Dr. Warren Shlomchik and Dr. Stuart Seropian,
Preparing for a Stem Cell Transplant
May 23, 2010
Welcome to Yale Cancer Center Answers with Dr. Ed Chu and Dr. 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 and Francine welcome Drs. Stuart Seropian and Warren Shlomchik. Dr. Seropian is an Associate Professor of Medical Oncology at Yale Cancer Center and Dr. Shlomchik is an Associate Professor of Internal Medicine and Immunobiology at Yale School of Medicine. Here is Ed Chu.
Chu
This evening our topic is stem cell transplantation. Why don't we
go ahead and start off by defining for our audience, what is stem
cell transplantation?
Seropian
I will try to answer that succinctly. Simply, a stem cell
transplant is a procedure that we use to treat patients with
malignancies, primarily cancers of the blood and immune system.
Stem cell transplant is also used to treat patients who have bone
marrow failure syndromes. It's a method by which we can
support the blood system when we give high doses of chemotherapy or
fix diseases where the bone marrow has failed.
Foss
Warren, we hear the terms both stem cell transplant and bone
marrow transplant. Can you tell us what a stem cell is?
Shlomchik
A stem cell was really defined in the hematopoietic system.
It is a cell that can give rise to all the other different types of
blood cells and it can do that for a long period of time. Stem
cells can both regenerate and make new stem cells and also they can
differentiate, which means that as they divide they can turn into
red blood cells which carry oxygen, white blood cells, which help
fight infection, and platelets which help prevent bleeding.
Chu
Stuart, what caused the change? I know that when Francine and I
were, back in the good old days, in training this was called bone
marrow transplantation, so what caused it to evolve from bone
marrow transplantation to stem cell transplantation?
Seropian
We use the term stem cell transplantation now because we have the
option of getting the cells we want out of the bone marrow or out
of the peripheral blood or blood system using some special
techniques, so when we get the cells out of the bone marrow, which
we still do on occasion, that's the bone marrow transplant.
When we get the cells out of the blood stream we call that a
peripheral blood stem cell transplant, so those are the two main
types
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of transplant. I think it's important to back up for a
moment to point out that
we are not talking about embryonic stem cells for people who are
listening, embryonic stem cells are a little more controversial and
not really used on a regular basis, these are blood stem cells or
cells that are used every day around the world and have been for
many, many years.
Chu
Now, when one gets these stem cells either from the bone marrow or
from the peripheral blood, is there a way to expand the number of
cells? Grow them, and then re-infuse them into a particular
patient?
Seropian
There has been a lot of research in how to expand these stem
cells. It's pretty easy and straight forward to expand the
cells that are not stem cells, but can only make white cells or can
only make platelets, or only make red cells. In the context
of peripheral blood stem cell transplantation, this type of
expansion is not necessary because we can already get enough cells
to quickly allow someone getting a lot of chemotherapy or radiation
that knocked down their own blood system, to come back with the
donor blood system. It has been more recently studied as a
way for cord blood to improve cord blood engraftment. So cord
blood, when a women gives birth the blood that is in the placenta
has a lot of these stem cells, but there are only enough stem cells
to reliably grow in small people, pediatrics, and there has been a
lot of research about how to expand cells from cord blood, but none
that has really hit the mainstream yet.
Foss
Warren, you bring up the stem cells sources from umbilical cord as
one of the sources and Stuart, I know that when we do
transplantation we look at a number of different donor types. Can
you just go through for the audience how we go about picking a
donor and what kind of donors we look at?
Shlomchik
Sure, I think when people think of the term bone marrow transplant
in particular, they think there is a donor involved.
Sometimes the donor is actually the patient, so the simplest and
most straight forward form of transplantation is to take a patient
who has a cancer of the blood or immune system such as lymphoma or
multiple myelomas as an example, and in the process of trying to
treat that disease more effectively by using more intensive or
higher dose chemotherapy, we can collect their stem cells in
advance and freeze them and then the patient can receive a very
strong, but more effective treatment, and then we just give their
own cells back. That's known as an autologous transplant. The times
when we think about doing that particular procedure is when the
disease in question is very sensitive to stronger dose
chemotherapy, so we are trying to cure the patient, we are
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trying to provide a more durable remission by intensifying the
therapy, and in that case the stem cells make the procedure safe.
