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New Cancer Treatments

Stem Cell Transplantation 
  Submitted By: Matt  Kalaycio, M.D

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Stem Cell Transplantation


Article by Matt Kalaycio, M.D.
Director, Leukemia Program

Cleveland Clinic Foundation

Introduction



Most people are familiar with the term “bone marrow transplantation”
and have at least a rudimentary concept of what it means. The idea
of “stem cell transplantation” is more foreign and difficult to grasp
even though the meaning is quite similar. This article will explore
the definition, classification, and application of stem cell transplantation.

Transplantation

Types of Stem Cell Transplants



· Autologous

- Bone marrow stem cell

- Peripheral stem cell

· Allogeneic

- Bone marrow stem cell

- Peripheral stem cell

There are two major categories of transplant: autologous and allogeneic.
Autologous transplant means that the transplanted tissue (stem cell) is
derived from the person for whom the transplant is intended. In other
words, the patient donates stem cells to himself. Oncologists take
advantage of this technique to deliver extremely high doses of chemo and
radiotherapy that would otherwise result in irreversible bone marrow damage.
The autologous transplant rescues the patient from the marrow damaging
effects of high-dose chemo and radiotherapy.

An allogeneic transplant requires a donor, usually a sibling. The
immune system uses certain determinants to identfy things as self (autologous)
or non-self (allogeneic). These determinants, also known as the HLA-system,
will reject allogeneic tissue. Thus, tissue donors must be HLA-matched
to the recipient in order for a successful transplant to take place.
Furthermore, the recipient must be immunosuppressed to reduce the possibility
of donor tissue (graft) rejection. Therefore, an allogeneic transplant
is more complicated than an autologous transplant and is used, not only
to administer high-dose chemo and radiotherapy, but also to physically
replace the recipient’s bone marrow and immune system with that of the
donor.



Stem Cells

Not to be confused with the politically charged embryonic stem cell,
the hematopoietic stem cell is capable of both self-replication and differentiation
into any of the formed blood elements: white cells, red cells, and platelets.
This cell resides in the bone marrow and was originally detected and isolated
from cultures derived from bone marrow cells. (1) Simultaneous technological
advances allowed for the harvesting of these marrow stem cells and their
subsequent re-infusion to reconstitute otherwise damaged bone marrow. (2)
Thus, the technique of bone marrow transplant was born.

However, these stem cells were also detected circulating in the peripheral
blood stream, albeit in small numbers. (3) In patients for whom bone marrow
harvesting was impossible for some reason or another, these circulating
peripheral stem cells could be harvested and stored over a several days
to weeks by a techniques known as leukopheresis and cryopreservation respectively.
(4) This method was costly, time-consuming, and labor-intensive.

The discovery and application of hematopoietic growth factors (HGF)
improved the ability to harvest stem cells. HGF are molecules manufactured
mostly in blood cells that help guide the development of blood cells from
stem cells to maturity. (5) They also help the body cope with environmental
changes to maintain adequate numbers of blood cells at all times.
The human HGF molecules can also be manufactured in other cell culture
systems in mass quantities. These molecules, such as granulocyte
colony-stimulating factor (GCSF), as granulocyte-macrophage colony-stimulating
factor (GM-CSF) and erythropoietin (EPO) are now widely available for medical
applications.

One application of HGF is the harvesting of peripheral blood stem
cells. Patients are given HGF by a series of subcutaneous injections
with only rare serious side effects. These injections result in an
increase in the white blood cell count and an increase in the number of
peripheral blood stem cells. (6) The stem cells are distinguished from
other cells by their unique ability to display the membrane protein CD34
on their surface. (7) These CD34+ cells are then harvested from the blood
stream by leukopheresis (Figure 1) much more efficiently and quicker than
non-growth factor stimulated stem cells.




While these harvested peripheral stem cells have some properties
that differ with regard to bone marrow stem cells, they repopulate the
bone marrow and grow new blood cells similarly. However, peripheral
blood stem cells accomplish this task much quicker. (8) This accelerated
blood cell recovery allows for a lower risk of infection and fewer transfusions
compared to bone marrow stem cells. As a result, peripheral stem
cell transplants in both the autologous and allogeneic transplant setting
are replacing bone marrow transplants in many instances.

Alternative Sources of Stem Cells


Alternative Sources of Stem Cells



· Matched Sibling

· Partially Matched Sibling

· Matched Unrelated Donor

· Placental Cord Blood

To perform an autologous or allogeneic transplant, both bone marrow
and peripheral blood stem cells may be used. Just about everybody
can donate his or her own stem cells for autologous transplantation.
Some academic centers store autologous stem cells early in the treatment
of a disease, but most collect them only when they are needed. Bone
marrow has a nearly inexhaustible supply of stem cells allowing for multiple
autologous transplants if necessary. (9)

Unfortunately, allogeneic transplants require an HLA-matched donor.
There is only a 25% chance that any one sibling will be HLA-matched to
another. Therefore, in this age of relatively small nuclear families,
most patients will not have an HLA-matched sibling who could donate stem
cells. For these patients, alternative stem cell sources are required.

Partially matched family members may serve as stem cell donors, but
these transplants require more intensive chemo and radiotherapy and are
generally more dangerous than matched sibling transplants. (10) Few transplant
centers perform these procedures.

