Stem Cell Transplantation
in Scleroderma: A Treatment Whose Time May Be Coming
By Daniel Furst, M.D. (originally
published in "Scleroderma Voice," 2003 #2)
In approximately 1996, the idea
occurred to several of us, on three separate continents, that stem cell
transplantation might be both an effective therapy for the right patient
with systemic sclerosis and a way to test how important the immune system
might be in the disease. That sentence needs a good deal of explanation.
What is stem cell transplantation?
Stem cell transplantation is
a treatment in which we take either the patient's own cells (in which
case the process is called "autologous") or a close relative's
cells (called "allogeneic") and give them back to the patient
after the patient's immune system has been removed as much as possible.
The idea is that one removes the cells that are doing harm and allows
a new immune system to develop in the presence of scleroderma. In this
case, the new immune system sees scleroderma as "normal" and
does not react against itself—so the body can heal.
To date, most stem cell transplantation
for scleroderma has been done with the patient's own cells (autologous
transplantation) because it is somewhat safer than the allogeneic transplantation.
The process requires the removal
of "stem cells" from the blood; these are the cells from our
bone marrow which can become all parts of our immune system and which
float around in our blood in small numbers.
The removal of these undifferentiated
cells is called "mobilization," and can be done using a variety
of medications and procedures. In autologous stem cell transplantation,
we take the patient's own cells, and give them back to the patient after
removing the immune system as much as possible.
After that, high-dose immunosuppressive
therapy, sometimes combined with proteins and/or radiation therapy which
kills immune cells, is used to get rid of the body's abnormal immune system;
this is called "conditioning." Again, numerous medications and
combinations of approaches can be used.
Finally, medication is given
to stimulate the new cells for faster recovery. It is as if the new immune
system is that of a little child's; and, in fact, patients who undergo
stem cell transplantation need revaccination after a year or so, just
as if their immune system was a child's.
Where did the idea of using stem cell transplantation
in scleroderma start?
Animal experiments indicated
that bone marrow transplantation or stem cell therapy of autoimmune disease
might be helpful, because when done in certain ways, it could cause complete
remission of the autoimmune disease in these animals.
In addition, there were some
patients who had autoimmune diseases such as rheumatoid arthritis or systemic
lupus erythematosus and who also had cancers which required bone marrow
transplantation. With transplantation, the autoimmune disease went into
long-term remission. This, and the animal data, made us and others think
that stem cell transplantation might be useful in scleroderma.
Ten to 15 years ago, most stem
cell transplantation was actually called bone marrow transplantation.
This is because at that time bone marrow was used for the transplantation.
New technology has allowed us to remove stem cells
from the blood using machines similar to dialysis machines; this is safer
and easier and is actually "stem cell transplantation" rather
than bone marrow transplantation.
Who is the "right" patient? Who should be
given stem cell transplantation for scleroderma?
Of course, this therapy is still
experimental, and much still needs to be done. In general, because this
is a dangerous procedure (see below), only the patients who will, predictably,
do very poorly should undergo this therapy. Thus, stem cell transplantation,
at this time, needs to be reserved only for those patients who have a
great deal of skin involvement and internal organ involvement (particularly
the lungs or kidneys) and whose disease duration is less than four years.
These are patients whose likelihood of survival after five years is less
than 50% and are there fore, the sickest patients.
On the other hand, patients must,
in general, be healthy otherwise and not have "too much" internal
organ involvement so they can tolerate the treatments.
Thus, we estimate that no more
than 5% to 15% of patients who have early systemic sclerosis should consider
stem cell transplantation for their scleroderma.
What has been done so far?
Most stem cell transplantation
thus far has been autologous. An excellent co-operative effort is ongoing
between researchers in North America and in Europe and there have been
over 100 transplants done, overall, in patients with scleroderma.
In Europe, a number of different
regimens had been used but, in general, mobilization is now done using
cyclophosphamide (Cytoxan) and a stimulatory medication called GCSF. Conditioning
uses high doses of cyclophosphamide and another immunosuppressive medicine
called ATG.
In the United States, mobilization
does not use cyclophosphamide and less cyclophosphamide is used during
conditioning; on the other hand, increased immunosuppression is achieved
using radiation in moderately low doses, as well as the ATG. These two
sets of regimens are going to be compared, so that we can tell which one
will be better.
There is a registry in Europe
which records the different regimens used and the general outcomes. The
most recent publication was in 2002 and listed the 66 patients with scleroderma
who were treated through the middle of 2001.
In these cases, there were three
mobilization regimens and seven different conditioning regimens, so the
results cannot be considered in terms of "stem cell transplantation"
but rather in terms of a general approach of high-dose immunosuppressive
therapy followed by stem cell rescue.
Using this mixed group of treatments,
50% of patients registered improvement, another 15% initially improved
but later relapsed, 2% did not respond, and 5% worsened. Thirteen percent
of patients died from either their underlying scleroderma or the complications
of treatment.
In the United States, there have
been approximately 30 stem cell transplants in scleroderma patients. These
patients have all undergone the same stem cell transplants therapy and
so can be examined more closely.
While this is an open study and
subject to the biases of such a study, there has been an approximately
40% improvement in skin score and an impressive 90% improvement in ability
to function.
It is also encouraging that internal
organs such as the lungs and kidneys have remained stable, while one would
have expected them to worsen with many other treatments over the 1 to
3 years of follow-up. As in Europe, about 13% of patients died.
Yes, but ... given that these
particular patients would have done extremely badly without stem cell
transplantation, the results thus far are quite encouraging.
On the other hand, what about side effects?
When this therapy was initially
started, some of the problems arose because treatment was too aggressive.
In Europe, a few patients died
during mobilization, possibly related to too much cyclophosphamide or
to their underlying disease.
In the United States, the combination
of radiation and cyclophosphamide was too much for two patients and they
died. Since the radiation has been decreased, the patients have had no
significant problems of this sort. However, one patient in the United
States died when a particular form of ATG was used and the patient developed
a very aggressive form of lymphoma.
During the initial two to three
weeks of therapy, the body's immune system is nonfunctional, so we have
to be extremely careful about infections. For example, if a visitor has
a cold, they are not even allowed on the same floor with the patient undergoing
transplantation.
Also, as mentioned above, the
patient's immune system doesn't come back to normal for a number of months
and they have to be careful for approximately a year before they can go
out into normal crowded conditions.
In fact, during the first two
to three months, they are asked to stay near the hospital where they had
their transplantation and they are checked every two to three days to
be sure that they are all right. This means they may need to stay in an
apartment near the hospital and away from their home for several months.
Summary
Stem cell transplantation is
a very hopeful therapy in patients with very severe systemic sclerosis.
This treatment may be able to significantly improve the quality of life
and longevity of patients with the severest form of this disease. On the
other hand, stem cell transplantation is dangerous, and we are only in
the beginning stages of learning how to use it to its best advantage and
how good it really is.
For those interested in this
study, you may contact the author:
Daniel Furst, M.D.
1000 Veteran Avenue
Room 32-59
Los Angeles, CA 90025
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