And because it is the patient's own stem cells, there really isn't
a major concern about problems with immune function long
term. The second major form of transplantation would be
allogeneic transplant, that's where a donor is involved. A
family member or unrelated individual is a volunteer, and that's a
more complicated procedure, that's really like an organ transplant
where we are replacing the blood in the immune system and that's a
necessary approach for a patient who has a bone marrow failure
syndrome, for instance, severe aplastic anemia. When thinking
about doing a transplant and choosing a donor in the family, or an
unrelated individual, versus using the patient's own cells, if we
have to replace the bone marrow and blood system we are going to
choose an unrelated donor or family member. In addition to
bone marrow failure syndromes certain cancers do not necessarily
respond as well to very strong chemotherapy and we choose
allogeneic transplant in those circumstances when we are trying to
also get the advantages that giving a new immune system provide us,
such as graft-versus-leukemia or graft- versus-lymphoma effect and
that's an effect where the donor cells are able to fight the
leukemia as well.
Chu
Stuart, could you review for our listeners the types of cancers
where you think of using say the allogeneic transplant
approach?
Seropian
The most common would be acute leukemias, so acute myelogenesis
leukemia, acute lymphoblastic leukemia. In addition,
non-Hodgkin's lymphoma is also common. There are some
low-grade lymphomas where we do consider transplantation, although
there are many other options for those diseases, but follicular
lymphomas for instance, and chronic lymphocytic leukemia, is a very
common form of leukemia, but there are some patients who do not do
all of the standard therapies that we consider allogeneic
transplant for.
Foss
Are there also some other diseases such as sickle cell anemia or
other diseases that are being transplanted now-a-days?
Seropian
That's a great question. Intermittently there has been a lot
of enthusiasm for transplanting patients with sickle cell. If you
were to look world-wide at any given moment the number of people
who would benefit, if it could be done safely, from allogeneic
transplant, those with sickle anemia and thalassemia exceed those
with leukemia, however, it's a tough decision to make for families
because there is always a small risk upfront that someone could die
from the treatment and for something that's not an immediately
lethal
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disease, like sickle cell anemia, it's a very hard decision to make. Although, there have been a number of trials in children who are not doing well, particularly those who have problems with the lung, something called acute chest syndrome or have neurologic problems in their sickle cell disease.
Chu
What about the cancers where you would typically think about using
an autologous transplant procedure?
Seropian
One of the most common cancers that we do autologous transplant
for is multiple myeloma, and then aggressive Hodgkin's lymphomas
and there are several of those, also a few rare cancers like
germ-cell cancers which are often cured with standard therapy, but
may recur, are potentially curable with the transplant and then
Hodgkin's disease as well may also be cured with autologous
transplant, if it recurs after primary chemotherapy.
Foss
One of the areas that patients often ask about with autologous
transplant is how you are sure that none of my tumor cells are
going back in? And there has certainly been some data looking at
what we call kind of purging these stem cells products, would you
like to talk a little bit about that?
Seropian
Sure, it's a good question. When we are performing an
autologous transplant we are very careful about selecting patients
to make sure that we are doing the procedure in an individual who
will benefit from it. If we take a patient who has a lot of
multiple myeloma for instance, or Non-Hodgkin's lymphoma where the
disease is not well controlled, there really is quite a high risk
that we may collect tumor cells and just give them back to the
patient, and also our chemotherapy, even in high doses, is not
terribly effective. We select patients who are already in a
good remission and that decreases the chances of selecting tumor
cells. For non-Hodgkin's lymphoma, we have a great drug
called rituximab, which I am sure any patient with B cell lymphoma
knows already of this medicine and has probably received it and
that's the medicine that we give to patients that does purge
lymphoma cells out of the blood stream which is where we go to
collect the stem cells, so we have good medicine for one disease to
do that. For other diseases, there has been a lot of research
trying to find and remove tumor cells from grafts. There was
a very well designed and conducted study in multiple myeloma that
effectively removed tumor cells from the graft and it really did
not seem to improve the outcome, so we do know that because there
are limits to our ability to get around that problem, if we select
the right patients and deliver the right chemotherapy that we still
benefit
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patients and it's probably the disease the patients have remaining
at the time of transplant that contributes to any recurrence of
disease, not the contamination of stem cell product with tumor
cells.
