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The promising future of transplantation
Costs decline, success rates rise, more people benefit,
reports Hutch's Nobel Prize-winning Thomas team
[The following is reprinted by permission from the November/December
edition of Franklin, Tenn.-based COPING magazine.]
By Dr. E. DONNALL THOMAS and DOTTIE THOMAS
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Dr. E. Donnall and Dottie
Thomas pose with some of the 200 patients who attended the Spirit
of Seattle 2000 reunion on Aug. 5 in Seattle.
-Photo by Jim Linna
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They came from as far away as Switzerland and Japan,
from cities like New York and small towns like Kalispell.
More than 200 former patients and almost as many family members
gathered (last summer) in Seattle to celebrate their successful
battle against leukemia and other blood disorders.
They shared stories with their ward mates during their hospital
stay and compared experiences with more recent patients.
Everyone agreed that remarkable progress had been made since
the late 1960s when the first patients were treated.
The basic concept of marrow transplantation is still very
much he same, however. Lethal doses of radiation and chemotherapy,
alone or in combination, are used to eliminate a malignant disease.
Unfortunately, this highly toxic dose also destroys the ability
to make blood and immune cells, making it essential to replace
the hematopoietic system with normal marrow from another source.
Stem-cell sources
The cells necessary to rescue the treated patient are referred
to as stem cells. No matter what the source of these cells, they
must be human leukocyte antigen (HLA) compatible with the patient.
The most frequently used source initially was marrow from
a normal brother or sister (an allogeneic transplant).
In some cases, the patient's own marrow could be collected,
store and given back (an autologous transplant). However, there
were still many people without a suitable source of stem cells.
Peripheral blood
With the development of various growth factors to stimulate
production of stem cells, it became possible to collect sufficient
numbers of these unique cells directly from the donor's vein.
This procedure is usually referred to as a peripheral blood stem-cell
transplant.
Now, hematologists worldwide are trying to use the term hematopoietic
cell transplant since it is the stem cell that provides the life-saving
cell regeneration, whether it is obtained from the marrow or
from the peripheral blood.
Cord blood
Another major development was the use of placental cord blood
collected at the time of delivery. The infant's cord is usually
discarded at birth, but it is a rich source of hematopoietic
stem cells. These cells can be HLA typed and stored by freezing.
There are now more than 20 cord-blood banks worldwide with
cells available for rapid shipment to people without other stem-cell
sources.
The National Bone Marrow Donor Program
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EXTENDED APPLICATION
Initially, transplants were undertaken to treat leukemia
or marrow failure. As the success rates increased, physicians
applied the treatment to other diseases, like hereditary
conditions such as sickle cell disease and thalassemia major.
Malignant diseases such as breast cancer and others are
now being treated in this way, since the same general principles
of destroying malignant cells with mega doses of drugs and radiation
are used.
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Another striking development has been the tremendous
increase in the use of hematopoietic stem cells from volunteer
unrelated donors.
The National Marrow Donor Program now has more than 4 million
registered volunteers, 2.2 million of whom have been fully HLA
typed. Almost 10,000 transplants have been facilitated by the
program since its beginning in 1987.
An additional 2 million donors are available through registries
in other countries, and stem cells can be exchanged readily through
these cooperative programs.
Donor lymphocyte infusion
It has been known for some time that people who develop the
immunological reaction known as graft-vs.-host disease (GVHD)
are less likely to have a recurrence of leukemia after hematopoietic
cell transplantation. This effect is known as the graft-vs.-leukemia
(GVL) reaction.
More recently, in an effort to take advantage of the GVL reaction,
additional lymphocytes were collected from the donor and given
to patients who had had a recurrence of leukemia after a graft.
Sometimes GVHD resulted, but more often the GVL effect eliminated
the recurrent leukemia without any other treatment.
Investigators are now studying ways to minimize the GVHD effect
and maximize the GVL effect.
Mini-transplants
The term "mini-transplants" describes those achieved
by doses of drugs or irradiation that do not completely destroy
the person's marrow and leukemic cells.
The use of very immunosuppressive drugs such as fludarabine
or mycophenolate mofetil permits cell engraftment after less-than-lethal
chemo-radiotherapy.
Over a period of days or weeks, the engrafted cells can take
over the production of blood cells and immune cells. The immune
cells may eradicate the leukemia through the GVL reaction.
These transplants are much easier on the patient and can often
be done without admission to the hospital. These procedures are
so new that long-term effects and survival are still being evaluated,
but early results are encouraging.
Targeted therapy
A single lymphocyte producing a single antibody can be isolated
and with the aid of the cytokine IL-2 grown into many millions
of cells. The lymphocyte can be a natural one from the peripheral
blood.
Alternatively, more commonly it is from the fusion of a single
immune cell with a mouse myeloma cell to produce a monoclonal
antibody.
Monoclonal antibodies alone have been somewhat disappointing
as therapeutic agents. However, monoclonal antibodies can be
combined with active agents such as drugs or radioactive isotopes
to produce potent agents.
Depending on the specificity of the antibody, these agents
can react with specific cells such as a cell infected with a
virus or a leukemic cell.
Since these agents react with a specific abnormal cell, they
are not toxic to normal cells. They can be used alone or, more
commonly, to increase the kill of abnormal cells in conjunction
with a regular hematopoietic cell graft or a mini-transplant.
Many studies are under way with these promising specific agents.
Expanded application of hematopoietic transplantation
Initially, transplants were undertaken to treat leukemia or
marrow failure. As the success rates increased, physicians applied
the treatment to other diseases, like hereditary conditions such
as sickle cell disease and thalassemia major.
Malignant diseases such as breast cancer and others are now
being treated in this way, since the same general principles
of destroying malignant cells with mega doses of drugs and radiation
are used.
Responses in breast cancer vary, but more time is necessary
to evaluate the long-term results. Some autoimmune diseases are
also now the subjects of treatment with stem-cell transplants.
Through the extensive research being carried out worldwide
on all aspects of hematopoietic cell transplants, costs are coming
down, success rates are going up and more people are benefiting
from this form of therapy.
[Dr. E. Donnall Thomas, who received the 1990 Nobel Prize
in medicine, began investigating transplantation in the 1950s
and is director emeritus of the Hutch Clinical Research Division.
His wife Dottie is his lifelong research partner.]
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