BONE MARROW TRANSPLANTATION
Haemopoietic stem cell transplantation is usually carried out for one of the two reasons:
to replace an abnormal but not malignant marrow that has been purposefully destroyed with either radiation or chemotherapy,
to allow for the administration of higher than usual doses of myelotoxic chemotherapy and/or radiation therapy to treat a malignancy.
The types of bone marrow abnormalities treated with this procedure include both congenital and acquired diseases;the malignancies treated with hemopoietic support include acute leukemias and lymphomas, as well as solid tumours that appear to have a dose-response curve to chemotherapy.
SOURCE OF HEMOPOIETIC STEM CELLS
Stem cells may be obtained from the bonemarrow, peripheral blood, cord blood, or fetal liver of another individual, generally one who is immunologically matched at the major histocompatibility complex.
Cord blood is usually available in too small a volume to reconstitute a adult;thus cord blood transplants are performed nearly exclusively in children.Fetal liver between 10 and 14 weeks of gestation is a rich source of hemopoietic stem cells, but such transplants are rarely done because of the scarcity of the material.
TYPES OF MARROW TRANSPLANTS
When another individual is the stem cell donor, the transplantation is termed allogenic.Autologous bone marrow and peripheral blood may also be stored before marrow ablation for reinfusion after myeloablative therapy.Such transplants are termed autologous.In the special case where the donor is an identical twin, i.e., genetically identical to the recipient, the transplantation is termed syngeneic.In all these types of transplants, hemopoietic stem cells are infused into a peripheral vein of the recipient and the stem cells home to the marrow to re-establish hematopoiesis.
DISEASES TREATED WITH HEMOPOIETIC STEM CELL TRANSPLANTATION
MALIGNANCIES
| CONDITIONS | Allogenic | Autologous |
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| Acute leukemia | + | + |
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| Chronic myelogenous leukemia | + | + |
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| Lymphoma | + | + |
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| Hodgkin's disease | + | + |
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| Multiple Myeloma | + | + |
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| Chronic lymphocytic leukemia | + | + |
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| Myelofibrosis | + | - |
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| Breast cancer | - | + |
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| Testicular cancer | | -+ |
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| Ovarian cancer | - | + |
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| Neuroblastoma | + | + |
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| Peripheral neuroepithelial tumors | - | + |
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| Wilm's tumour | - | + |
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| Ewing's sarcoma | - | ++ |
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NON-MALIGNANCIES
| CONDITIONS | Allogenic | Autologous |
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| Lesch-Nyhan syndrome | + | - |
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Hemoglobunuria[PNH] | + | - |
| Aplastic anaemia | + | - |
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| Pure red cell aplasia | + | - |
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| Fanconi's anaemia | + | - |
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| Severe Combined immunodeficiency | + | - |
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| Sickle cell anaemia | + | - |
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| Thalessemia | + | - |
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| Met.. leukodystrophy | | +- |
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| Adrenoleukodystrophy | + | - |
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| Osteopetrosis | + | - |
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| Type IIa glycogen storage disease | + | - |
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| Radiation accidents | + | - |
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| Others | |
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ALLOGENIC AND SYNGENEIC BONE MARROW TRANSPLANTATION
Allogenic marrow transplantation is usually restricted to persons less than 60 yrs of age.The results tend to be poorer in older patients because of increased complications associated with graft-versus host disease (GVHD) in this population.For patients with a twin, an HLA-matched sibling donor is the best choice for an allogenic bone marrow transplantation.For patients who may benefit from an allogenic bonemarrow transplanatation but lack an HLA-matched sibling donor, there are two possibile solutions.One is to identify an unrelated but closely HLA-matched person willing to donate marrow or peripheral blood, and the other is to use marrow from a related donor who is less than perfectly matched.The extremely large number of HLA phenotypes makes the search for an unrelated donor a difficult undertaking.Fortunately, in patients with a similar genetic background certain HLA phenotypes occur more frequently than might be expected based upon random population genetics.
Bonemarrow transplantation using unrelated donors has become a widely applied therapy.While the results remain somewhat inferior to those seen when using an HLA-matched sibling donor, treatment outcomes with this approach have been improving as the techniques to manage GVHD and graft rejection have been refined. An alternative approach is to identify a related individual who shares most, but not all, of the patient's HLA antigens.Successful allogenic marrow transplantation can be performed using marrow from such donors, but the risk of graft rejection and GVHD increases with the level of mismatch.There is a somewhat higher rate of death from GVHD, but there is a somewhat lower rate of death from tumor relapse because the mismatched marrow exerts a greater graft-versus-tumour effect. Once a donor has been identified, the actual transplant procedure begins.It consists of three phases: preparation for transplant, transplant and management after transplant.
PREPARATION FOR TRANSPLANT
High doses of chemotherapy with or without radiation are delivered to the recipient with two main goals: destruction of residual malignant or dysfunctional cells and destruction of the immune system of sufficient degree to avoid rejection of the allograft by residual, immunologically active cells in the host.Most preoperative regimens employ cyclophosphamide,ifosfamide,busulfan, or melphalan; topoisomerase II inhibitors such as etoposide; antimetabolites such as cytarabine; and nitrosureas such as carmustine.When allogenic transplants are performed using T cell depleted donor marrow to lower the risk of GVHD, engraftment is not so efficient.Many such patients develop so-called mixed chimerism in which the cells of both donor and host origin are present, indicating survival of host hemopoietic cells.No single pre-operative regimen has been proven superior to others.