Chu
I am just curious, is there any age requirement for a patient who
is being considered for transplantation?
Seropian
Well, we kind of joke that the age limit is usually the age of the
Director of any given program at any given year, and that's just
the way of saying that it seems that every decade we have managed
to improve the procedure in terms of safety so that older patients
are eligible. We transplant patients routinely in their 60s
with either type of procedure, allogeneic or autologous, and up
around the age of 70 we do become more selective but we don't have
a chronologic age cut off. It's really what we call a
physiologic age cut off and that's the way of saying that if
patients are otherwise healthy, without other major medical
problems, and during the pre-transplant testing process we don't
discover anything that we think would increase the risk of
transplant, we will transplant patients based on the indication of
what their disease is doing.
Shlomchik
Some of that stems from the recognition that for an allogeneic
transplant some of the efficacy for some of the diseases is really
immune mediated, and so these are when the donors immune system
recognizes the patient as being foreign and in a way rejects the
patient's malignancy, and so for those patients in which
we're relying on that effect, you really don't need to give a very
intensive chemotherapy or radiation therapy regimen, and so that
has allowed a lot of older patients to tolerate that, and as Stuart
said, many of us joke that people who pioneered this were kind of
the first generation of transplantars who had become too old to get
the high intensity conditioning regimens, so we commonly use these
types of regimens.
Foss
That will be a great topic for us to jump into during the second
part of our program. We are going to take a short break now
for a medical minute. Please stay tuned to learn more
information about stem cell transplantation with our guests Dr.
Stuart Seropian and Dr. Warren Shlomchik.
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designated comprehensive cancer center such as Yale Cancer Center to test innovative new treatments for melanoma. The Specialized Programs of Research Excellence in Skin Cancer grant at Yale, also known as SPORE grant, will help establish national guidelines on modifying behavior and on prevention as well as the identification of new drug targets. This has been medical minute, brought to you as a public service by Yale Cancer Center. More information is available at yalecancercenter.org. You are listening to the WNPR Health Forum on the Connecticut Public Radio Network.
Foss
Welcome back to Yale Cancer Center Answers. This is Dr.
Francine Foss, and we are here today with our guests Dr. Stuart
Seropian and Dr. Warren Shlomchik to discuss the topic of stem cell
transplantation. Before the break Warren, you were talking a
little bit about the whole process of graft-versus-host disease and
the kind of conditioning that we do for transplant. Can you
back up a step and explain for our listeners exactly what the
process is for stem cell transplant?
Shlomchik
The first process, as Stuart has mentioned, is having a right
patient and so a team needs to evaluate the patient and see if they
are an appropriate candidate for stem cell transplant in terms of
their disease and their stage of disease. The second process
for allogeneic is determining whether they have someone who is what
we called a match, and there are certain genes called HLA genes
that confer the greatest risk of having immune problems with the
transplant, and so we do tests on the patient and then first on
their siblings to determine whether they have a family member who
is matched at these genes and it's roughly a one in four chance
that any given sibling will be a match. If they don't have a
match, then we look in registries. People have seen bone
marrow drives or ways to register for this registry. It is to see
whether there is an unrelated person that also shares these HLA
genes. Once that is done, then the actual treatment commences
and that comprises of collecting the stem cells from the donor and
as Stuart mentioned this is typically done with collecting them
from peripheral blood. It turns out that you can give a white
cell growth factor that for mysterious reasons causes stem cells to
circulate in the blood at high numbers and then there is a machine
called an apheresis machine that can collect those stem cells, and
then we will give a chemotherapy or chemo radiation regimen to the
patient that has a few different purposes. One purpose,
especially when it's a higher dose regimen is to try to kill
whatever residual cancer cells they have left, and the second
purpose of it is to be an immunosuppressant to prevent their own
cells from rejecting the non identical donor cells, and then
once
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that regimen is completed there is some infusion of the donor cells and then the patients are also treated with drugs that suppress the donor immune system to prevent those cells from attacking the patient.
