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Hematopoietic stem cell transplantation (HSCT) is the transplantation of
blood stem cells derived from the bone marrow (that is, bone marrow
transplantation) or blood. Stem cell transplantation is a medical procedure in
the fields of hematology and oncology, most often performed for people with
diseases of the blood, bone marrow, or certain types of cancer.
Stem cell transplantation was pioneered using bone-marrow-derived stem cells by
a team at the Fred Hutchinson Cancer Research Center from the 1950s through the
1970s led by E. Donnall Thomas, whose work was later recognized with a Nobel
Prize in Physiology and Medicine. Thomas' work showed that bone marrow cells
infused intravenously could repopulate the bone marrow and produce new blood
cells. His work also reduced the likelihood of developing a life-threatening
complication called Graft-versus-host disease.
With the availability of the stem cell growth factors GM-CSF and G-CSF, most
hematopoeitic stem cell transplantation procedures are now performed using stem
cells collected from the peripheral blood, rather than from the bone marrow.
Collecting stem cells provides a bigger graft, and does not require that the
donor be subjected to general anesthesia to collect the graft.
Hematopoeitic stem cell transplantation remains a risky procedure with many
possible complications; it has always been reserved for patients with
life-threatening diseases.
Indications for stem cell transplantation:
Most recipients of HSCTs are leukemia patients who would benefit from treatment
with high doses of chemotherapy or total body irradiation. Other conditions
treated with stem cell transplants include sickle-cell disease, myelodysplastic
syndrome, neuroblastoma, lymphoma, Ewing's Sarcoma, Desmoplastic small round
cell tumor, Hodgkin's disease, and multiple myeloma. More recently non-myeloablative,
or so-called "mini transplant," procedures have been developed that require
smaller doses of preparative chemo and radiation. Mini transplants remain in the
experimental domain of medicine as of May, 2007.
Hematopoietic SCT-Types/Donors/HSC Sources & Storage:
Autologous HSCT involves isolation of HSC from the patient, storage of the
hematopoeitic stem cells in a freezer, high-dose chemotherapy to eradicate the
patient's malignant cell population at the cost of also eliminating the
patient's bone marrow stem cells, then return of the patient's own stored stem
cells to their body. Autologous transplants have the advantage of a lower risk
of graft rejection and infection, since the recovery of immune function is
rapid. There is no chance for graft-versus-host disease, since the donor and
recipient are the same individual.
Allogeneic HSCT involves two people, one is the (normal) donor and one is the
(patient) recipient. Allogeneic HSC donors must have a tissue (HLA) type that
matches the recipient. Matching is performed on the basis of variability at
three or more loci of the (HLA) gene, and a perfect match at these loci is
preferred. Even if there is a good match at these critical alleles, the
recipient will require immunosuppressive medications to mitigate
graft-versus-host disease. Allogeneic transplant donors may be related (usually
a sibling) or unrelated volunteers. Allogeneic transplants are also performed
using umbilical cord blood as the source of stem cells.
Donor selection To avoid rejection of the transplanted stem cells or severe
graft-versus-host disease, the donor should have the same human leukocyte
antigens (HLA) as the recipient. About 25 to 30 percent of potential HSCT
recipients have an HLA-identical sibling. Even so-called "perfect matches" may
have mismatched minor alleles that contribute to graft-versus-host disease.
Sources of HSC Peripheral blood stem cells are now the most common source of
stem cells for HSCT. They are collected from the blood through a process known
as apheresis. The donor's blood is withdrawn through a sterile needle in one arm
and passed through a machine that removes white blood cells. The red blood cells
are returned to the donor. The peripheral stem cell yield is boosted with daily
subcutaneous injections of Granulocyte-colony stimulating factor, which
mobilizes stem cells from the donor's bone marrow into the peripheral
circulation.
Umbilical cord blood is obtained when parents elect to harvest and store the
blood from a newborn's umbilical cord and placenta after birth. Cord blood has a
higher concentration of HSC than is normally found in adult blood.
