Hematopoietic stem cell transplantation

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"HSCT" redirects here. For the supersonic aircraft, see High Speed Civil Transport.

Hematopoietic stem cell transplantation (HSCT) is the transplantation of Pluripotential hemopoietic stem cell 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 cancer.

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[1] 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.[2][3]

History

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 cells. His work also reduced the likelihood of developing a life-threatening complication called graft-versus-host disease.[4]

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.

Indications for stem cell transplantation

Many recipients of HSCTs are multiple myeloma[5] or leukemia patients[6] 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[7] who have lost their stem cells after birth. Other conditions[8] treated with stem cell transplants include sickle-cell disease, myelodysplastic syndrome, neuroblastoma, lymphoma, 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.

Further information in section Conditions treated with HSC transplantation below

Graft types

Autologous

Autologous HSCT requires the extraction (apheresis) 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.[9] 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.[10] 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, at the time of this writing, it is premature to speculate as to whether these experiments will lead to effective treatments for diabetes.[11]

Allogeneic

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), 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). 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 HCSTs appear to improve chances for cure or long-term remission once the immediate transplant-related complications are resolved.[12][13][14]

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. [1]

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.

Bone marrow

File:Bone marrow biopsy.jpg
Bone marrow harvest.

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.

Peripheral blood stem cells

Main article: Peripheral stem cell transplantation

Peripheral blood stem cells[1] 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.

Amniotic fluid

It is also possible to extract hematopietic stem cells from 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 cord 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.

It is used e.g. in children being born after preimplantation genetic diagnosis (PGD) for human leucocyte antigen (HLA) matching (see PGD for HLA matching) in order to donate to a sick sibling requiring HSCT.

Storage of HSC

Unlike other organs, bone marrow cells can be frozen for prolonged 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.)

Transplant as a use for treatment of HIV

A bone marrow transplant performed on an American man residing in Germany appears to have successfully cured him of both leukemia as well as HIV. Researchers emphasize that this is an unusual case.[15] The donor marrow was selected from 60 matching donors for being [CCR5]-Δ32 homozygous. This genetic trait blocks the primary route by which HIV attaches itself to cells for entry. Roughly 1:100 Europeans and Americans have this inherited mutation but it is rarer in other populations.[16][17]

Conditioning regimens

Myeloablative transplants

The chemotherapy 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 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 leukemias this can coincide with protection against cancer relapse owing to the graft versus tumor effect.[18] Autologous 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 and radiation 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 relapse.[19][20] Also significantly, while requiring high doses of immunosuppressive agents in the early stages of treatment, these doses are less than for conventional transplants.[21] 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.[20]

Engraftment

After several weeks of growth in the bone marrow, expansion of HSC and their progeny is sufficient to normalize the blood cell counts and reinitiate the immune system. 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 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, mucositis, infections (sepsis) and graft-versus-host disease.

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 infection. This puts a patient at high risk of infections, sepsis 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 or polio. For this reason transplant patients must be re-vaccinated with childhood vaccines once they are off immunosuppressive medications.

Veno-occlusive disease

Severe liver injury is termed hepatic veno-occlusive disease (VOD). Elevated levels of bilirubin, hepatomegaly and fluid retention are clinical hallmarks of this condition. There is now a greater appreciation of the generalized cellular injury and obstruction in hepatic vein sinuses, and it has thus been referred to as sinusoidal obstruction syndrome (SOS). Severe cases are associated with a high mortality. Anticoagulants or defibrotide may be effective in reducing the severity of VOD but may also increase bleeding complications. Ursodiol has been shown to help prevent VOD, presumably by helping the flow of bile.

Mucositis

The injury of the mucosal lining of the mouth and throat and is a common regimen-related toxicity following ablative HSCT regimens. It is usually not life-threatening but is very painful, and prevents eating and drinking. Mucositis is treated with pain medications plus intravenous infusions to prevent dehydration and malnutrition.

Graft-versus-host disease (GVHD)

Main article: 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, intestine, 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[citation needed].

Graft-versus-tumor effect (GVT)

The beneficial aspect of the Graft-versus-Host phenomenon is known as the "graft versus tumor" or "graft versus leukemia" effect. 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.[22][23] 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.

