Stem Cell Transplantation
in Scleroderma: A Treatment Whose Time May Be Coming
By Daniel Furst,
M.D. (originally published in "Scleroderma Voice,"
2003 #2)
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| Daniel
Furst, M.D. |
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 |
