Dr. Stuart Seropian, What is a Stem Cell
Transplantation?
January 6 , 2008
Welcome to Yale Cancer Center Answers with Drs. Ed Chu and Ken Miller. I am Bruce Barber. Dr. Chu is Deputy Director and Chief of Medical Oncology at Yale Cancer Center, and Dr. Miller specializes in pain and palliative care. If you would like to join the discussion you can contact the doctors directly. The address is canceranswers@yale.edu and the phone number is 1888-234-4YCC. This evening, Dr. Chu and Dr. Miller are joined by Dr. Stuart Seropian, Associate Professor of Medical Oncology and an integral member of the Yale Cancer Center Leukemia, Lymphoma, and Myeloma Program. Dr. Seropian's clinical and research interests are in the area of stem cell transplantation.
Miller
Let us start off by talking about the basics of what a stem cell
transplant and bone marrow transplant are.
Seropian
A stem cell transplant, which now a days I think is the preferred
term, is a procedure where we use stem cells, either from the blood
or from the bone marrow, in support of chemotherapy, often in high
doses, to treat certain cancers; mostly hematologic malignancies or
cancers of the blood marrow or lymph system.
Miller
There is a lot of controversy about stem cells, are these the same
stem cells we're talking about?
Seropian
No, and that is an important point to emphasize. We are
talking about stem cells that are more grown up than the embryonic
stem cells that you hear about a lot in the news. These are cells
that make blood. They make the cells that are part of the
immune system. They are not the kind of cells that there is
controversy about. These cells have been used for more than
20 years to support patients who have cancer.
Chu
Where do these cells come from specifically?
Seropian
A lot of people are familiar with the term bone marrow transplant,
which had its origins in the late 1960s, early 1970s. Things have
evolved to the point where a lot of the cells that we used to get
out of the bone marrow for this procedure, can now be taken out of
the blood stream. It is more common to get these cells out of the
blood stream now, but many of them originate in bone marrow.
Chu
The original perception of bone marrow transplantation was that it
would be painful to get cells out of the bone marrow, but with the
new technology, there really is no pain involved.
Seropian
It is easier to get the type of cells we need out of the blood
stream than out of the bone marrow, so the experience for donors,
if we are doing a transplant from a brother or sister for instance
to the patient, is easier than it used to be. The methods are
different. There are sometimes side effects from the treatments,
but donors do not have to go to the operating room and have
multiple bone marrow aspirates under general or spinal
anesthesia anymore.
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Miller
If someone is considering being a donor, there are donor drives
throughout the state and elsewhere. What is involved, do you have
to give blood or have a physical exam if you want to consider being
a donor?
Seropian
Before we launch into that let's get into a little background about
the different kinds of transplants. There are transplants where
there are donors involved and then there are also transplants where
the patient is donating stem cells to themselves. For example, a
patient with the disease multiple myeloma, we have known for a long
time that higher doses of chemotherapy can be more effective in
treating this disease, but there are limits to the doses of
chemotherapy we can administer because the blood counts drop and
take a long time to recover. We can harvest the patient's own
stem cells out of the blood stream and freeze them, then give the
high doses of chemotherapy and return their stem cells to the body.
Their blood counts will get better in 9 or 10 days, whereas without
those stem cells, without that support, it might take 3 weeks or
even longer; which would be quite dangerous. This is called an
autologous transplant. It is really just a safer way to give
a more effective dose of chemotherapy to patients with less side
effects, discomfort or risk to the patient. An autologous
transplant is a very commonly performed procedure where the patient
is donating to themselves.
Chu
In follow-up to that, is there ever any concern that there may be
minimal numbers of tumor cells that are in that collection of
cells?
Seropian
Sure, in fact, that is one of the factors when deciding what kind
of transplant to perform. We might switch to a different donor than
the patient. For a patient who has a disease like leukemia, which
is a disease of the blood and the bone marrow, that is a major
concern. It is one of the original reasons why the other kind of
transplant, allogeneic transplant, became popular. Allogeneic
transplant is where we take a brother or sister's stem cells and
use them to support the procedure. If we are using a
patient's own stem cells to support a transplant there are ways to
check and see if they are contaminating tumor cells in the graft.
The best way to know is the remission status of the patient. In
other words, if a patient receives chemotherapy, has a good
response and goes into remission, then we know that we have reduced
the burden of cancer in the body and when we collect the stem cells
we know there are not going to be a lot of tumor cells in
there. For a disease like myeloma, with the understanding
that sometimes there are tumor cells still in there, giving a
higher dose of chemotherapy benefits the patient.
