Bone marrow transplant
Encyclopedia
Hematopoietic stem cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cell or blood
, usually derived from bone marrow, peripheral blood stem cells, or umbilical cord 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 cancer
s.
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.
A total of 50,417 first hematopoietic stem cell transplants were reported as taking place worldwide in 2006, according to a global survey of 1327 centers in 71 countries conducted by the Worldwide Network for Blood and Marrow Transplantation. Of these, 28,901 (57%) were autologous and 21,516 (43%) were allogeneic (11,928 from family donors and 9,588 from unrelated donors). The main indications for transplant were lymphoproliferative disorders (54.5%) and leukemias (33.8%), and the majority took place in either Europe (48%) or the Americas (36%). In 2009, according to the world marrow donor association, stem cell products provided for unrelated transplantation worldwide had increased to 15,399 (3,445 bone marrow donations, 8,162 peripheral blood stem cell donations, and 3,792 cord blood units).
While it remains a procedure involving a high degree of risk, one must keep in mind that many disorders (mainly acute leukemias and neoplastic lymphoproliferative disorders) treated by this procedure—which is usually not attempted unless necessary because of prior treatment failures or the patient's emergent condition (unresponsive or severe acute leukemia, relapsed acute leukemia, or progressing, formerly chronic leukemias that have not responded to other regimens and have entered blast crisis)- themselves will usually carry a mortality and morbidity rate that is as high and often higher than that for the procedure. Further, less severe complications from this procedure, and even those that carry a worse prognosis such as many cases of acute graft versus host disease, can be dealt with at least to a point, if the patient was in acceptable health beforehand and the condition was noticed and aggressively treated early, with modern standards of tertiary medical care.
, a French oncologist, performed the first bone marrow transplant in 1959 on five Yugoslavian nuclear workers whose own marrow had been damaged by irradiation caused by a Criticality accident
at the Vinča Nuclear Institute
, but all of these transplants were rejected. Mathé later pioneered the use of bone marrow transplants in the treatment of leukemia.
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 or Medicine
. Thomas' work showed that bone marrow cells infused intravenously could repopulate the bone marrow and produce new blood cell
s. 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 on a disease other than cancer was Robert A. Good
at the University of Minnesota
in 1968.
or leukemia
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
, neuroblastoma
, lymphoma
, Ewing's Sarcoma, Desmoplastic small round cell tumor
, chronic granulomatous disease
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.
) of haematopoietic stem 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 with the intention of eradicating the patient's malignant cell population at the cost of partial or complete bone marrow
ablation (destruction of patient's bone marrow function to grow new blood cells). The patient's own stored stem cells are then returned to his/her body, where they replace destroyed tissue and resume the patient's normal blood cell production. Autologous transplants have the advantage of lower risk of infection during the immune-compromised portion of the treatment since the recovery of immune function is rapid. Also, the incidence of patients experiencing rejection (graft-versus-host disease
) is very rare due to the donor and recipient being the same individual. These advantages have established autologous HSCT as one of the standard second-line treatments for such diseases as lymphoma
. However, for others such as Acute Myeloid Leukemia
, the reduced mortality of the autogenous relative to allogeneic HSCT may be outweighed by an increased likelihood of cancer relapse and related mortality, and therefore the allogeneic treatment may be preferred for those conditions. Researchers have conducted small studies using non-myeloablative hematopoietic stem cell transplantation as a possible treatment for type I (insulin dependent) diabetes in children and adults. Results have been promising; however, it was premature to speculate whether these experiments will lead to effective treatments for diabetes.
) 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), syngeneic (a monozygotic or 'identical' twin of the patient - necessarily extremely rare since few patients have an identical twin, but offering a source of perfectly HLA matched stem cells) or unrelated (donor who is not related and found to have very close degree of HLA matching). Unrelated donors may be found through a registry of bone marrow donors such as the National Marrow Donor Program
. People who would like to be tested for a specific family member or friend without joining any of the bone marrow registry data banks may contact a private HLA testing laboratory and be tested with a mouth swab to see if they are a potential match. A "savior sibling
" may be intentionally selected by preimplantation genetic diagnosis
in order to match a child both regarding HLA type and being free of any obvious inheritable disorder. 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 HSCTs appear to improve chances for cure or long-term remission once the immediate transplant-related complications are resolved.
A compatible donor is found by doing additional HLA-testing from the blood of potential donors. The HLA genes fall in two categories (Type I and Type II). In general, mismatches of the Type-I genes (i.e. HLA-A, HLA-B, or HLA-C) increase the risk of graft rejection. A mismatch of an HLA Type II gene (i.e. HLA-DR, or HLA-DQB1
) increases the risk of graft-versus-host disease. In addition a genetic mismatch as small as a single DNA
base pair
is significant so perfect matches require knowledge of the exact DNA sequence of these genes for both donor and recipient. Leading transplant centers currently perform testing for all five of these HLA genes before declaring that a donor and recipient are HLA-identical.
Race and ethnicity are known to play a major role in donor recruitment drives, as members of the same ethnic group are more likely to have matching genes, including the genes for HLA. http://www.marrow.org/DONOR/ABCs/index.html
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.
In the case of a bone marrow transplant, the HSC are removed from a large bone of the donor, typically the pelvis
, through a large needle
that reaches the center of the bone. The technique is referred to as a bone marrow harvest and is performed under general anesthesia.
. 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.
for both autologous or heterologous use at the time of childbirth.
and placenta
after birth. Cord blood
has a higher concentration of HSC than is normally found in adult blood. However, the small quantity of blood obtained from an umbilical cord (typically about 50 mL) makes it more suitable for transplantation into small children than into adults. Newer techniques using ex-vivo expansion of cord blood units or the use of two cord blood units from different donors are being explored to allow cord blood transplants to be used in adults.