THE TRANSPLANT PROCEDURE
Collection of bonemarrow from a donor is termed harvesting.Marrow is usually harvested by repeated aspiration from the posterior iliac crest until an adequate number of cells has been removed.If a sufficient number of cells cannot be obtained from the posterior iliac crest, marrow can also be harvested from the anterior iliac crest and sternum.If peripheral blood is being used for harvesting, then the donor may recieve CSF to augment the production of stem cells.The risk to the donor is very slight and predominantly associated with the risk of anaesthesia used.The procedure is usually accomplished on an out-patient basis, and the donors usually return promptly to their usual activities, requiring only oral analgesia.
The smallest number of nucleated marrow cells required for long-term hemopoietic repopulation in humans is not precisely known.Operationally, the number of marrow cells harvested is usually 1 to 3*10power8 per kilogram of recipient body weight.For a number of conditions, it appears that the more marrow cells are given, the better the outcome.A larger number of donor cells is also required when the donor marrow is depleted of T cells or when the donor and the host are mismatched.
Marrow is sometimes treated invitro to remove unwanted cells before being administered to the patient.When the donor and the patient have a major ABO red cell incompatibility, it is necessary to remove the mature erythrocytes from the graft to avoid a hemolytic transfusion reaction.Alternatively, one may avoid a hemolytic transfusion reaction by performing a plasma exchange and removing anti-A or anti-B antibodies from the recipient's circulation.The removal of T-cells from an allograft can reduce the incidence and severity of GVHD, but this has never been shown to translate into better long-term survival, probably because T-cell depletion also increases the risk of graft rejection and tumor relapse.
MANAGEMENT AFTER TRANSPLANT
All patients undergoing bone marrow transplantation require intense supportive care between the time that the hemopoietic progenitor cells are infused and when they are able to produce adequate number of granulocytes, platelets, and erythrocytes.Early after transplantation therapy is focused on prophylactix against infection, bleeding, and GVHD.Beyond careful HLA-matching some combination of methotrexate, cyclosporine, and prednisolone appears to be the most effective prophylactic drug regimen.In addition, supportive care usually includes blood components as needed to keep the platelet count above 20,000/mcL and the hemoglobin above 80g/L, protective isolation, and broad spectrum antibiotics.Blood components should be irradiated to avoid inducing GVHD mediated by lymphocytes from an HLA-incompatible donor.
COMPLICATIONS OF ALLOGENIC BONE MARROW TRANSPLANTATION
EARLY COMPLICATIONS
REGIMEN RELATED-
-TOXICITY
- Cystitis
- Mucositis
- Pulmonary complications
- Renal toxicity
- Neurologic toxicity
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OTHERS
- Venoocclusive disease of the liver
- Idiopathic pneumonia syndrome
- Graft failure
- Immunodeficiency
- Acute graft Vs host disease
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LATE COMPLICATIONS
REGIMEN RELATED-
- TOXICITY
- Cataracts
- Neurologic toxicity
- Gonadal toxicity
- Endocrine toxicity
- Abnormal growth &
development
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OTHERS
- Immunodeficiency
- Infection
- Chronic graft Vs host disease
- Relapse of primary tumor
- Second malignancy
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AUTOLOGOUS BONE MARROW TRANSPLANTATION
Autologous bone marrow transplantation involves the use of patient's own hemopoietic progenitor cells to reestablish hemopoietic cell function after the administration of high-dose chemotherapy and/or radiation therapy.The reinfused hematopoietic progenitors may come from the patients marrow or peripheral blood.Generally, before peripheral stem cell harvest, the stem cell content of the blood is augmented by treating the patient with chemotherapy and CSFs, especially granulocyte CSF, a manipulation that results in marrow stem cells being released in to the peripheral blood.
Autologous bone marrow transplantation differs from allogenic transplantation in several ways.Although many of the complications are similar to those encountered in allogenic transplants, usually the incidence is lower and there are no complications related to GVHD.The early clinical problems arise mainly from regimen-related toxicity.CSFs are essentially always used in autologous transplants.Because of this more favourable toxicity profile, autologous transplantation may safely be employed in older patients.
A concern related specifically to autologous transplantation is the possible presence of contaminating tumor cells in the graft.A number of approaches have been employed to rid the graft of tumor cells, including purging tumor cells with antibody plus complement, an immunotoxin, and incubating the marrow with chemotherapeutic agents.It has also been observed that the act of freezing the marrow and thawing it for delivery to the patient may preferentially kill the tumor cells.Despite all this concern, there is little evidence that purging-techniques influence disease free survival.Nevertheless, three pieces of information support the concept that the graft may be a source of tumour.
PATIENT FOLLOW-UP AFTER BONE MARROW TRANSPLANTATION
The most important long-term complications that need to be monitored are infection and the development of relapse of the underlying disorder.Late infections, particularly herpes zoster are not rare.Recurrence of malignancy is the major cause of death after autologous marrow transplants.Patients recieving radiotherapy are at the risk of developing hypothyroidism.Most patients who undergo marrow transplantation will be infertile.Patients sometime recover from infertility following transplantation.Women seem more likely to recover fertility than men.All patients who have been irradiated as part of their primary treatment or as part of the bone marrow transplant preoperative regimen are at the risk for development of late solid tumours.This increased risk should lead to early institution of appropriate screening procedures in such transplanted patients, such as mammography,regular clinical examination etc.The treating physician should be aware of such possibilities as discussed above, and institute appropriate post-transplant followup of such patients.
CONCLUSIONS
Allogenic marrow transplantations is likely to remain an important treatment modality for leukemia, aplastic anaemia, and certain genetic disorders for many years to come.Autologous marrow transplantation as a treatment for malingant disease might be avoided in some patients as effective new chemotherapeutic agents are developed and/or new generations of hematopoietic growth factors become available.IF genetic manipulation of hemopoietic progenitor cells becomes practical, autologous bone marrow transplantation might become a common treatment for a variety of non-malignant disorders.
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