Bone marrow transplants

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cells derive from hematopoietic stem cells that reside in the red bone marrow. They give rise to different precursor cells that eventually will differentiate and ...
Bone marrow transplants The bone marrow is located in the interior of the bones and produces white cells for the immune system, red cells for oxygen transportation and platelets for blood clotting. There are two types of bone marrow. Red marrow consists of mainly hematopoietic tissue and yellow marrow consists mainly of fat cells. At birth all marrow is red but with age half of it is transformed into yellow marrow. Red marrow is found mainly in the flat bones such as the pelvis, sternum and cranium, and in the ends of long bones such as the femur and humerus. Here hematopoiesis take place which is the formation of blood cellular components. Approximately 1011–1012 new blood cells are produced daily in order to maintain steady state levels in the blood stream. All blood cells derive from hematopoietic stem cells that reside in the red bone marrow. They give rise to different precursor cells that eventually will differentiate and become mature blood cells. The bone marrow stroma is made up of other cell types such as fibroblasts and cells involved in the formation of bone structure such as osteoblasts and osteoclasts. They are indirectly involved in hematopoiesis by secreting growth factors and cytokines which influence the development of different cell types. Since the 1950’s there has been a tremendous development of the procedure where bone marrow is transplanted from a healthy donor to a patient in need of a restored bone marrow function and since the 1970’s it is in clinical use. In 1990 E. Donnal Thomas and Joseph E. Murray received the Nobel Prize in Physiology or Medicine for their pioneering work on bone marrow transplantation. Today this is mainly used for patients with diseases originated in the bone marrow such as acute leukemia but an increasing number of patients is treated for a wide variety of other diseases. A bone marrow transplantation is today mainly synonymous with a hematopoietic stem cell transplantation (HSCT) where the cells are harvested by a procedure called apheresis from the peripheral blood of a healthy donor or the patient prior to treatment. Apheresis is a technique where a persons blood is passed from a vein through a machine that sort out the stem cells and then the blood is given back. The cells could also be harvested as bone marrow by aspiration from the pelvic bone or from the umbilical cord of newborn infants. This is mainly used for donations to siblings with malignant or inborn diseases but donation to unrelated children and adults is also possible.

Allogeneic transplantation An allogeneic transplantation is a procedure where stem cells are transferred from a healthy person to a patient. Candidates for this regimen is mainly patients with cancer diseases of

the blood such as acute leukemias where conventional cytostatics has failed or the genetic profile of the disease predicts a poor prognosis. Other conditions treated with stem cell transplants include sickle-cell disease, myelodysplastic syndrome and aplastic anemia. Children could be treated for diseases such as severe combined immunodeficiency (SCID) or congenital neutropenia. A thorough investigation of both the patient and the donor is carried out in order to ensure that they could manage the treatment. This includes examination of vital organ function such as heart, lung and kidney but also screening for diseases that could complicate the transplantation. The donor should preferably be a sibling or an unrelated donor with a matching HLA (human leukocyte antigen) profile. This is to ensure that the transplanted cells do not attack the patients’ tissues and causes graft-versus-host disease (GVHD). This could present as skin rash, impairment of liver function or inflammation of the colon with severe diarrhea. Since there is always some minor mismatch between donor and recipient the patient need to take immunosuppressant drugs at least a couple of months after transplantation in order to prevent GVHD. There is one beneficial aspect of having a mild GVDH since the immune reaction carried out by the donors Tlymphocytes against the diseased bone marrow then is believed to lower the risk of relapse. This is called graft-versus-leukemia effect (GVL). There are newer regimens where doses of cytostatics and irradiation have been lowered in order to make use of the GVL effect by leaving a small part of the recipient’s bone marrow intact. An increasing number of patients is today getting a transplant from a sibling without full HLA match (haploidentical) thus facilitating the search for an acceptable donor. This is made possible by new techniques that decrease the risk of serious GVDH. The donor is given a short treatment in order to mobilize the stem cells from the bone marrow to the blood stream and the cells are then collected by apheresis. There is today a worldwide network with interconnected registers which makes it possible to search for unrelated donors. Depending on the time between apheresis and transplantation the cells are collected and transported to the recipient either fresh or frozen. If there are any cells left after transplantation they are usually frozen and stored for later use if the patient does not respond as expected after transplantation. Before the transplantation the patient is given different chemotherapeutic regimens depending on diagnosis and sometimes also irradiation. The goal is to eradicate the disease and give possibility for the donor cells to reestablish a new hematopoietic system. It is crucial that the patient is being kept isolated after transplantation since the immune system is severely impaired and infections could easily arise. Prophylactic treatment against fungal and viral infections is given during this time and strict surveillance to detect and treat any bacterial infection is crucial.