Cord blood is typically harvested from the umbilical cord of a child being born after preimplantation genetic diagnosis
(PGD) for human leucocyte antigen (HLA) matching (see PGD for HLA matching) in order to donate to an ill sibling requiring HSCT.
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 controlled-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
.
or irradiation
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
with busulfan
or total body irradiation
is commonly employed. This treatment also has an immunosuppressive effect that prevents rejection of the HSC by the recipient's immune system
. The post-transplant prognosis often includes acute and chronic graft-versus-host disease
that may be life-threatening. However in certain leukemias this can coincide with protection against cancer relapse owing to the graft versus tumor effect. Autologous transplants may also use similar conditioning regimens, but many other chemotherapy combinations can be used depending on the type of disease.
and radiation
, which are too low to eradicate all 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 relapse. 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.
. The offspring of donor-derived hematopoietic stem cells have been documented to populate many different organs of the recipient, including the heart
, liver
, and muscle
, and these cells had been suggested to have the abilities of regenerating injured tissue in these organs. However, recent research has shown that such lineage infidelities does not occur as a normal phenomenon .
, infections (sepsis
), graft-versus-host disease
and the development of new malignancies
.
. This puts a patient at high risk of infections, sepsis
and septic shock
, despite prophylactic antibiotic
s. However, antiviral
medication
s, such as acyclovir and valacyclovir, are quite effective in prevention of HSCT-related outbreak of herpetic
infection in seropositive
patients. 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 immunosuppressive medications.
, 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 hepatic VOD has lately been referred to as sinusoidal obstruction syndrome (SOS). Severe casesof SOS are associated with a high mortality rate. Anticoagulant
s 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 facilitating the flow of bile
.
Acute graft-versus-host disease typically occurs in the first 3 months after transplantation and may involve the skin
, intestine
, or the liver
.. 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, which react to foreign peptides presented on the MHC
of the host.
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 that do not employ the highest immuno-suppressive regimens.
Graft versus tumor is mainly beneficial in diseases with slow progress, e.g. chronic leukemia, low-grade lymphoma, and some cases multiple myeloma. However, it is less effective in rapidly growing acute leukemias.
If cancer relapses after HSCT, another transplant can be performed, infusing the patient with a greater quantity of donor white blood cells.
carcinoma
. Post-HSCT oral cancer
may have more aggressive behavior with poorer prognosis, when compared to oral cancer in non-HSCT patients.
Mortality for allogeneic stem cell transplantation can be estimated using the prediction model created by Sorror et al., using the Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI). The HCT-CI was derived and validated by investigators at the Fred Hutchinson Cancer Research Center (Seattle, WA). The HCT-CI modifies and adds to a well-validated comorbidity index, the Charlson Comorbidity Index (CCI) (Charlson et al.) The CCI was previously applied to patients undergoing allogeneic HCT but appears to provide less survival prediction and discrimination than the HCT-CI scoring system.
procedure, and the colony-stimulating factor used (G-CSF, GM-CSF). G-CSF drugs include Filgrastim
(Neupogen, Neulasta), and lenograstim
(Graslopin).
The question of whether patients over 65 react the same as patients under 65 has not been sufficiently examined. Coagulation issues and inflammation of atherosclerotic plaques are known to occur as a result of G-CSF injection. G-CSF has also been described to induce genetic changes in mononuclear cells of normal donors. There is evidence that myelodysplasia (MDS) or acute myeloid leukaemia (AML) can be induced by GCSF in susceptible individuals.
were experienced in 20% of women and 8% of men, these adverse events primarily consisted of numbness/tingling, multiple line attempts, and nausea.
.
In one metastudy that incorporated data from 377 donors, 44% of patients reported having adverse side effects after peripheral blood HSCT. Side effects included pain prior to the collection procedure as a result of GCSF injections, post-procedural generalized skeletal pain, fatigue and reduced energy.
One study based on a survey of medical teams covered approximately 24,000 peripheral blood HSCT cases between 1993 and 2005, and found a serious cardiovascular adverse reaction rate of about 1 in 1500. This study reported a cardiovascular-related fatality risk within the first 30 days HSCT of about 2 in 10000. For this same group, severe cardiovascular events were observed with a rate of about 1 in 1500. The most common severe adverse reactions were pulmonary edema/deep vein thrombosis, splenic rupture, and myocardial infarction. Haematological malignancy induction was comparable to that observed in the general population with only 15 reported cases within 4 years. ..
. 12.2 million of these registered donors had been ABDR typed, allowing easy matching. A further 453,000 cord blood units had been received by one of 44 cord blood units from 26 countries participating. The highest total number of bone marrow donors registered were those from the USA (6.4 million), and the highest number per capita were those from Cyprus (10.6% of the population).
, performed a stem cell transplant for a leukaemia
patient who was also HIV-positive. From 60 matching
donors, they selected a [CCR5]-Δ32 homozygous
individual with two genetic copies
of a rare variant of a cell surface receptor. This genetic trait confers resistance to HIV infection by blocking attachment of HIV to the cell. Roughly one in 1000 people of European ancestry have this inherited mutation, but it is rarer in other populations. The transplant was repeated a year later after a relapse. Over three years after the initial transplant and despite discontinuing antiretroviral therapy, researchers cannot detect HIV in the transplant recipient's blood or in various biopsies. Levels of HIV-specific antibodies have also declined, leading to speculation that the patient may have been functionally cured of HIV. However, scientists emphasise that this is an unusual case. Potentially fatal transplant complications (the "Berlin patient" suffered from graft-versus-host disease
and leukoencephalopathy
) mean that the procedure could not be performed in others with HIV, even if sufficient numbers of suitable donors were found.
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
, usually derived from bone marrow, peripheral blood stem cells, or umbilical cord blood. Stem cell transplantation is a medical procedure in the fields of hematology
Hematology
Hematology, also spelled haematology , is the branch of biology physiology, internal medicine, pathology, clinical laboratory work, and pediatrics that is concerned with the study of blood, the blood-forming organs, and blood diseases...
and oncology
Oncology
Oncology is a branch of medicine that deals with cancer...