Storage of HSC Unlike other organs, bone marrow cells can be frozen for
prolonged time periods (cryopreserved) without damaging too many cells. This is
necessary for autologous HSC because the cells must be harvested months in
advance of the transplant treatment. In the case of allogeneic transplants fresh
HSC are preferred in order to avoid cell loss that might occur during the
freezing and thawing process. Allogeneic cord blood is stored frozen at a cord
blood bank because it is only obtainable at the time of childbirth. To
cryopreserve HSC a preservative, DMSO, must be added and the cells must be
cooled very slowly in a control rate freezer to prevent osmotic cellular injury
during ice crystal formation. HSC may be stored for years in a cryofreezer which
typically utilizes liquid nitrogen because it is non-toxic and it is very cold
(boiling point -196°C.)
Conditioning regimens:
The chemotherapy or irradiation given immediately prior to a transplant is
called the conditioning or preparative regimen. The purpose is to help eradicate
the patient's disease prior to the infusion of HSC and to suppress immune
reactions. The bone marrow can be ablated at doses that cause minimal injury to
other tissues. In allogeneic transplants a combination of cyclophosphamide with
busulfan or total body irradiation is commonly employed. This treatment also has
an immunosuppressive effect which prevents rejection of the HSC by the
recipient's immune system. Autologous transplants may also use these
conditioning regimens but many other chemotherapy combinations can be used
depending on the type of disease.
Non-myeloablative' allogeneic HSCT is a newer treatment approach which uses
lower doses of chemotherapy and radiation which are too low to eradicate all of
the bone marrow cells of a recipient. Instead, non-myeloablative transplants
exploit the graft versus tumor effect for their benefit. They do require high
doses of immunosuppressive agents in the early stages of treatment. This leads
to a state of mixed chimerism early after transplant where both recipient and
donor HSC coexist in the bone marrow space. Decreasing doses of
immunosuppressive therapy then allows donor T-cells to eradicate the remaining
recipient HSC and to induce graft-versus-host disease and the graft versus tumor
effect.
Non-myeloablative (or "mini") allogeneic transplants, because of their gentler
conditioning regimens, are associated with a lower risk of transplant-related
mortality and therefore allow patients who are considered too high-risk for
conventional allogeneic HSCT to undergo potentially curative therapy for their
disease. These new transplant strategies are experimental, for the most part,
and available at academic research centers.
Engraftment:
After several weeks of growth in the bone marrow, expansion of HSC and their
progeny is sufficient to normalize the blood cell counts and reinitiate the
immune system. Donor-derived hematopoeitic stem cells have been documented to
populate many different organs of the recipient, including the heart, liver, and
muscle, a phenomenon known as stem cell plasticity.
Side effects and complications:
HSCT is associated with a fairly high mortality in the recipient (10% or
higher), which limits its use to conditions that are themselves
life-threatening. Major causes of complications are veno-occlusive disease,
mucositis, infection-sepsis and graft-versus-host disease.
Veno-Occlusive Disease- Severe liver injury is termed hepatic veno-occlusive
disease (VOD). Elevated levels of bilirubin, hepatomegaly and fluid retention
are clinical hallmarks of this condition. There is now a greater appreciation of
the generalized cellular injury and obstruction in hepatic vein sinuses, and it
has thus been referred to as sinusoidal obstruction syndrome (SOS). Severe cases
are associated with a high mortality. Anticoagulants or defibrotide may be
effective in reducing the severity of VOD but may also increase bleeding
complications. Ursodiol has been shown to help prevent VOD, presumably by
helping the flow of bile.
Mucositis- The injury of the mucosal lining of the mouth and throat and is a
common regimen-related toxicity following ablative HSCT regimens. It is usually
not life-threatening but is very painful, and prevents eating and drinking.
Mucositis is treated with pain medications plus intravenous infusions to prevent
dehydration and malnutrition.
Infection- Bone marrow transplantation usually requires that the recipient's own
bone marrow is destroyed ("myeloablation"). Prior to "engraftment" patients may
go for several weeks without appreciable numbers of white blood cells to help
fight infection. This puts a patient at risk of infections, sepsis and septic
shock despite prophylactic antibiotics. The immunosuppressive agents employed in
allogeneic transplants for the prevention or treatment of graft-versus-host
disease further increase the risk of opportunistic infection. Immunosuppressive
drugs are given for a minimum of 6-months after a transplantation, or much
longer if required for the treatment of graft-versus-host disease. Transplant
patients lose their acquired immunity, for example immunity to childhood
diseases such as measles or polio. For this reason transplant patients must be
re-vaccinated with childhood vaccines once they are off of immunosuppressive
medications.