Foss
One of the major complications of transplantation is the rejection
process, the process called graft-versus-host disease, and I know
Warren, you have done a lot of research in that area. Can you
let our audience know a little bit about what that process is and
what we can do about it?
Shlomchik
Well most people don't have autoimmunity and that is you have
immune cells in particular, T-lymphocytes that help fight infection
and they go around and they can recognize lots of different
proteins, but they don't attack you because as they developed those
cells that could potentially attack you are either killed off or
rendered non-functional. However, even in a sibling they
differ in many, many proteins and that's why unless you have an
identical sibling, you look different than your siblings and all of
those things that help make you look different those things can
cause differences in proteins, and those can be recognized by the
donor cells as non-self and so when you infuse those cells in,
those cells go around and they treat you as if you have a viral
infection in every cell, and they can get activated and those that
are reactive against the donor can actually go and attack some of
the tissues of the patient and the tissues that are classically
involved are the skin, the liver, and the gastrointestinal
tract.
Chu
Then the patient would present with what, a skin rash, or
diarrhea, dysfunction of the liver?
Shlomchik
We carefully examine the patients after the transplant, and we look
to see whether they develop skin rash, or they can develop a
diarrhea, as you said, and then we measure in the blood things
their liver makes or can be released from the liver and those would
give us indications that there could be an immune response against
the liver.
Foss
Stuart, you have done a lot of work and you have a protocol now
looking at drugs that might help prevent this rejection.
Seropian
I should mention that unless we are doing a transplant from an
identical twin we always have to provide some method to prevent
graft-versus-host disease. We do not just give the cells from
the donor and wait and see what happens. The most commonly
used way we to try and prevent graft-versus- host disease is to use
immunosuppressant medicines that typically target the cells that
Warren was mentioning, lymphocytes, and prevent them from being
over active and that's effective in many people and we always try
to
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find ways to make those drugs more effective. Graft-versus-host disease is particularly problematic when we don't have a well-matched donor and there are situations in leukemia in particular where we know that a transplant from a mismatched donor, although suboptimal, may still be the best option to try and cure an otherwise incurable disease. We have been studying new drug combinations at Yale for several years and think that things are working better and this is really the focus of most research in allogeneic transplant, trying to find new ways to prevent this problem of graft-versus-host disease.
Chu
I am just curious, about what fraction of patients who undergo
allogeneic transplant will develop graft-versus-host disease?
Usually what's the time frame from the point that someone undergoes
the transplant to developing graft-versus-host disease?
Seropian
I think a good number to remember is a big picture number, it is
probably about half, so it's very common. I think the
important thing is that what we are trying to do is prevent severe
graft-versus-host disease. We have known for a long time that
there is an association with graft-versus-host disease and patients
not relapsing, so we kind of think of graft-versus-host disease as
a double-edged sword so to speak. What we do not want is a
severe form that makes patients very ill and also requires a lot
more immunosuppressant medications that open the door for
infections.
Shlomchik
That's a good jumping off point to talk about why we subject people
to the risk of graft-versus-host disease which Stuart is
mentioning, and it is really this immune effect against
particularly the leukemia's and lymphomas. It's worth pointing out
that you may read in the newspaper about cancer vaccines and
immunotherapy for cancer, but this as a field was really invented
in the bone marrow transplant field and I think more people
probably get cured every month in the world by the immune effect
from bone marrow transplant then in the entire history of
immunotherapy for other cancers. For example, probably the best
example, was chronic myelogenous leukemia in which if you relapsed
after your transplant, you could just get white cells from your
original donor and go into complete remission and the effect is so
strong that even if they use the most sensitive methods using DNA
to detect the leukemic cells, you cannot find them.
Foss
Warren, basically you are saying that if you have a stem cell
transplant in the case of CML, for instance, your disease comes
back and certainly this is true in lymphomas as well, that you can
go back and just get peripheral blood cells for the patient from
the donor?