, most often performed for people with diseases of the blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
, bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
, or certain cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
s.
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
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
, the risk of fatal complications appears too high to gain wider acceptance.
A total of 50,417 first hematopoietic stem cell transplants were reported as taking place worldwide in 2006, according to a global survey of 1327 centers in 71 countries conducted by the Worldwide Network for Blood and Marrow Transplantation. Of these, 28,901 (57%) were autologous and 21,516 (43%) were allogeneic (11,928 from family donors and 9,588 from unrelated donors). The main indications for transplant were lymphoproliferative disorders (54.5%) and leukemias (33.8%), and the majority took place in either Europe (48%) or the Americas (36%). In 2009, according to the world marrow donor association, stem cell products provided for unrelated transplantation worldwide had increased to 15,399 (3,445 bone marrow donations, 8,162 peripheral blood stem cell donations, and 3,792 cord blood units).
While it remains a procedure involving a high degree of risk, one must keep in mind that many disorders (mainly acute leukemias and neoplastic lymphoproliferative disorders) treated by this procedure—which is usually not attempted unless necessary because of prior treatment failures or the patient's emergent condition (unresponsive or severe acute leukemia, relapsed acute leukemia, or progressing, formerly chronic leukemias that have not responded to other regimens and have entered blast crisis)- themselves will usually carry a mortality and morbidity rate that is as high and often higher than that for the procedure. Further, less severe complications from this procedure, and even those that carry a worse prognosis such as many cases of acute graft versus host disease, can be dealt with at least to a point, if the patient was in acceptable health beforehand and the condition was noticed and aggressively treated early, with modern standards of tertiary medical care.
History
Georges MathéGeorges Mathé
Georges Mathé was a French oncologist and immunologist. In 1959, he performed the first successful bone marrow transplant not performed on identical twins.-Biography:...
, a French oncologist, performed the first bone marrow transplant in 1959 on five Yugoslavian nuclear workers whose own marrow had been damaged by irradiation caused by a Criticality accident
Criticality accident
A criticality accident, sometimes referred to as an excursion or a power excursion, is an accidental increase of nuclear chain reactions in a fissile material, such as enriched uranium or plutonium...
at the Vinča Nuclear Institute
Vinča Nuclear Institute
Vinča Nuclear Institute is a nuclear physics research institution near Belgrade, in Serbia.-History:The Institute was originally established in 1948 as the Institute for Physics. In 1953 it was renamed in favour of Boris Kidrič. Several different research groups started in the 1950s, and two...
, but all of these transplants were rejected. Mathé later pioneered the use of bone marrow transplants in the treatment of leukemia.
Stem cell transplantation was pioneered using bone-marrow-derived stem cells by a team at the Fred Hutchinson Cancer Research Center
Fred Hutchinson Cancer Research Center
The Fred Hutchinson Cancer Research Center, is one of the world’s leading cancer research institutes...
from the 1950s through the 1970s led by E. Donnall Thomas
E. Donnall Thomas
Dr. Edward Donnall Thomas is an American physician, professor emeritus at the University of Washington, and director emeritus of the clinical research division at the Fred Hutchinson Cancer Research Center. In 1990 he shared the Nobel Prize in Physiology or Medicine with Joseph E. Murray for the...
, whose work was later recognized with a Nobel Prize in Physiology or Medicine
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...
. Thomas' work showed that bone marrow cells infused intravenously could repopulate the bone marrow and produce new blood cell
Blood cell
A blood cell, also called a hematocyte, is a cell normally found in blood. In mammals, these fall into three general categories:* red blood cells — Erythrocytes* white blood cells — Leukocytes* platelets — Thrombocytes...
s. His work also reduced the likelihood of developing a life-threatening complication called graft-versus-host disease
Graft-versus-host disease
Graft-versus-host disease is a common complication after a stem cell transplant or bone marrow transplant from another person . Immune cells in the donated marrow or stem cells recognize the recipient as "foreign". The transplanted immune cells then attack the host's body cells...
.
The first physician to perform a successful human bone marrow transplant on a disease other than cancer was Robert A. Good
Robert A. Good
-External links:** can be found at The Center for the History of Medicine at the Countway Library, Harvard Medical School....
at the University of Minnesota
University of Minnesota
The University of Minnesota, Twin Cities is a public research university located in Minneapolis and St. Paul, Minnesota, United States. It is the oldest and largest part of the University of Minnesota system and has the fourth-largest main campus student body in the United States, with 52,557...
in 1968.
Indications
Many recipients of HSCTs are multiple myelomaMultiple myeloma
Multiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies...
or leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
patients who would not benefit from prolonged treatment with, or are already resistant to, chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
. Candidates for HSCTs include pediatric cases where the patient has an inborn defect such as severe combined immunodeficiency
Severe combined immunodeficiency
Severe combined immunodeficiency , is a genetic disorder in which both "arms" of the adaptive immune system are impaired due to a defect in one of several possible genes. SCID is a severe form of heritable immunodeficiency...
or congenital neutropenia
Neutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
with defective stem cells, and also children or adults with aplastic anemia
Aplastic anemia
Aplastic anemia is a condition where bone marrow does not produce sufficient new cells to replenish blood cells. The condition, per its name, involves both aplasia and anemia...
who have lost their stem cells after birth. Other conditions treated with stem cell transplants include sickle-cell disease
Sickle-cell disease
Sickle-cell disease , or sickle-cell anaemia or drepanocytosis, is an autosomal recessive genetic blood disorder with overdominance, characterized by red blood cells that assume an abnormal, rigid, sickle shape. Sickling decreases the cells' flexibility and results in a risk of various...
, myelodysplastic syndrome
Myelodysplastic syndrome
The myelodysplastic syndromes are a diverse collection of hematological medical conditions that involve ineffective production of the myeloid class of blood cells....