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.[24]

If cancer relapses after HSCT, another transplant can be performed, infusing the patient with even more of the donor's white blood cells.[24]

General 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.[12][13] In recent years, survival rates have been gradually improving across almost all populations and sub-populations receiving transplants.[25]

Mortality for allogeneic stem cell transplantation can be estimated using the prediction model created by Sorror et al.,[26] 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.[27]) 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 following Peripheral Harvesting of Stem Cells

The risks of a complication depend on patient characteristics, health care providers and the apheresis procedure, and the colony-stimulating factor used (G-CSF, GM-CSF). G-CSF drugs include Filgrastim (Neupogen, Neulasta), and lenograstim(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).[28][29][30] In addition, platelet and hemoglobin levels dip post-procedure, not returning to normal until one month.[30]

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.[29] G-CSF has also been described to induce genetic changes in mononuclear cells of normal donors.[29] There is evidence that myelodysplasia (MDS) or acute myeloid leukaemia (AML)can be induced by GCSF in susceptible individuals.[31]

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 apheresis were experienced in 20% of women and 8% of men, these adverse events primarily consisted of numbness/tingling, multiple line attempts, and nausea.[30]

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.[30] 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%.[30] 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.It is recommended for people with back pain history, not to be a donor.[30] Other symptoms observed in more than 40% of donors include myalgia, headache, fatigue, and insomnia.[30] These symptoms all returned to baseline 1 month post-donation, except for some cases of persistent fatigue in 3% of donors.[30] . In one metastudy that incorporated data from 377 donors, 44% of patients reported having adverse side effects after peripheral blood HSCT.[31] Side effects included pain prior to the collection procedure as a result of GCSF injections, post-procedural generalized skeletal pain, fatigue and reduced energy.[31]

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.[30] Donors were not observed to have higher than normal rates of cancer with up to 4–8 years of follow up.[30] 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.[29] 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.[29]

