Hematopoietic precursor transplantation, better known as bone marrow transplantation, is the treatment by which a patient’s bone marrow is destroyed and replaced with new hematopoietic precursors. It is usually performed in patients with cancer or congenital blood or bone marrow disease. The goal is to remove diseased or defective cells and introduce stem cells that produce healthy blood cells.
Origin of bone marrow transplantation
The first bone marrow transplant was performed by Georges Mathé, a French oncologist, in 1958, in an attempt to save the lives of six nuclear researchers who had been accidentally subjected to radiation at the Vinca Nuclear Institute. Although all the patients suffered rejection of the transplant, Mathé understood the need to improve the procedure, which had great potential in the field of immunotherapy.
After years of research, Mathé succeeded in improving the technique, becoming the pioneer in the use of bone marrow transplantation in the treatment of leukemia. The transplantation was performed using bone marrow stem cell derivatives by a team at the Fred Hutchinson Cancer Research Center from 1950 to 1970 by E. Donnall Thomas, whose work was later recognized with the Nobel Prize in Medicine.
What is bone marrow transplantation used for?
Bone marrow or purified hematopoietic progenitor transplantation is used to treat several types of diseases:
- – Bone marrow aplasia
- – Hereditary diseases
- – Leukemia
- – Lymphoma
- – Immunodeficiencies
Many recipients are multiple myeloma or leukemia patients who would not benefit from prolonged cytostatic treatment, or who already have resistance to chemotherapy. Pediatric cases where the patient has a severe congenital bone marrow defect, such as congenital neutropenia or combined immunodeficiency, with defective stem cells, and also children or adults with aplastic anemia, who have lost their stem cells at birth, are also candidates.
Other diseases treated with bone marrow transplants include: sickle cell anemia, myelodysplastic syndrome, neuroblastoma, lymphoma, Ewing’s sarcoma, desmoplastic small round cell tumor, chronic granulomatous disease or Hodgkin’s disease.
Also, recently, non-myeloablative transplantation or “mini transplantation” has developed procedures that require lower doses of preparative chemotherapy and radiation. This has made it possible to extend the therapy to older patients, along with other patients considered too weak to sustain such aggressive treatment.
Types of hematopoietic stem cell or bone marrow transplantation
After several weeks of growth in the bone marrow, the expansion of hematopoietic stem cells and their progeny is sufficient to normalize blood cell counts and restart the immune system.
According to the origin of stem cells, we know the following:
This type of procedure uses hematopoietic precursors from the same patient who is to receive the transplant. As the transplanted cells are taken from the already damaged marrow, many protocols employ some techniques to choose the healthy cells to be returned to the patient. This process may require drugs or antibodies designed to eliminate certain types of cells or purge the marrow of neoplastic cells.
To perform this therapy requires the removal (apheresis) of hematopoietic stem cells from the patient and storing the collected cells in a freezer. The patient is then treated with high doses of chemotherapy with or without radiotherapy, with the intention of eradicating the malignant cells, resulting in total or partial ablation of the bone marrow (destruction of the bone marrow’s capacity to produce new cells). Subsequently, healthy hematopoietic progenitors are returned to the patient’s bloodstream, replacing the destroyed tissue and resuming normal production of all hematological series.
An autologous transplant has the advantage of having a lower risk of infection during the immunocompromised part of the treatment, since recovery of immune function is rapid. In addition, the incidence of patients experiencing rejection is very rare, due to the fact that the donation and reception is from the same individual. These advantages have led hematology experts to consider autologous transplantation as a standard treatment for diseases such as lymphomas. However, for other diseases such as acute myeloid leukemia, the increased probability of relapse makes the allogeneic modality the modality of choice.
This type of transplant uses hematopoietic precursors taken from a donor other than the recipient. This transplant has, in turn, different varieties, depending on the donor and the similarity of the Human Leukocyte Antigen (HLA) system. It is important to recognize what type of transplant we are talking about, since both the usefulness and the results vary from one to another. When the donor is an univitelline twin sibling, it is called a syngeneic transplant. However, when the donor is an HLA sibling, it is called an allogeneic HLA-identical sibling transplant. If the donor is a relative who shares only one haplotype of the HLA system, it is called a haploidentical transplant, which can be any relative (father, mother, siblings, cousins) who shares only half of the genes involved in the HLA system. If the donor is an unrelated donor it is called an unrelated donor transplant.
Transplants involving a non-genetically identical donor and recipient are always associated with graft-host HLA differences. In these cases, the transplanted immune system recognizes the HLA antigens of the recipient’s cells as foreign and attacks them. It is therefore necessary to select donors maximizing the amount of HLA antigens shared by donor and recipient. HLA antigens are inherited in a Mendelian fashion, so often a relative is found who shares the HLA genes. If there is no matched related donor, an unrelated HLA-matched donor can be sought.
Allogeneic transplants are also performed using umbilical cord blood as a source of stem cells. In general, by transplanting healthy stem cells from the recipient’s immune system, allogeneic hematopoietic stem cell transplants appear to increase the chances of cure or long-term remission.
Source of Hematopoietic Progenitors
Bone marrow was the first source of transplanted stem cells. As mentioned above, this type of transplantation is done with cells taken directly from the donor’s bone marrow, usually aspirated from the iliac crests through a large needle that reaches the center of the bone. The technique is performed under general anesthesia.
Hematopoietic cells can be collected from the donor’s blood using a process called apheresis. Prior to transplantation, the donor is stimulated by injections of granulocyte colony-stimulating factor (G-CSF) to produce and mobilize more hematopoietic precursors. Donor procurement or collection is performed by a needle placed in a vein in the arm connected to a machine, which collects the cells to be transplanted. The remaining blood is returned to the donor.
Umbilical cord blood
Cord blood contains stem cells that can be transplanted after hematopoietic cell separation from the rest of the tissue (CD34+ or Lin-). Cord blood transplants do not require as much matching between donor and recipient. However, the low number of cells available in each cord makes the use of a single donor for transplantation in an adult or young adult difficult. Sometimes cord blood from two different donors is used so that the number of transplanted cells is sufficient.
It is obtained when a mother donates her baby’s umbilical cord and placenta after birth. Cord blood has a higher concentration of hematopoietic progenitors than those circulating in the blood of an adult person. However, the small amount of blood from an umbilical cord (typically 50 ml) makes it more suitable for transplantation in young children than in adults. New techniques using ex-vivo expansion of cord blood units or the use of two cord blood units from different donors allow this type of transplantation to be used in adults.
In most cases, progenitors already present in the recipient’s bone marrow need to be removed. During this process, called conditioning, high doses of chemotherapy and/or radiation therapy are used to destroy all of the patient’s bone marrow in order to eliminate cancer cells, prevent graft rejection, and make room for the graft. Common regimens include some drugs.
The conditioning leaves the patient without an immune system and unable to produce red blood cells, so he or she would die without a new marrow transplant. The toxic therapies used in this process can damage a variety of tissues and are associated with complications such as pulmonary and neurological disorders and a higher risk of cancer in the future.
In severe immunodeficiencies, the recipient’s immune system is already weak enough that transplantation can be performed without preparation.
Immediately after transplantation, the transplanted stem cells lodge in the bones and begin to reconstitute the patient’s hematopoietic tissues. This process, known as budding, takes place over a few weeks (usually between day 15 and 21) after implantation. Graft rejection can prevent engraftment and leave the patient without sufficient hematopoietic function.