, neuroblastoma
Neuroblastoma
Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence of about 650 cases per year in the US , and 100 cases per year in the UK . Close to 50 percent of neuroblastoma cases occur in children younger than two years old...
, lymphoma
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
, Ewing's Sarcoma, Desmoplastic small round cell tumor
Desmoplastic small round cell tumor
Desmoplastic small-round-cell tumor is classified as a soft tissue sarcoma. It is an aggressive and rare tumor that primarily occurs as masses in the abdomen. Other areas affected may include the lymph nodes, the lining of the abdomen, diaphragm, spleen, liver, chest wall, skull, spinal cord, large...
, chronic granulomatous disease
Chronic granulomatous disease
Chronic granulomatous disease is a diverse group of hereditary diseases in which certain cells of the immune system have difficulty forming the reactive oxygen compounds used to kill certain ingested pathogens...
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
Autologous HSCT requires the extraction (apheresisApheresis
Apheresis is a medical technology in which the blood of a donor or patient is passed through an apparatus that separates out one particular constituent and returns the remainder to the circulation...
) of haematopoietic stem cells (HSC) from the patient and storage of the harvested cells in a freezer. The patient is then treated with high-dose chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
with or without radiotherapy with the intention of eradicating the patient's malignant cell population at the cost of partial or complete bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
ablation (destruction of patient's bone marrow function to grow new blood cells). The patient's own stored stem cells are then returned to his/her body, where they replace destroyed tissue and resume the patient's normal blood cell production. Autologous transplants have the advantage of lower risk of infection during the immune-compromised portion of the treatment since the recovery of immune function is rapid. Also, the incidence of patients experiencing rejection (graft-versus-host disease
Graft-versus-host disease
Graft-versus-host disease is a common complication after a stem cell transplant or bone marrow transplant from another person . Immune cells in the donated marrow or stem cells recognize the recipient as "foreign". The transplanted immune cells then attack the host's body cells...
) is very rare due to the donor and recipient being the same individual. These advantages have established autologous HSCT as one of the standard second-line treatments for such diseases as lymphoma
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
. However, for others such as Acute Myeloid Leukemia
Acute myeloid leukemia
Acute myeloid leukemia , also known as acute myelogenous leukemia, is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute...
, the reduced mortality of the autogenous relative to allogeneic HSCT may be outweighed by an increased likelihood of cancer relapse and related mortality, and therefore the allogeneic treatment may be preferred for those conditions. Researchers have conducted small studies using non-myeloablative hematopoietic stem cell transplantation as a possible treatment for type I (insulin dependent) diabetes in children and adults. Results have been promising; however, it was premature to speculate whether these experiments will lead to effective treatments for diabetes.
Allogeneic
Allogeneic HSCT involves two people: the (healthy) donor and the (patient) recipient. Allogeneic HSC donors must have a tissue (HLAHuman leukocyte antigen
The human leukocyte antigen system is the name of the major histocompatibility complex in humans. The super locus contains a large number of genes related to immune system function in humans. This group of genes resides on chromosome 6, and encodes cell-surface antigen-presenting proteins and...
) type that matches the recipient. Matching is performed on the basis of variability at three or more loci
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
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
Immunosuppression
Immunosuppression involves an act that reduces the activation or efficacy of the immune system. Some portions of the immune system itself have immuno-suppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reaction to treatment of other...
medications to mitigate graft-versus-host disease
Graft-versus-host disease
Graft-versus-host disease is a common complication after a stem cell transplant or bone marrow transplant from another person . Immune cells in the donated marrow or stem cells recognize the recipient as "foreign". The transplanted immune cells then attack the host's body cells...
. Allogeneic transplant donors may be related (usually a closely HLA matched sibling), syngeneic (a monozygotic or 'identical' twin of the patient - necessarily extremely rare since few patients have an identical twin, but offering a source of perfectly HLA matched stem cells) or unrelated (donor who is not related and found to have very close degree of HLA matching). Unrelated donors may be found through a registry of bone marrow donors such as the National Marrow Donor Program
National Marrow Donor Program
National Marrow Donor Program® Be The Match is the global leader in providing marrow and umbilical cord blood transplants to patients with leukemia, lymphoma and other diseases. The nonprofit organization matches patients with donors, educates health care professionals and conducts research so more...
. People who would like to be tested for a specific family member or friend without joining any of the bone marrow registry data banks may contact a private HLA testing laboratory and be tested with a mouth swab to see if they are a potential match. A "savior sibling
Savior sibling
A savior sibling is a child who is born to provide an organ or cell transplant to a sibling that is affected with a fatal disease, such as cancer or Fanconi anemia, that can best be treated by hematopoietic stem cell transplantation....
" may be intentionally selected by preimplantation genetic diagnosis
Preimplantation genetic diagnosis
In medicine and genetics pre-implantation genetic diagnosis refers to procedures that are performed on embryos prior to implantation, sometimes even on oocytes prior to fertilization. PGD is considered another way to prenatal diagnosis...
in order to match a child both regarding HLA type and being free of any obvious inheritable disorder. Allogeneic transplants are also performed using umbilical cord blood
Cord blood
Umbilical cord blood is blood that remains in the placenta and in the attached umbilical cord after childbirth. Cord blood is collected because it contains stem cells which can be used to treat hematopoietic and genetic disorders.-Collection:...
as the source of stem cells. In general, by transplanting healthy stem cells to the recipient's immune system, allogeneic HSCTs appear to improve chances for cure or long-term remission once the immediate transplant-related complications are resolved.
A compatible donor is found by doing additional HLA-testing from the blood of potential donors. The HLA genes fall in two categories (Type I and Type II). In general, mismatches of the Type-I genes (i.e. HLA-A, HLA-B, or HLA-C) increase the risk of graft rejection. A mismatch of an HLA Type II gene (i.e. HLA-DR, or HLA-DQB1
HLA-DQB1
Major histocompatibility complex, class II, DQ beta 1, also known as HLA-DQB1, is a human gene and also denotes the genetic locus that contains this gene...