Graft-versus-host disease (GVHD)- An inflammatory disease that is unique to
allogeneic transplantation. It is an attack of the "new" bone marrow's immune
cells against the recipient's tissues. This can occur even if the donor and
recipient are HLA-identical because the immune system can still recognize other
differences between their tissues. It is aptly named graft-versus-host disease
because bone marrow transplantation is the only transplant procedure in which
the transplanted cells must accept the body rather than the body accepting the
new cells. Acute graft-versus-host disease typically occurs in the first 3
months after transplantation and may involve the skin, intestine, or the liver.
Corticosteroids such as prednisone are a standard treatment. Chronic
graft-versus-host disease may also develop after allogeneic transplant and is
the major source of late complications. In addition to inflammation, chronic
graft-versus-host disease may lead to the development of fibrosis, or scar
tissue, similar to scleroderma or other autoimmune diseases and may cause
functional disablity, and the need for prolonged immunosuppressive therapy.
Graft-versus-host disease is usually mediated by T cells when they react to
foreign peptides presented on the MHC of the host. Removal of these T cells
before donation can lessen the risk of this disease.
Graft versus tumor effect- The beneficial aspect of the Graft-versus-Host
phenomenon is known as the "graft versus tumor" or "graft versus leukemia"
effect. For example, leukemia patients with chronic graft-versus-host disease
after an allogeneic transplant have a lower risk of leukemia relapse. This is
due to a therapeutic immune reaction of the grafted donor lymphocytes, more
specifically, the Natural Killer cells, against the diseased bone marrow of the
recipient. This lower rate of relapse accounts for the increased success rate of
allogeneic transplants compared to transplants from identical twins, and
indicates that allogeneic HSCT is a form of immunotherapy. GVT is the major
benefit of transplants which do not employ high dose chemotherapy or radiation.
Conditions treated with bone marrow or HSC transplantation:
Acquired
Acute lymphocytic leukemia
Acute myelogenous leukemia
Aplastic anemia
Chronic myelogenous leukemia (accelerated phase or blast crisis)
Hodgkin's disease
Multiple myeloma (Kahler's disease)
Myelodysplasia
Non-Hodgkin's lymphoma
Paroxysmal nocturnal hemoglobinuria (PNH; severe aplasia)
Radiation poisoning
chronic lymphocytic leukemia
AL amyloidosis
Congenital
Adrenoleukodystrophy
Amegakaryocytic Thrombocytopenia
Sickle cell disease
Griscelli syndrome type II
Hurler syndrome
Kostmann syndrome
Krabbe disease
Metachromatic leukodystrophy
Thalassemia
Hemophagocytic lymphohistiocytosis (HLH)
Wiskott-Aldrich syndrome
Neuroblastoma
Some inborn errors of metabolism
References
Thomas ED, Lochte HL, Lu WC et al. Intravenous infusion of bone marrow in
patients receiving radiation and chemotherapy. N Engl J Med 1957; 157: 491-496.
PMID 13464965. Google Scholar
Socié, Gérard, et al. (December 2001). "Busulfan plus cyclophosphamide compared
with total-body irradiation plus cyclophosphamide before marrow transplantation
for myeloid leukemia: long-term follow-up of 4 randomized studies". Blood
98(13): 3569-3574. Fulltext. PMID 11739158.
Richardson PG, et al. (December 2002). "Multi-institutional use of defibrotide
in 88 patients after stem cell transplantation with severe veno-occlusive
disease and multisystem organ failure: response without significant toxicity in
a high-risk population and factors predictive of outcome". Blood 100(13):
4337-43. PMID 12393437
Guglielmi, PT, et al. (December 1995). "Autologous bone marrow transplantation
as compared with salvage chemotherapy in relapses of chemotherapy-sensitive
non-Hodgkin's lymphoma". New England Journal of Medicine 333(23): 1540-5. PMID
7477169.
Barker JN, et al. (December 2005). "Transplantation of 2 partially HLA-matched
umbilical cord blood units to enhance engraftment in adults with hematologic
malignancy". Blood 105(3): 1343-1347. Fulltext. PMID 15466923.
Retrieved from
"http://en.wikipedia.org/wiki/Hematopoietic_stem_cell_transplantation"
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