Miller
Let's stick to the autologous transplant, how difficult a process
is it for a patient?
Seropian
There are potential side effects and risks that are possible with
the patient's high-dose chemotherapy, which is really the purpose
of using a patient's own stem cells. It is a supportive way of
giving high-dose chemotherapy. When we used to use bone
marrow for that purpose, which in the autologous setting does not
appear to work as well as using the stem cells out of the blood
stream, patients had to undergo the procedure in the
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hospital and it could take 2 weeks or longer for the blood counts
to get better, so patients would get quite ill. High-dose
chemotherapy can irritate the lining of the mouth and the bowels,
people lose their appetite when the blood counts are low, and get
fevers and infections.
Miller
Have you been able to do this procedure, autologous transplant,
without a patient having to be admitted?
Seropian
With peripheral blood stem cells, which are the grafts that are
used for autologous transplant, at Yale, we do not admit people to
the hospital unless they have a problem such as a fever, or if they
are not feeling well after a transplant. In that case we will put
them in the hospital quickly, but this is an outpatient procedure
at our institution and in many institutions now. With the
antibiotics we have and the supportive care and the rapidity with
which the blood counts get better using the patient's own blood
stem cells, there is not a clear reason why people have this
procedure in the hospital.
Chu
That is a very important point that you just raised Stuart.
We've certainly gotten a lot better in terms of the supportive care
of patients who undergo intense chemotherapy and autologous
transplants.
Seropian
We have much better antibiotics to prevent viral infections,
bacterial infections and fungal infections. We have drug
growth factors like Neupogen, or filgrastim, a medicine that helps
to speed up the recovery of the blood counts after transplant,
which can make a big difference of 3 or 4 days in terms of the
patient's white blood cell count recovering after this kind of
procedure. It helps patients feel better more quickly, and it
prevents a lot of our patients from needing to be admitted to the
hospital. Right now, after an autologous transplant, probably
about half of the patients will end up being admitted to the
hospital at some point, but half of them are seen in our outpatient
clinic where they get fluids and antibiotics. It is fair to say
that most patients prefer not to be in the hospital for a long
period of time if they can avoid it.
Chu
When do you typically recommend an autologous transplant to a
patient?
Seropian
There are pretty well agreed upon criteria for performing
autologous transplant, and I should emphasize that these procedures
in general are for patients who have cancers of the lymph nodes,
blood, and the bone marrow. Diseases like multiple myeloma,
non-Hodgkin's lymphoma, Hodgkin's disease and testicular cancers
are examples. These are diseases that respond well to
chemotherapy. For patients who go into remission where we know
there is very high risk of relapse at some point in the future,
transplantation can help to either keep the patients in remission
longer, or sometimes cure them. Multiple myeloma is an
illness where there are a lot of good drugs to get people into
remission. There are not standard therapies that cure patients of
myeloma. Transplantation is often performed in first
remission and has the benefit of keeping people in remission for
a
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longer period of time where they don't have to take chemotherapy
or other medicines. Non-Hodgkin's lymphoma is cured sometimes
with standard therapy, but 40% to 50% of patients will have a
relapse and many of those patients are cured if they have a
transplant in a second remission. That is a typical
indication for an autologous stem cell transplant.
Miller
It sounds like for some patients it is a curative form of therapy
and for others it at least helps give them a longer remission.
Seropian
That is right, and because the side effects and the risks of
autologous transplant have been reduced greatly over the last 10-15
years, we are more likely to consider performing that procedure for
patients. We like to do this procedure when we are trying to cure a
patient, but if we know we can transplant a patient, and they will
be off therapy for 1 year or 2 years because of the transplant
procedure, which is a 4- to 6-week commitment, then that is often
the best thing for the patient.
Miller
We would like to remind you to e-mail your questions to canceranswers@yale.edu.
We are going to take a short break for a medical minute. Please
stay tuned to learn more information about stem cell
transplantation with Dr. Stuart Seropian from the Yale Cancer
Center.
Miller
Welcome back to Yale Cancer Center Answers. This Dr. Ken
Miller, I am here with my co-host Dr. Ed Chu and Dr. Stuart
Seropian who is an expert in stem cell transplantation at the Yale
Cancer Center.
Chu
Before the break we were talking about autologous transplants.
Maybe we can turn to the other transplant known as allogeneic stem
cell transplantation. Can you give our listeners a brief
description of what that involves?