) increases the risk of graft-versus-host disease. In addition a genetic mismatch as small as a single DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
base pair
Base pair
In molecular biology and genetics, the linking between two nitrogenous bases on opposite complementary DNA or certain types of RNA strands that are connected via hydrogen bonds is called a base pair...
is significant so perfect matches require knowledge of the exact DNA sequence of these genes for both donor and recipient. Leading transplant centers currently perform testing for all five of these HLA genes before declaring that a donor and recipient are HLA-identical.
Race and ethnicity are known to play a major role in donor recruitment drives, as members of the same ethnic group are more likely to have matching genes, including the genes for HLA. http://www.marrow.org/DONOR/ABCs/index.html
Sources and storage of cells
To limit the risks of transplanted stem cell rejectionTransplant rejection
Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of immunosuppressant drugs after...
or of severe graft-versus-host disease
Graft-versus-host disease
Graft-versus-host disease is a common complication after a stem cell transplant or bone marrow transplant from another person . Immune cells in the donated marrow or stem cells recognize the recipient as "foreign". The transplanted immune cells then attack the host's body cells...
in allogeneic HSCT, the donor should preferably have the same human leukocyte antigens (HLA)
Human leukocyte antigen
The human leukocyte antigen system is the name of the major histocompatibility complex in humans. The super locus contains a large number of genes related to immune system function in humans. This group of genes resides on chromosome 6, and encodes cell-surface antigen-presenting proteins and...
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.
Bone marrow
Pelvis
In human anatomy, the pelvis is the lower part of the trunk, between the abdomen and the lower limbs .The pelvis includes several structures:...
, through a large needle
Hypodermic needle
A hypodermic needle is a hollow needle commonly used with a syringe to inject substances into the body or extract fluids from it...
that reaches the center of the bone. The technique is referred to as a bone marrow harvest and is performed under general anesthesia.
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 apheresisApheresis
Apheresis is a medical technology in which the blood of a donor or patient is passed through an apparatus that separates out one particular constituent and returns the remainder to the circulation...
. 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.
Amniotic fluid
It is also possible to extract hematopoietic stem cells from amniotic fluidAmniotic fluid
Amniotic fluid or liquor amnii is the nourishing and protecting liquid contained by the amniotic sac of a pregnant woman.- Development of amniotic fluid :...
for both autologous or heterologous use at the time of childbirth.
Umbilical cord blood
Umbilical cord blood is obtained when a mother donates her infant's umbilical cordUmbilical cord
In placental mammals, the umbilical cord is the connecting cord from the developing embryo or fetus to the placenta...
and placenta
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
after birth. Cord blood
Cord blood
Umbilical cord blood is blood that remains in the placenta and in the attached umbilical cord after childbirth. Cord blood is collected because it contains stem cells which can be used to treat hematopoietic and genetic disorders.-Collection:...
has a higher concentration of HSC than is normally found in adult blood. However, the small quantity of blood obtained from an umbilical cord (typically about 50 mL) makes it more suitable for transplantation into small children than into adults. Newer techniques using ex-vivo expansion of cord blood units or the use of two cord blood units from different donors are being explored to allow cord blood transplants to be used in adults.
Cord blood is typically harvested from the umbilical cord of a child being born after preimplantation genetic diagnosis
Preimplantation genetic diagnosis
In medicine and genetics pre-implantation genetic diagnosis refers to procedures that are performed on embryos prior to implantation, sometimes even on oocytes prior to fertilization. PGD is considered another way to prenatal diagnosis...
(PGD) for human leucocyte antigen (HLA) matching (see PGD for HLA matching) in order to donate to an ill sibling requiring HSCT.
Storage of HSC
Unlike other organs, bone marrow cells can be frozen (cryopreserved) for prolonged periods, without damaging too many cells. This is a necessity with autologous HSC because the cells must be harvested from the recipient 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 bloodCord blood
Umbilical cord blood is blood that remains in the placenta and in the attached umbilical cord after childbirth. Cord blood is collected because it contains stem cells which can be used to treat hematopoietic and genetic disorders.-Collection:...
is stored frozen at a cord blood bank
Cord blood bank
A cord blood bank is a facility which stores umbilical cord blood for future use. Both private and public cord blood banks have developed since the mid- to late-1990s in response to the potential for cord blood transplants in treating diseases of the blood and immune systems.Public banks accept...
because it is only obtainable at the time of childbirth
Childbirth
Childbirth is the culmination of a human pregnancy or gestation period with the birth of one or more newborn infants from a woman's uterus...
. To cryopreserve HSC, a preservative, DMSO
Dimethyl sulfoxide
Dimethyl sulfoxide is an organosulfur compound with the formula 2SO. This colorless liquid is an important polar aprotic solvent that dissolves both polar and nonpolar compounds and is miscible in a wide range of organic solvents as well as water...
, must be added, and the cells must be cooled very slowly in a controlled-rate freezer to prevent osmotic
Osmosis
Osmosis is the movement of solvent molecules through a selectively permeable membrane into a region of higher solute concentration, aiming to equalize the solute concentrations on the two sides...
cellular injury during ice crystal formation. HSC may be stored for years in a cryofreezer, which typically utilizes liquid nitrogen
Liquid nitrogen
Liquid nitrogen is nitrogen in a liquid state at a very low temperature. It is produced industrially by fractional distillation of liquid air. Liquid nitrogen is a colourless clear liquid with density of 0.807 g/mL at its boiling point and a dielectric constant of 1.4...
.
Myeloablative transplants
The chemotherapyChemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
or irradiation
Irradiation
Irradiation is the process by which an object is exposed to radiation. The exposure can originate from various sources, including natural sources. Most frequently the term refers to ionizing radiation, and to a level of radiation that will serve a specific purpose, rather than radiation exposure to...