There is also need for blood and platelet transfusions since this production is also impaired. Another severe side effect is inflammation of the mucosal tissue in the mouth and the patients often need to get nutrition through a nasogastric tube.

Autologous transplantation An autologous transplantation could also be performed where cells are harvested from the patients own blood and then frozen in order to be re-transplanted after intensive chemotherapy treatment has been given. Today this is standard treatment for patients with multiple myeloma and also widely used for lymphoma patients and many other solid tumors such as testicular cancer. Depending on diagnosis different cytostatic regimens are given in order to eradicate as much as possible of the cancer cells and to make the patients condition suitable for transplantation. This is followed by a treatment that mobilizes the stem cells to the blood stream in order to sort them out by apheresis. A high dose of cytostatics is then given prior to transplantation. As opposed to allogeneic transplantation where the GVL effect is an active part of the treatment, the autologous transplantation is only carried out in order to be able to give so intensive cytostatic therapy that the bone marrow otherwise would not be able to restore its function. There is no risk for GVHD since the cells derive from the patients own immune system and the re-establishment of a new bone marrow function is more rapid than in allogeneic transplantation. The need for hospital care is then shortened and there is also a lower risk for severe infections. However, in acute leukemia the risk of relapse is higher with autologous transplantation and therefore not considered an option today. At the moment there is a rapid development where patients with autoimmune diseases such as severe multiple sclerosis is being transplanted.

Donor register Bone marrow donors worldwide (BMDW) is an organization based in Leiden, Netherlands, that coordinates registration of now 22,5 million donors from 72 hematopoietic cell donor registries in 52 countries. The donor’s personal HLA characteristics together with other relevant data are made searchable for today 850 transplanting physicians and search coordinators. The chance of finding a good match depends on the patients’ origin since some minorities still have less representation. Another factor is the genetic diversity in a population. As an example people of African descent are more genetically diverse than European descendants and therefore need more potential donors to find a good match.

Prognosis The prognosis after HSCT depends on disease type, cytostatic regimen and how well the donor matches the patient. Allogeneic transplantation is considered the only curative treatment in some forms of acute leukemia and if the patients survives the risks of transplantation, such as infections and GVHD, there is a good chance of long-term survival. Autologous transplantation is not considered as a curative treatment but leads to prolonged life expectancy of both myeloma and lymphoma patients. There are also promising results that autologous HSCT could help patients with severe multiple sclerosis and efficiently reduce the autoimmune reactions where the patients own immune system otherwise rapidly would cause progressive neurological disability.

SEE ALSO: blood; cancer; stem cell renewal; umbilical cells; cell sorting

BIBLIOGRAPHY: Bone Marrow Donors Worldwide (BMDW), http://www.bmdw.org; The European Group for Blood and Marrow Transplantation (EBMT), http://www.ebmt.org; Worldwide Network for Blood and Marrow Transplantation (WBMT), http://www.wbmt.org/.

OSCAR LINDBLAD JULHASH U. KAZI LARS RÖNNSTRAND DEPARTMENT OF LABORATORY MEDICINE, LUND UNIVERSITY