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.
The first physician to perform a successful human bone marrow transplant was Robert A. Good.
With the availability of the stem cell growth factors GM-CSF and G-CSF, most hematopoietic stem cell transplantation procedures are now performed using stem cells collected from the peripheral blood, rather than from the bone marrow. Collecting peripheral blood stem cells provides a bigger graft, does not require that the donor be subjected to general anesthesia to collect the graft, results in a shorter time to engraftment, and may provide for a lower long-term relapse rate.
Hematopoietic stem cell transplantation remains a risky procedure with many possible complications; it has traditionally been reserved for patients with life-threatening diseases. While occasionally used experimentally in nonmalignant and nonhematologic indications such as severe disabling auto-immune disease and cardiovascular disease, the risk of fatal complications appears too high to gain wider acceptance.
Indications for stem cell transplantation
Many recipients of HSCTs are multiple myeloma
patients who would not benefit from prolonged treatment with, or are already resistant to chemotherapy
. Candidates for HSCTs include pediatric
cases where the patient has an inborn defect such as severe combined immunodeficiency
or congenital neutropenia
with defective stem cells, and also children or adults with aplastic anemia
who have lost their stem cells after birth. Other conditions treated with stem cell transplants include sickle-cell disease
, myelodysplastic syndrome
, Ewing's Sarcoma
, Desmoplastic small round cell tumor
and Hodgkin's disease
. More recently non-myeloablative, or so-called "mini transplant," procedures have been developed that require smaller doses of preparative chemo and radiation. This has allowed HSCT to be conducted in the elderly and other patients who would otherwise be considered too weak to withstand a conventional treatment regimen.
Autologous HSCT involves isolation of haematopoietic stems cells (HSC) from the patient and storage of the harvested cells in a freezer. The patient is then treated with high-dose chemotherapy
with or without radiotherapy in the form of total body irradiation
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. Also, the incidence of a patient experiencing graft-versus-host disease
is close to none as the donor and recipient are the same individual. However, in malignant disease the likelihood of cancer relapse and related mortality is high relative to allogeneic HCST.
Allogeneic HSCT involves two people: the (healthy) donor and 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 closely HLA matched sibling) or unrelated
(donor who is not related and found to have very close degree of HLA matching ). Allogeneic transplants are also performed using umbilical cord blood
as the source of stem cells. In general, by transplanting healthy stem cells to the recipient's immune system, allogeneic HCSTs appear to improve chances for cure or long-term remission once the immediate transplant-related complications are resolved.
HSC sources and storage
To limit the risks of transplanted stem cell rejection
or of severe graft-versus-host disease
in allogeneic HSCT, the donor should preferably have the same human leukocyte antigens (HLA)
as the recipient. About 25 to 30 percent of allogeneic HSCT recipients have an HLA-identical sibling. Even so-called "perfect matches" may have mismatched minor alleles that contribute to graft-versus-host disease.
Peripheral blood stem cells
Peripheral blood stem cells are now the most common source of stem cells for allogeneic 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
, serving to mobilize stem cells from the donor's bone marrow into the peripheral circulation.
Umbilical cord blood
Umbilical cord blood is obtained when parents elect to harvest and store the blood from a newborn's umbilical cord
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.)
given immediately prior to a transplant is called the conditioning or preparative regimen, the purpose of which 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
with dose-levels that cause minimal injury to other tissues. In allogeneic transplants a combination of cyclophosphamide
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
. The post-transplant prognosis often includes acute and chronic graft-versus-host disease
which may be life-threatening; however in certain leukamias this can coincide with protection against cancer relapse owing to the graft versus tumor
transplants may also use similar conditioning regimens, but many other chemotherapy combinations can be used depending on the type of disease.
Non-myeloablative (or "mini") allogeneic transplants
This is a newer treatment approach using lower doses of chemotherapy
which are too low to eradicate all of the bone marrow cells
of a recipient. Instead, non-myeloablative transplants run lower risks of serious infections and transplant-related mortality while relying upon the graft versus tumor
effect to resist the inherent increased risk of cancer relpase. Also significantly, while requiring high doses of immunosuppressive agents
in the early stages of treatment, these doses are less than for conventional transplants. 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 the graft versus tumor effect. This effect is often accompanied by mild graft-versus-host disease
, the appearance of which is often a surrogate for the emergence of the desirable graft versus tumor effect, and also serves as a signal to establish an appropriate dosage level for sustained treatment with low levels of immunosuppressive agents
Because of their gentler conditioning regimens, these transplants 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 still somewhat experimental, but are being used more widely on elderly patients unfit for myeloablative regimens and for whom the higher risk of cancer relapse may be acceptable.
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
. The offspring of donor-derived hematopoietic stem cells
have been documented to populate many different organs of the recipient, including the heart
, and muscle
, and these cells were have been suggested to have the abilities of regenerating injured tissue in these organs, however recent research have shown that such lineage infidelities does not occur as a normal phenomenon.
Complications and side effects
HSCT is associated with a high treatment-related mortality in the recipient (10% or higher), which limits its use to conditions that are themselves life-threatening. Major complications are veno-occlusive disease
, infections (sepsis
) and graft-versus-host disease
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 high risk of infections
and septic shock
, despite prophylactic antibiotics
, and accounts for a large share of treatment-related mortality. 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
. For this reason transplant patients must be re-vaccinated with childhood vaccines
once they are off of immunosuppressive medications.
Severe liver injury is termed hepatic veno-occlusive disease
(VOD). Elevated levels of bilirubin
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
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
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.
Graft-versus-host disease (GVHD)
GVHD is 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
, or the liver
, and is often fatal. High-dose corticosteroids
such as prednisone
are a standard treatment; however this immuno-suppressive treatment often leads to deadly infections.
Chronic graft-versus-host disease
may also develop after allogeneic transplant. It is the major source of late treatment-related complications, although it less often results in death. In addition to inflammation, chronic graft-versus-host disease may lead to the development of fibrosis, or scar tissue, similar to scleroderma
; it may cause functional disability and require 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.
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, HCST patients with either acute and in particular chronic graft-versus-host disease after an allogeneic transplant tend to have a lower risk of cancer relapse. This is due to a therapeutic immune reaction of the grafted donor T lymphocytes 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 the highest immuno-suppressive regimens.
Prognosis in HCST varies widely dependent upon disease type, stage, stem cell source, HLA-matched status (for allogeneic HCST) and conditioning regimen. A transplant offers a chance for cure or long-term remission if the inherent complications of graft versus host disease, immuno-suppressive treatments and the spectrum of opportunistic infections can be survived. In recent years, survival rates have being gradually improving across almost all populations and sub-populations receiving transplants.
Conditions treated with bone marrow or HSC transplantation
Acquired Metabolic disorders Environmentally-induced diseases
Hematologic diseases Anemias Cytopenias Hemophagocytic syndromes
- T-cell deficiencies
- Combined T- and B-cell deficiencies
- Well-defined syndromes
- Phagocyte disorders
- Immune dysregulation diseases
- Innate immune deficiencies