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
Cyclophosphamide
Cyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group....
with busulfan
Busulfan
Busulfan is a cancer drug, in use since 1959.Busulfan is a cell cycle non-specific alkylating antineoplastic agent, in the class of alkyl sulfonates...
or total body irradiation
Total body irradiation
Total body irradiation is a form of radiotherapy used primarily as part of the preparative regimen for haematopoietic stem cell transplantation. As the name implies, TBI involves irradiation of the entire body, though in modern practice the lungs are often partially shielded to lower the risk of...
is commonly employed. This treatment also has an immunosuppressive effect that prevents rejection of the HSC by the recipient's immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
. The post-transplant prognosis often includes acute and chronic graft-versus-host disease
Graft-versus-host disease
Graft-versus-host disease is a common complication after a stem cell transplant or bone marrow transplant from another person . Immune cells in the donated marrow or stem cells recognize the recipient as "foreign". The transplanted immune cells then attack the host's body cells...
that may be life-threatening. However in certain leukemias this can coincide with protection against cancer relapse owing to the graft versus tumor effect. Autologous transplants may also use similar conditioning regimens, but many other chemotherapy combinations can be used depending on the type of disease.
Non-myeloablative allogeneic transplants
This is a newer treatment approach using lower doses of chemotherapyChemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
and radiation
Radiation
In physics, radiation is a process in which energetic particles or energetic waves travel through a medium or space. There are two distinct types of radiation; ionizing and non-ionizing...
, which are too low to eradicate all 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 relapse. 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
Chimera (genetics)
A chimera or chimaera is a single organism that is composed of two or more different populations of genetically distinct cells that originated from different zygotes involved in sexual reproduction. If the different cells have emerged from the same zygote, the organism is called a mosaic...
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
Graft-versus-host disease
Graft-versus-host disease is a common complication after a stem cell transplant or bone marrow transplant from another person . Immune cells in the donated marrow or stem cells recognize the recipient as "foreign". The transplanted immune cells then attack the host's body cells...
, 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.
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 systemImmune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
. The offspring of donor-derived hematopoietic stem cells have been documented to populate many different organs of the recipient, including the heart
Heart
The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
, liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
, and muscle
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
, and these cells had been suggested to have the abilities of regenerating injured tissue in these organs. However, recent research has shown that such lineage infidelities does not occur as a normal phenomenon .
Complications
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, mucositisMucositis
Mucositis is the painful inflammation and ulceration of the mucous membranes lining the digestive tract, usually as an adverse effect of chemotherapy and radiotherapy treatment for cancer. Mucositis can occur anywhere along the gastrointestinal tract, but oral mucositis refers to the particular...
, infections (sepsis
Sepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
), graft-versus-host disease
Graft-versus-host disease
Graft-versus-host disease is a common complication after a stem cell transplant or bone marrow transplant from another person . Immune cells in the donated marrow or stem cells recognize the recipient as "foreign". The transplanted immune cells then attack the host's body cells...
and the development of new malignancies
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
.
Infection
Bone marrow transplantation usually requires that the recipient's own bone marrow be destroyed ("myeloablation"). Prior to "engraftment" patients may go for several weeks without appreciable numbers of white blood cells to help fight infectionInfection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
. This puts a patient at high risk of infections, sepsis
Sepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
and septic shock
Septic shock
Septic shock is a medical emergency caused by decreased tissue perfusion and oxygen delivery as a result of severe infection and sepsis, though the microbe may be systemic or localized to a particular site. It can cause multiple organ dysfunction syndrome and death...
, despite prophylactic antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
s. However, antiviral
Antiviral
Antiviral may refer to:*Antiviral drug*Antiviral protein*Antivirus software*Antiviral Therapy, an academic journal...
medication
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
s, such as acyclovir and valacyclovir, are quite effective in prevention of HSCT-related outbreak of herpetic
Herpes simplex
Herpes simplex is a viral disease caused by both Herpes simplex virus type 1 and type 2 . Infection with the herpes virus is categorized into one of several distinct disorders based on the site of infection. Oral herpes, the visible symptoms of which are colloquially called cold sores or fever...
infection in seropositive
Serostatus
Serostatus is a term used to refer to the presence or absence of specific substances in the blood serum. Most commonly, this medical test is looking for specific antibodies in an effort to diagnose a particular disease....
patients. The immunosuppressive agents employed in allogeneic transplants for the prevention or treatment of graft-versus-host disease further increase the risk of opportunistic infection
Opportunistic infection
An opportunistic infection is an infection caused by pathogens, particularly opportunistic pathogens—those that take advantage of certain situations—such as bacterial, viral, fungal or protozoan infections that usually do not cause disease in a healthy host, one with a healthy immune system...
. 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
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
, for example immunity to childhood diseases such as measles
Measles
Measles, also known as rubeola or morbilli, is an infection of the respiratory system caused by a virus, specifically a paramyxovirus of the genus Morbillivirus. Morbilliviruses, like other paramyxoviruses, are enveloped, single-stranded, negative-sense RNA viruses...
or polio
Poliomyelitis
Poliomyelitis, often called polio or infantile paralysis, is an acute viral infectious disease spread from person to person, primarily via the fecal-oral route...
. For this reason transplant patients must be re-vaccinated with childhood vaccines once they are off immunosuppressive medications.
Veno-occlusive disease
Severe liver injury can result from hepatic veno-occlusive disease (VOD). Elevated levels of bilirubinBilirubin
Bilirubin is the yellow breakdown product of normal heme catabolism. Heme is found in hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases...
, hepatomegaly
Hepatomegaly
Hepatomegaly is the condition of having an enlarged liver. It is a nonspecific medical sign having many causes, which can broadly be broken down into infection, direct toxicity, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdominal mass...