Seropian
The same principal applies to allogeneic transplant as the
autologous transplant; we use
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stem cells to support the administration of chemotherapy. However,
there are a lot of differences. An allogeneic transplant is
performed using a donor other than the patient, ideally a brother
or a sister who is matched for the genes. Sometimes, the donor is
an unrelated person and the cells are obtained with the help of the
National Marrow Donor Program. This is a different kind of
transplant in that we are treating malignancy in part by giving
chemotherapy, but also by replacing the patient's blood in the
immune system with somebody else's. In contrast to the autologous
transplant, we're after the benefits of getting a new immune system
in some cases, so it may be a more powerful therapy, but because we
are replacing the patient's immune system, this is a more
complicated procedure.
Chu
For other diseases in organ transplantation we always hear
concerns about long waiting lists and waiting times for someone to
actually find a potential donor, is that the same for bone marrow
transplantation, stem cell transplantation?
Seropian
It is a little different. When we are looking for a donor for
an allogeneic transplant, it is within the family, the brothers and
sisters typically are the eligible donors. It is quite rare for a
child or a parent of the patient to be a donor. It is not
entirely unheard of, but the genetics of the HLA genes, which are
the genes that are important, predict that typically it is only
going to be a brother or sister who is matched. If a brother or
sister is matched, then transplant often can be performed very
quickly. When we need to find a donor who is unrelated, we
search through the National Marrow Donor Program which can take
longer. It typically takes somewhere in the order of three months
to secure a donor, but the National Marrow Donor Program actually
has made some advances in the way the typing is performed.
There are patients in the registry where sometimes we can get
grafts as quickly as 6 to 8 weeks.
Chu
What is the importance of looking at the underlying genetics in
the HLA haplotypes?
Serpoian In order to perform an allogeneic transplant we have to have a donor who matches either 100% or 90% of the genes that we know are predictive of success with the transplant. Patients often want to type a lot of their friends or cousins, but genes are much more complex in comparison to the ABO blood system. You don't need to be matched for your blood type with the donor, because you are not going to acquire the donor's blood type, but you really have to be matched for these genes. Our requirement is that the patient and the donor be matched for 9/10 genes that we test for, otherwise the risks of transplant are really quite high.
Miller
What is the role of the donor's immune system in trying to prevent
the disease from coming back?
Seropian
As I mentioned that is one of the things we try and take advantage
of. It is a little different depending on the disease that we are
forming a transplant to try and eradicate. Chronic myelogenous
leukemia, for example, which is an illness where transplant has
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been performed for many years, less commonly now because of other
new therapies, is a disease where it has been well demonstrated
that the major manner in which patients are cured is by donor
lymphocytes killing the leukemic cells in the patient. We
call that a graft versus tumor, or graph versus leukemia,
effect. We know that the immune systems between the patient
and a donor, unless we have an identical twin, are not really
identical. We hope they are minor differences because we don't want
to have complications if the donor's immune cells react badly to
the patient. Those differences probably account for donor cells
recognizing leukemic cells in the body and killing them in many
instances. This is a very strong effect for patients who have
chronic myelogenous leukemia, but we think that this effect is
there for other leukemias and for lymphomas. When we are
trying to decide what kind of transplant to perform, we take into
account a number of things. One of them is whether or not a
patient's own stem cells could be contaminated with tumor cells. If
a patient has a cancer that is not in a good remission, and giving
them a high-dose of chemotherapy is not going to do the trick, we
look for the extra benefit of the donor's immune system trying to
eradicate the tumor cells.
Chu
What are the types of diseases that you consider for allogeneic
transplant?
Seropian
Similar hematologic malignancies, more in the way of acute
leukemia's. This is where we would tend to perform an allogeneic
transplant as opposed to an autologous transplant, in part because
we think there is more benefit to this graft versus tumor effect
and also because those diseases originate in the bone marrow. It is
harder to eradicate tumor cells from a graft if we were to use the
patient's own cells to try and support a transplant
procedure. So similar diseases, mainly hematologic
malignancies.
Chu
So you would really never think about using this for colon cancer,
lung cancer or breast cancer? That is a common question that I
get.
Seropian
No you wouldn't. It is not a standard therapy because the graft
versus tumor effect has been demonstrated in the hematologic
malignancies. There are transplant programs that have done
research asking the question; could this graft versus tumor effect
apply to solid tumors? In fact, there is some evidence in certain
diseases that this can occur. Renal cell cancer is the solid
tumor where there is the most evidence of that. There are
patients who have had this kind of transplant with renal cell
cancer and have gone into remission and clearly it was the donor
cells that did the trick. So, there is research being done
for renal cell cancer and for breast cancer. There has been
some research for ovarian cancer as well, but in terms of the solid
tumors it is still in its infancy. We have not figured out how to
apply allogeneic transplant to those diseases effectively.