Rarely, people unrelated to the patient will be HLA-matched by chance.
Finding these people would prove difficult if they were randomly tested
for HLA determinants. To circumvent this problem, the National Marrow
Donor Program (NMDP) was established in the United States to serve as a
central repository for volunteer donors who have been HLA-typed. (11) Other
registries serve other countries, but most are electronically linked for
ease of international searches. With well over 5 million registered
volunteers, patients searching for a matched, unrelated donor have between
a 50-75% chance of finding a match through the NMDP.

The results of matched unrelated donor stem cell transplants are
not quite as good as with sibling donors, but are a viable source of stem
cells offering the opportunity for cure when none exist otherwise. (12)
However, an unrelated donor transplant takes time to locate and recruit
a donor. Thus, careful planning is critical early in a patient’s
treatment.

Another source of stem cells is placental umbilical cord blood.
The volume of blood and the total number of stem cells are generally small,
but adults can reconstitute hematopoiesis with cord blood cells. (13) Cord
blood stem cells are immunologically naďve and therefore perfect HLA-matching
is not required. More important are the number of stem cells and
the volume of infused blood. Furthermore, large cord blood banks
have made cord blood cells rapidly available providing an advantage compared
to volunteer donor stem cells. However, the limited amount of stem
cells per cord blood unit results in a longer time to bone marrow and immune
system recovery increasing the risk of infections. This disadvantage
notwithstanding, cord blood is a viable alternative source of stem cells,
particularly for children. (14)

The Future of Stem Cell Transplantation

The hematopoietic stem cell is multiplastic. That means that
the stem cell can develop into more than just blood cells. Under
the right conditions, blood stem cells can be forced to develop into different
tissue such as heart muscle, bone, and blood vessel cells. (15) The science
of stem cell plasticity is in its infancy, but promises to revolutionize
the way we think about about organ regeneration and transplantation.

Summary

The ability to isolate, harvest, and manipulate hematopoietic stem
cells has led to the cure of thousands of otherwise incurable people with
a variety of both malignant and non-malignant disorders. These stem
cells are readily available and most people who need them should have reasonable
access to them whether they originate in a family member, unrelated volunteer
donor, or a placental cord blood unit. In the future these stem cells
will yield to additional manipulations that may result in far greater clinical
applications that could have been dreamed possible when they were first
discovered.
 



 


Additional Authors:  

Works Cited:  
  1. Ford CE, Haverton JC, Barnes DWH, Loutit JF. Cytological identification of radiation chimeras. Nature 177: 452, 1956
2. Thomas ED, Lochte HL, Lu WC, Ferrebee JW. Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy. New Engl J Med 257: 491, 1957.
3. Barr RD, Whang-Peng J, Perry s. Hemopoietic stem cells in human peripheral blood. Science 190: 284, 1975.
4. Kessinger A, Armitage JO, Landmark JD et al. Reconstitution of human hematopoietic function with autologous cryopreserved circulating stem cells. Exp Hematol 14: 192, 1986
5. Oster W, Mertelsmann R, and Herrmann F. Regulation of cell function by hematopoietic growth factors. In: Hematopoietic Growth Factors in Clinical Applications. Eds, Mertelsmann R and Herrmann F. Marcel Dekker, New York, NY. Pg 25-39, 1990.
6. Gianni AM, Siena S, Bregni M, et al. Granulocyte-macrophage colony-stimulating factor to harvest circulating hematopoietic stem cells for autotransplantation. Lancet 9: 580, 1989
7. Siena S, Bregni M, Brando B, et al. Circulation of CD34+ hematopoietic stem cells in the peripheral blood of high-dose cyclophosphamide-treated patients enhanced by intravenous rHuGM-CSF. Blood 74: 1905, 1989
8. Chao NJ, Schriber JR, Grimes K, et al. Granulocyte colony-stimulating factor “mobilized” peripheral blood progenitor cells accelerate granulocyte and platelet recovery after high-dose chemotherapy. Blood 81:2031, 1993.
9. Pettengel R, Woll PJ, Thatcher N, Dexter TM, Testa NG. Multicyclic, dose-intensive chemotherapy supported by sequential reinfusion of hematopoietic progenitor cells in whole blood. J Clin Oncol 13: 148, 1995
10. Aversa F, Tabilio, A, Velardi A, et al. Treatment of high-risk acute leukemia with T-cell depleted stem cells from related donors with one fully mismatched HLA haplotype. N Engl J Med 339: 1186, 1998.
11. Confer DL. Unrelated marrow donor registries. Curr Opin Hematol 4: 408, 1997.
12. Kernan NA, Bartsch G, Ash RC, et al. Analysis of 462 unrelated marrow transplants facilitated by The National Marrow Donor Program. N Engl J Med 328: 593, 1993
13. Laughlin MJ, Barker J, Baumbach B, et al. Hematopoietic engraftment and survival in adult recipients of umbilical-cord blood from unrelated donors. N Engl J Med 344: 1815, 2001
14. Gluckman E. Hematopoietic stem-cell transplants using umbilical cord blood. N Engl J Med 344: 1860, 2001
15. Körbling M, Katz RL, Khanna A, et al. Hepatocytes and epithelial cells of donor origin in recipients of peripheral-blood stem cells. N Engl J Med 346:738, 2002



 
 


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