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 hepatic VOD has lately been referred to as sinusoidal obstruction syndrome (SOS). Severe casesof SOS are associated with a high mortality rate. Anticoagulant
Anticoagulant
An anticoagulant is a substance that prevents coagulation of blood. A group of pharmaceuticals called anticoagulants can be used in vivo as a medication for thrombotic disorders. Some anticoagulants are used in medical equipment, such as test tubes, blood transfusion bags, and renal dialysis...
s or defibrotide
Defibrotide
Defibrotide is a deoxyribonucleic acid derivative derived from cow lung or porcine mucosa. It is an anticoagulant with a multiple mode of action .It has been used with antithrombin III.-Pharmacokinetics:...
may be effective in reducing the severity of VOD but may also increase bleeding complications. Ursodiol
Ursodiol
Ursodiol, also known as ursodeoxycholic acid and the abbreviation UDCA, is one of the secondary bile acids, which are metabolic byproducts of intestinal bacteria.-Endogenous effects:...
has been shown to help prevent VOD, presumably by facilitating the flow of bile
Bile
Bile or gall is a bitter-tasting, dark green to yellowish brown fluid, produced by the liver of most vertebrates, that aids the process of digestion of lipids in the small intestine. In many species, bile is stored in the gallbladder and upon eating is discharged into the duodenum...
.
Mucositis
The injury of the mucosal lining of the mouth and throat 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
Graft-versus-host disease (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
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
, intestine
Intestine
In human anatomy, the intestine is the segment of the alimentary canal extending from the pyloric sphincter of the stomach to the anus and, in humans and other mammals, consists of two segments, the small intestine and the large intestine...
, or the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
.. High-dose corticosteroids such as prednisone
Prednisone
Prednisone is a synthetic corticosteroid drug that is particularly effective as an immunosuppressant drug. It is used to treat certain inflammatory diseases and some types of cancer, but has significant adverse effects...
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
Fibrosis
Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. This is as opposed to formation of fibrous tissue as a normal constituent of an organ or tissue...
, or scar tissue, similar to scleroderma
Scleroderma
Systemic sclerosis or systemic scleroderma is a systemic autoimmune disease or systemic connective tissue disease that is a subtype of scleroderma.-Skin symptoms:...
; it may cause functional disability and require prolonged immunosuppressive therapy.
Graft-versus-host disease is usually mediated by T cells, which react to foreign peptides presented on the MHC
MHC
-Biology:*Myosin heavy chain - part of the motor protein myosin's quaternary protein structure*Major histocompatibility complex - a highly polymorphic region on chromosome 6 with genes particularly involved in immune functions-Colleges:...
of the host.
Graft-versus-tumor effect
Graft-versus-tumor effect (GVT) or "graft versus leukemia" effect is the beneficial aspect of the Graft-versus-Host phenomenon. For example, HSCT 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 marrowBone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
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 that do not employ the highest immuno-suppressive regimens.
Graft versus tumor is mainly beneficial in diseases with slow progress, e.g. chronic leukemia, low-grade lymphoma, and some cases multiple myeloma. However, it is less effective in rapidly growing acute leukemias.
If cancer relapses after HSCT, another transplant can be performed, infusing the patient with a greater quantity of donor white blood cells.
Oral carcinoma
Patients after HSCT are at a higher risk for oralMouth
The mouth is the first portion of the alimentary canal that receives food andsaliva. The oral mucosa is the mucous membrane epithelium lining the inside of the mouth....
carcinoma
Squamous cell carcinoma
Squamous cell carcinoma , occasionally rendered as "squamous-cell carcinoma", is a histologically distinct form of cancer. It arises from the uncontrolled multiplication of malignant cells deriving from epithelium, or showing particular cytological or tissue architectural characteristics of...
. Post-HSCT oral cancer
Oral cancer
Oral cancer is a subtype of head and neck cancer, is any cancerous tissue growth located in the oral cavity. It may arise as a primary lesion originating in any of the oral tissues, by metastasis from a distant site of origin, or by extension from a neighboring anatomic structure, such as the...
may have more aggressive behavior with poorer prognosis, when compared to oral cancer in non-HSCT patients.
Prognosis
Prognosis in HSCT 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 been gradually improving across almost all populations and sub-populations receiving transplants.Mortality for allogeneic stem cell transplantation can be estimated using the prediction model created by Sorror et al., using the Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI). The HCT-CI was derived and validated by investigators at the Fred Hutchinson Cancer Research Center (Seattle, WA). The HCT-CI modifies and adds to a well-validated comorbidity index, the Charlson Comorbidity Index (CCI) (Charlson et al.) The CCI was previously applied to patients undergoing allogeneic HCT but appears to provide less survival prediction and discrimination than the HCT-CI scoring system.
Risks to donor
The risks of a complication depend on patient characteristics, health care providers and the apheresisApheresis
Apheresis is a medical technology in which the blood of a donor or patient is passed through an apparatus that separates out one particular constituent and returns the remainder to the circulation...
procedure, and the colony-stimulating factor used (G-CSF, GM-CSF). G-CSF drugs include Filgrastim
Filgrastim
Filgrastim is a granulocyte colony-stimulating factor analog used to stimulate the proliferation and differentiation of granulocytes. It is produced by recombinant DNA technology. The gene for human granulocyte colony-stimulating factor is inserted into the genetic material of Escherichia coli. ...
(Neupogen, Neulasta), and lenograstim
Lenograstim
Lenograstim is a recombinant granulocyte colony-stimulating factor which functions as a immunostimulator. It is developed by Ligand Pharmaceuticals under the brand name Graslopin....
(Graslopin).
