone deacetylase inhibitors and how they
combine with other chemotherapies, not only in lymphoma, but also
in other solid tumors.  It's very exciting now to have two new
drugs approved in one year.Chu
It really is very exciting and remarkable.  Do you think the
reason we have seen these advances is that we are finally seeing
the payoff from all the years of basic research trying to
understand what turns on or turns off these various lymphomas?Foss
 That's a very important point Ed, and that is that nothing new
happens in the clinic unless a lot of work gets done behind the
scenes in the basic science laboratory, understanding the molecular
biology of these diseases, and we have come a long way, as I have
mentioned, in identifying specific proteins that we can target on
these cells, were looking at specific pathways that are activated
to which we could direct targeted therapies.  I want to
mention one of those in particular, if we look at a certain subset
of T cell lymphomas, the ALK-positive anaplastic large cell
lymphomas, they express this protein called ALK.  There has
been the development of an inhibitor of ALK that interestingly is
in clinical trials in lung cancer and will also be used in patients
with ALK-positive T cell lymphoma.Chu
Francine, you have been very actively involved in developing new
agents, new treatment regimens, tell us a little bit about what's
going on with your program at Yale Cancer Center.23:35 into mp3 file 
http://www.yalecancercenter.org/podcast/mar2110-cancer-answers-foss.mp3Foss             
 Our program involves trying to get some of these new drugs into
patients with lymphoma and also trying to look at some of the
combinations that we can use that would capitalize on synergistic
interactions in targeting pathways that are important in these
patients.  We are very interested in the histone deacetylase
inhibitors and looking at how we can combine them with other agents
that affect the transcription of genes, and so we have a
combination of a drug called Doxil with a histone deacetylase
inhibitors called vorinostat, and that's open for patients with all
types of lymphoma.  Interestingly, we have seen some very
significant activity in Hodgkin's disease, which we would not have
expected, and so that's an example of learning something new about
your drug combination by opening up your trial to a number of
different types of patients.  In addition, we are looking at
some of the novel histone deacetylase inhibitors and we have also
done a clinical trial combining the drug ONTAK with CHOP as a
first-line therapy in patients with aggressive T cell
lymphoma.  We have actually shown that combination works
better than the CHOP alone and that perhaps could be a major
advance in the treatment of some of these patients with aggressive
T cell lymphomas.  We are also looking at some novel phase 1
molecules and trying on incorporate them into treatment of patients
with relapse B cell lymphoma, in particular, because those
patients, if they don't go to bone marrow transplant, don't have
really good options.Chu
We have talked a lot about chemotherapy and these new targeted
agents, and you just mentioned bone marrow transplantation. 
When would one consider recommending transplantation to a patient
with lymphoma?Foss
 Bone marrow transplant for lymphoma is done under very defined
conditions and a lot of this has been defined based on the medical
literature and also the NCCN guidelines which direct us in terms of
what the standards of care are for different diseases.  So,
for patients with diffuse large B cell lymphoma, generally
speaking, at least half of those patients will go into remission
with chemotherapy and never relapse, however, if they do relapse
and they get additional chemotherapy, than a bone marrow transplant
for consolidation is the recommendation at that point, or if the
patient has failed their first-line therapy, and we give them a
consolidation therapy, then we may consider moving them to a
transplant.  For patients with a follicular lymphoma often
times those patients can go on to many other therapies and
transplant really is not required or necessary until they have had
multiple therapies and they have shown that their disease is less
responsive and we really need to do something to consolidate their
response.  The autologous transplant is high dose chemotherapy
to try to consolidate a response in a patient with lymphoma where
as an allogeneic transplant involves getting cells from another
person and therefore getting an immune effect, so up-regulating
your own bodies chance of responding to a cancer by giving yourself
new immune cells from a different person. That's a whole difference
strategy and we do use that strategy in patients particularly with
relapsed and refractory lymphomas, people that have very difficult
diseases.  With respect to the T cell lymphomas, often times
we need to go to that allogeneic transplant first because we know
that T cell lymphomas tend not to do as well with the27:09 into mp3 file 
http://www.yalecancercenter.org/podcast/mar2110-cancer-answers-foss.mp3autologous transplant.Chu
What are some of the complications that are typically associated
with say the allogeneic transplant?Foss
 I want to mention to our listeners when we talk about the word
transplant people tend to put autologous and allogeneic together,
and it's important to separate the two because autologous
transplant is really very safe and the chance of dying from an
autologous transplant is really very low, it's probably one percent
or less.  Whereas an allogeneic transplant, as I mentioned,
involves getting cells from a donor, from somebody else, one of the
risks of that is that donor cells could recognize proteins in your
body that are slightly different and they could attack your body
and that process is called graft-versus-host disease.  When we
do an allogeneic transplant, we hope that those new cells are
fighting against the tumor cells because they recognize the tumor
cells as being foreign but we would like to diminish the chance of
those cells fighting against the body and generating graft-
versus-host disease.Chu
Francine, you have been very actively involved in trying to develop
novel strategies to reduce the incidence of graft-versus-host
disease, but at the same time enhance the tumor effects, can you
quickly tell us about that?Foss
 Based on some work that we have done in the laboratory, we have
shown that the use of photopheresis treatment prior to the
conditioning regimen for allogeneic transplant decreases the chance
of graft-versus-host disease, and in fact, we have had a clinical
trial that has been ongoing here at Yale, but also in other
centers, to look at the use of photophoresis in this setting. And
particularly for lymphoma patients we have seen very good results
and by decreasing the chance of graft-versus-host disease, we have
been able to transplant patients successfully and had a graft-
versus-tumor effect such that their lymphoma is in remission after
the transplant, so I think this is a major step forward in our
ability to transplant more patients with lymphoma.Chu
Francine, it's amazing.  The time has quickly gone by. 
It has been great having you on the show and hearing about all of
the wonderful advances that are taking place in the treatment of
lymphoma.Foss
 Thank you Ed, it has been a pleasure to be here to talk with you
tonight.Chu
Until next week, this is Dr. Ed Chu from Yale Cancer Center wishing
you a safe and healthy week.If you have questions or would like to share your comments,
visit yalecancercenter.org, where you can also subscribe to our
podcast and find written transcripts of past programs.  I am
Bruce Barber and you are listening to the WNPR Health Forum on the
Connecticut Public Broadcasting Network.