Conditions treated with bone marrow or HSC transplantation

Acquired

Congenital

See also

References

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  1. ↑ 1.0 1.1 Cutler C, Antin JH (2001). "Peripheral blood stem cells for allogeneic transplantation: a review" ([dead link]). Stem Cells. 19 (2): 108–17. doi:10.1634/stemcells.19-2-108. PMID 11239165. 
  2. ↑ Tyndall A, Fassas A, Passweg J; et al. (1999). "Autologous haematopoietic stem cell transplants for autoimmune disease--feasibility and transplant-related mortality. Autoimmune Disease and Lymphoma Working Parties of the European Group for Blood and Marrow Transplantation, the European League Against Rheumatism and the International Stem Cell Project for Autoimmune Disease". Bone Marrow Transplant. 24 (7): 729–34. doi:10.1038/sj.bmt.1701987. PMID 10516675. 
  3. ↑ Burt RK, Loh Y, Pearce W; et al. (2008). "Clinical applications of blood-derived and marrow-derived stem cells for nonmalignant diseases". JAMA. 299 (8): 925–36. doi:10.1001/jama.299.8.925. PMID 18314435. 
  4. ↑ Thomas ED, Lochte HL, Lu WC; et al. (1957). "Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy". New England Journal of Medicine. 157 (11): 491–496. doi:10.1056/NEJM195709122571102. PMID 13464965. 
  5. ↑ Bladé J, Samson D, Reece D; et al. (1998). "Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant". Br. J. Haematol. 102 (5): 1115–23. doi:10.1046/j.1365-2141.1998.00930.x. PMID 9753033. 
  6. ↑ Pavletic SZ, Khouri IF, Haagenson M; et al. (2005). "Unrelated donor marrow transplantation for B-cell chronic lymphocytic leukemia after using myeloablative conditioning: results from the Center for International Blood and Marrow Transplant research". J. Clin. Oncol. 23 (24): 5788–94. doi:10.1200/JCO.2005.03.962. PMID 16043827. 
  7. ↑ Locasciulli A, Oneto R, Bacigalupo A; et al. (2007). "Outcome of patients with acquired aplastic anemia given first line bone marrow transplantation or immunosuppressive treatment in the last decade: a report from the European Group for Blood and Marrow Transplantation (EBMT)". Haematologica. 92 (1): 11–8. doi:10.3324/haematol.10075. PMID 17229630. 
  8. ↑ "CIBMTR Summary Slides I". 
  9. ↑ Canellos, George (1997). "The Role of Salvage Therapy in Malignant Lymphomas". The Oncologist. 2 (3): 181–183. 
  10. ↑ Bruno B, Rotta M, Patriarca F; et al. (2007). "A comparison of allografting with autografting for newly diagnosed myeloma". N. Engl. J. Med. 356 (11): 1110–20. doi:10.1056/NEJMoa065464. PMID 17360989. 
  11. ↑ Couri C, et al. "C-peptide levels and insulin independence following autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus" JAMA 2009; 301: 1573-1579.
  12. ↑ 12.0 12.1 Russell N, Bessell E, Stainer C, Haynes A, Das-Gupta E, Byrne J (2000). "Allogeneic haemopoietic stem cell transplantation for multiple myeloma or plasma cell leukaemia using fractionated total body radiation and high-dose melphalan conditioning". Acta Oncol. 39 (7): 837–41. doi:10.1080/028418600750063596. PMID 11145442. 
  13. ↑ 13.0 13.1 Nivison-Smith I, Bradstock KF, Dodds AJ, Hawkins PA, Szer J (2005). "Haemopoietic stem cell transplantation in Australia and New Zealand, 1992-2001: progress report from the Australasian Bone Marrow Transplant Recipient Registry". Intern Med J. 35 (1): 18–27. doi:10.1111/j.1445-5994.2004.00704.x. PMID 15667464. 
  14. ↑ CLL article
  15. ↑ http://www.aidsmeds.com/articles/hiv_aids_stemcell_2042_14199.shtml
  16. ↑ "Bone marrow 'cures HIV patient'". BBC News. 2008-11-13. Retrieved 2009-01-02. 
  17. ↑ http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0030339
  18. ↑ Toze CL, Galal A, Barnett MJ; et al. (2005). "Myeloablative allografting for chronic lymphocytic leukemia: evidence for a potent graft-versus-leukemia effect associated with graft-versus-host disease". Bone Marrow Transplant. 36 (9): 825–30. doi:10.1038/sj.bmt.1705130. PMID 16151430. 
  19. ↑ Alyea EP, Kim HT, Ho V; et al. (2006). "Impact of conditioning regimen intensity on outcome of allogeneic hematopoietic cell transplantation for advanced acute myelogenous leukemia and myelodysplastic syndrome". Biol. Blood Marrow Transplant. 12 (10): 1047–55. doi:10.1016/j.bbmt.2006.06.003. PMID 17067911. 
  20. ↑ 20.0 20.1 Alyea EP, Kim HT, Ho V; et al. (2005). "Comparative outcome of nonmyeloablative and myeloablative allogeneic hematopoietic cell transplantation for patients older than 50 years of age". Blood. 105 (4): 1810–4. doi:10.1182/blood-2004-05-1947. PMID 15459007. 
  21. ↑ Mielcarek M, Martin PJ, Leisenring W; et al. (2003). "Graft-versus-host disease after nonmyeloablative versus conventional hematopoietic stem cell transplantation". Blood. 102 (2): 756–62. doi:10.1182/blood-2002-08-2628. PMID 12663454. 
  22. ↑ Baron F, Maris MB, Sandmaier BM; et al. (2005). "Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning". J. Clin. Oncol. 23 (9): 1993–2003. doi:10.1200/JCO.2005.08.136. PMID 15774790. 
  23. ↑ Toze CL, Galal A, Barnett MJ; et al. (2005). "Myeloablative allografting for chronic lymphocytic leukemia: evidence for a potent graft-versus-leukemia effect associated with graft-versus-host disease". Bone Marrow Transplant. 36 (9): 825–30. doi:10.1038/sj.bmt.1705130. PMID 16151430. 
  24. ↑ 24.0 24.1 Memorial Sloan-Kettering Cancer Center > Blood & Marrow Stem Cell Transplantation > The Graft-versus-Tumor Effect Last Updated: Nov. 20, 2003. Retrieved on 6 April 2009
  25. ↑ Data analysis slides by Center for International Blood and Marrow Transplant Research
  26. ↑ Sorror et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 2005;106:2912-2919.
  27. ↑ Charlson et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373-38.
  28. ↑ Neupogen Prescription information provided by Amgen http://pi.amgen.com/united_states/neupogen/neupogen_pi_hcp_english.pdf
  29. ↑ 29.0 29.1 29.2 29.3 29.4 Halter J,Kodera Y,Urbano-Ipizua A, Greinix HT, Schmitz N, Favre G,Baldomero H, Niederwieser D,Apperley JF, and Gratwohl A (2009). "Severe events in donors after allogeneic hematopoietic stem cell donation". Haematologica. 94 (1): 94–101. doi:10.3324/haematol.13668. PMC 2625420 Freely accessible. PMID 19059940. 
  30. ↑ 30.0 30.1 30.2 30.3 30.4 30.5 30.6 30.7 30.8 30.9 Pulsipher MA,Chitphakdithai P, Miller JP, Logan BR, King RJ,Rizzo JR, Leitman SR, Anderlini P, Haagenson MD,Kurian S, Klein JP, Horowitz MM, and Confer DL (2009). "Adverse events among 2408 unrelated donors of peripheral blood stem cells: results of a prospective trial from the National Marrow Donor Program". Blood. 113 (19): 3604–3611. doi:10.1182/blood-2008-08-175323. PMC 2668845 Freely accessible. PMID 19190248. 
  31. ↑ 31.0 31.1 31.2 Pamphilon D,Siddiq S, Brunskill S,Dore´e C,Hyde C,Horowitz M, and Stanworth S (2009). "Stem cell donation – What advice can be given to the donor?". British Journal of Haematology. 147 (1): 71–76. doi:10.1111/j.1365-2141.2009.07832.x. PMID 19681886. 
  32. ↑ Hütter G, Nowak D, Mossner M, Ganepola S, Müßig A, Allers K, Schneider T, Hofmann J, Kücherer C, Blau O, Blau IW, Hofmann WK and Thiel E (2009). "Long-Term Control of HIV by CCR5 Delta32/Delta32 Stem-Cell Transplantation". N Engl J Med. 360 (7): 692–698. doi:10.1056/NEJMoa0802905. PMID 19213682. 
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