Drug risks
Filgrastim is typically dosed in the 10 microgram/kg level for 4–5 days during the harvesting of stem cells. The documented adverse effects of filgrastim include splenic rupture (indicated by left upper abdominal or shoulder pain, risk 1 in 40000), Adult respiratory distress syndrome (ARDS), alveolar hemorrage, and allergic reactions (usually expressed in first 30 minutes, risk 1 in 300). In addition, platelet and hemoglobin levels dip post-procedure, not returning to normal until one month.The question of whether patients over 65 react the same as patients under 65 has not been sufficiently examined. Coagulation issues and inflammation of atherosclerotic plaques are known to occur as a result of G-CSF injection. G-CSF has also been described to induce genetic changes in mononuclear cells of normal donors. There is evidence that myelodysplasia (MDS) or acute myeloid leukaemia (AML) can be induced by GCSF in susceptible individuals.
Access risks
Blood was drawn peripherally in a majority of patients, but a central line to jugular/subclavian/femoral veins may be used in 16% of women and 4% of men. Adverse reactions during apheresisApheresis
Apheresis is a medical technology in which the blood of a donor or patient is passed through an apparatus that separates out one particular constituent and returns the remainder to the circulation...
were experienced in 20% of women and 8% of men, these adverse events primarily consisted of numbness/tingling, multiple line attempts, and nausea.
Clinical observations
A study involving 2408 donors (18–60 years) indicated that bone pain (primarily back and hips) as a result of filgrastim treatment is observed in 80% of donors by day 4 post-injection. This pain responded to acetaminophen or ibuprofen in 65% of donors and was characterized as mild to moderate in 80% of donors and severe in 10%. Bone pain receded post-donation to 26% of patients 2 days post-donation, 6% of patients one week post-donation, and <2% 1 year post-donation. Donation is not recommended for those with a history of back pain. Other symptoms observed in more than 40% of donors include myalgia, headache, fatigue, and insomnia. These symptoms all returned to baseline 1 month post-donation, except for some cases of persistent fatigue in 3% of donors..
In one metastudy that incorporated data from 377 donors, 44% of patients reported having adverse side effects after peripheral blood HSCT. Side effects included pain prior to the collection procedure as a result of GCSF injections, post-procedural generalized skeletal pain, fatigue and reduced energy.
Severe reactions
A study that surveyed 2408 donors found that serious adverse events (requiring prolonged hospitalization) occurred in 15 donors (at a rate of 0.6%), although none of these events were fatal. Donors were not observed to have higher than normal rates of cancer with up to 4–8 years of follow up.One study based on a survey of medical teams covered approximately 24,000 peripheral blood HSCT cases between 1993 and 2005, and found a serious cardiovascular adverse reaction rate of about 1 in 1500. This study reported a cardiovascular-related fatality risk within the first 30 days HSCT of about 2 in 10000. For this same group, severe cardiovascular events were observed with a rate of about 1 in 1500. The most common severe adverse reactions were pulmonary edema/deep vein thrombosis, splenic rupture, and myocardial infarction. Haematological malignancy induction was comparable to that observed in the general population with only 15 reported cases within 4 years. ..
Donor Registration and Recruitment
At the end of 2010, 14.9 million people had registered their willingness to be a bone marrow donor with one of the 64 registries from 45 countries participating in Bone Marrow Donors WorldwideBone Marrow Donors Worldwide
Bone Marrow Donors Worldwide is an organization based in Leiden, Netherlands, that coordinates the collection of the HLA phenotypes of volunteer hematopoietic cell donors and cord blood units....
. 12.2 million of these registered donors had been ABDR typed, allowing easy matching. A further 453,000 cord blood units had been received by one of 44 cord blood units from 26 countries participating. The highest total number of bone marrow donors registered were those from the USA (6.4 million), and the highest number per capita were those from Cyprus (10.6% of the population).
Experimental HIV treatment
In 2007, a team of doctors in Berlin, Germany, including Gero HütterGero Hütter
Gero Hütter is a German hematologist. Huetter and his medical team transplanted bone marrow deficient in a key HIV receptor to a leukemia patient, Timothy Ray Brown, who was also infected with human immunodeficiency virus . Subsequently, the patient's circulating HIV dropped to undetectable levels...
, performed a stem cell transplant for a leukaemia
Acute myeloid leukemia
Acute myeloid leukemia , also known as acute myelogenous leukemia, is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute...
patient who was also HIV-positive. From 60 matching
Human leukocyte antigen
The human leukocyte antigen system is the name of the major histocompatibility complex in humans. The super locus contains a large number of genes related to immune system function in humans. This group of genes resides on chromosome 6, and encodes cell-surface antigen-presenting proteins and...
donors, they selected a [CCR5]-Δ32 homozygous
CCR5
C-C chemokine receptor type 5, also known as CCR5, is a protein that in humans is encoded by the CCR5 gene. CCR5 is a member of the beta chemokine receptors family of integral membrane proteins...
individual with two genetic copies
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
of a rare variant of a cell surface receptor. This genetic trait confers resistance to HIV infection by blocking attachment of HIV to the cell. Roughly one in 1000 people of European ancestry have this inherited mutation, but it is rarer in other populations. The transplant was repeated a year later after a relapse. Over three years after the initial transplant and despite discontinuing antiretroviral therapy, researchers cannot detect HIV in the transplant recipient's blood or in various biopsies. Levels of HIV-specific antibodies have also declined, leading to speculation that the patient may have been functionally cured of HIV. However, scientists emphasise that this is an unusual case. Potentially fatal transplant complications (the "Berlin patient" suffered from graft-versus-host disease
Graft-versus-host disease
Graft-versus-host disease is a common complication after a stem cell transplant or bone marrow transplant from another person . Immune cells in the donated marrow or stem cells recognize the recipient as "foreign". The transplanted immune cells then attack the host's body cells...
and leukoencephalopathy
Leukoencephalopathy
The term Leukoencephalopathy is a broad term for leukodystrophy-like diseases . It is applied to all brain white matter diseases, whether their molecular cause is known or not...
) mean that the procedure could not be performed in others with HIV, even if sufficient numbers of suitable donors were found.