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Shlomchik Exactly right, I mean for CML we
don't do very many transplants anymore because of Gleevec and other
drugs that are very effective, but we still see, particularly as
you mentioned for low-grade lymphomas and chronic lymphocytic
leukemia, the immune effect is very strong and in fact you can
follow in the blood using sensitive methods over time someone who
has had transplant for CLL and you can watch the amount of CLL that
they have in cells go down over time, even though they haven't had
any chemotherapy for months, and so it's very potent. I think
there are two principle challenges, one is how do you get this
immune effect without having toxicity of graft-versus-host disease
and the second is how can you make cancers that are not as
susceptible for reasons that we do not understand to be more
susceptible?
Foss
And Warren, you have a very innovative clinical trial that is just
getting started at Yale Cancer Center. Can you talk a little
bit about that trial?
Shlomchik
Sure, in the lab we found that a certain type of T cell called the
memory T cell, these are T cells that have previously responded say
to an infection and then live in you for a long time in order to
protect you from future infections, have a reduced capacity to
induce graft-versus-host disease, and one of the main problems of
doing an allogeneic stem cell transplantation is actually immune
reconstitution. Patients are very susceptible to getting
infections, and there are many centers that feel that toxicity from
the graft-versus-host disease is so high that for patients who can
get high intensity chemotherapy regimens or radiation regimens,
they actually will physically remove the T cells from the donor
graft figuring that, although there is an increased risk of
relapse, there is a decreased risk of having toxicity from the
graft-versus-host disease. However, a major problem with that
is that because no T cells are given there is poor reconstitution
of memory against infection, so what our protocol is, is to give
patients who have acute leukemia who are young enough and healthy
enough to have a chemotherapy regimen that will be very active
against their leukemia to selectively give them memory T cells and
in that way we would reconstitute their T cell memory. We
also know from the lab that these cells have some ability to
mediate the so called graft-versus-leukemia effect, although we do
not really know in humans whether it is stronger or weaker.
Our longer term approach to this is actually to vaccinate the
donors against proteins that are on leukemia, make memory cells and
that way when we transfer memory cells we will both improve the
patient's ability to fight infection and also improve the
graft-versus-leukemia effect, and I should say that in mice that
approach works spectacularly well and we will see how it works in
humans.
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Chu
Stuart, other than graft-versus-host disease, are there any other
side effects or complications that are associated with
transplantation?
Seropian
Sure, and that depends a great deal on the therapy that was chosen
for an individual patient. When we are doing a standard
transplant in a younger individual and giving a very high dose of
chemotherapy, there are side effects with that treatment and that
includes discomfort in the form of mucositis, which is injury to
the lining of the mouth, or throat, or the bowels. There is a
risk of infection and the blood counts do get very low, although
temporarily, and so patients need transfusions and there are other
organs that may be susceptible to the effects of chemotherapy.
Pre-transplant testing is really designed to make sure that we are
not giving too strong a treatment to an individual who cannot
withstand it. Fatigue is a very common symptom following
transplant, and common after a lot of different types of anticancer
therapy, but that is particularly common as well.
Foss
Stuart, taking care of these patients in the hospital is a real
challenge because of the multiple issues, can you talk a little bit
about the multidisciplinary approach for managing these patients at
Yale Cancer Center?
Seropian
We collaborate with physicians and a lot of different specialties
both before and after transplantation. Some of the
disciplines that come to mind right away are the infectious disease
doctors who help us in terms of making sure that there are no
infectious problems before transplant that might come back. In a
situation where we are compromising the patient's immune system
temporarily, the pulmonary doctors help us quite a bit, and the
nephrologists, or kidneys doctors, are also really crucial to our
practice since many of the medicines that we use effect the
kidneys.
Shlomchik
I would also add to that radiology. We do a lot of imaging in
our patients and having radiologists that are experienced in the
types of issues of bone marrow transplantation, is really
important.
Chu
Great, and in the remaining few seconds that we have, if there are
listeners out there who would like to learn more information about
transplantation and the folks involved, is there a phone number or
website that you can provide to our listeners?
Seropian
Probably the best portal of entry is the Yale Cancer Center
website at yalecancercenter.org and the Hematologic Malignancies
Clinic is at 203- 200-HEME, so those are two other places to go for
more information.
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Chu
Terrific, well Warren and Stuart, thank you so much for being with
us this evening on Yale Cancer Center Answers to discuss stem cell
transplantation. We certainly look forward to having you back on a
future show to discuss all the great progress that has been made in
the world of transplantation. 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.