Miller
We have an e-mail question from George who lives in Stamford. He
asks, "I am 68 years old and have chronic myelogenous leukemia. My
doctors have talked about a transplant. Am I too old to get a
transplant?
Seropian
That is a good question. If you go back 10 or 15 years, the
answer would have been yes.
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The age cut-off in some centers used to be 55 years of age, at
others, 60 years of age. That has changed now. In fact, the
oldest patient that we have transplanted in our program with an
allogeneic transplant was 72. He is 76 now and doing
well. The reason this changed is because of our recognition
of this graft versus tumor effect that goes along with allogeneic
transplant. Once that was recognized, we took a step back and
said, well if the graft can do a lot of the work, do we have to
give the high doses of chemotherapy in the very beginning prior to
giving the donor cells? The answer to that question is no, we don't
have to do that. There are occasions where chemotherapy
really is very important, but for older patients, where that may be
too risky, there are some newer chemotherapy drugs and other
medicines that allow us to perform the procedure and give them
donor cells that will not be rejected. This is because we know a
little more about matching patients with donors and which
chemotherapy drugs are good at suppressing the patient's immune
system so they don't reject the cell. With a gentler
treatment that is safe, we can get a graft from a brother, sister
or unrelated donor into a patient even if they are older, and then
hope for a graft versus tumor effect. Particularly for a
patient with CML, if they are not doing well despite all the
wonderful new drugs for that disease, we would consider it.
Certainly other medical issues apply to all patients that need to
be investigated, but just on the basis of age, no.
Chu
We are obviously quite proud of the fact that the Yale Cancer
Center is the only accredited center here in the state of
Connecticut that is performing allogeneic stem cell
transplantation. Maybe you could tell our listeners how were we
able to get that accreditation designation. How many
transplants are being done and what research are you folks doing in
the transplant center?
Seropian
The current version of the transplant program at Yale has been
around since the mid 1990s. We perform over 100 transplants a year.
A little more than half of them are autologous transplant type, the
rest are allogeneic transplants. We are accredited by FACT
(Federation for the Accreditation of stem cell therapy, or Cell
Therapy. This is a national organization that inspects transplant
programs and makes sure they are following the standard safe
policies and procedures from top to bottom in terms of the way we
collect cells, the way we administer our therapies, the areas where
our patients are taken care of and the laboratory techniques. It is
a pretty rigorous inspection that happens every 3 or 4 years.
We were accredited initially in 2003, and just got reaccredited
recently.
Miller
In terms of research, what are some of the things that are
interesting that you are working on now?
Seropian
In terms of allogeneic stem cell transplant, I mentioned the
benefits of that type of procedure, graft versus tumor effects, but
we did not touch much on the potential side effects or risks
yet. The benefits of getting a new immune system from a
donor, we hope, translate into a better outcome in terms of curing
cancer, but there is also the possibility that the donor's immune
cells will recognize the patient's tissues as different, and there
can be reactions there, that is what graft versus host disease is.
Graft versus host disease
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is an illness that can occur after an allogenic transplant. Going
back to how we decide what kind of transplant we might perform for
a patient, we have to keep in mind the risks and side effects of
both procedures. The extra benefits we might get from an allogenic
transplant can be offset by higher risks of graft versus host
disease which is the most important complication when we consider
those factors. This is an illness that can cause a rash, it
could be relatively minor and treated readily, but it can also
affect the bowels and liver. A lot of our research is
directed at trying to reduce those complications.
Miller
If a patient or their family wants to learn more about bone marrow
transplant, how do they contact the transplant program?
Seropian
They can get information on the Yale Cancer Center website,
yalecancercenter.org, or they can call 1-866-Yale Cancer, which is
the direct number to the cancer center.
Miller
Terrific. Stuart, I want to thank you very-very much for
joining us.
Chu
This has been great, we look forward to having you on a future
session to hear more about transplantation. Until next week,
this is Dr. Ed Chu and Dr. Ken Miller from the Yale Cancer Center
wishing you a safe and healthy week.
If you have questions, comments, or would like to subscribe to our podcast, go to yalecancercenter.org, where you will also find transcripts of past broadcasts in written form. Next week, we will examine supportive care options for cancer patients.