Finding a Donor
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The ideal donor is a sibling who has inherited a specific set of genes identical to those of the patient. These genes express proteins called human leukocyte antigens (HLA). HLA molecules are found on the surfaces of white blood cells and help the body distinguish between its own cells and foreign invaders that should be destroyed.
The chance that a patient and his or her sibling will inherit a matched set of HLA genes is just one in four. Only about a third of patients who could benefit from a transplant, however, have both this ideal donor and also meet other eligibility criteria. For the remaining 60 to 70 percent of patients, physicians expand the search to other family members, who may be only partially HLA matched, and to donor registries like the National Marrow Donor Program and cord blood banks.
HLA Typing
Researchers have known for years that specific genes that comprise the HLA complex are indicators of a transplant's success. The closer the match between the patient and donor's HLA genes, the lower the chance that the patient will develop GvHD or that the graft will fail for other reasons. These genes include the HLA-A, -B, -C, DR, and DQ genes, which are strung like beads along the short arm of chromosome 6. As part of the typing process, these are identified by a number -- patients may have an HLA-A3 or A10, for example, or an HLA-DR4 or DR7. People inherit one set of these genes from each parent, and so they have two sets total. They will pass along one of the sets of the pair to each of their own children.
The tests used in the past to identify the proteins expressed by these genes are called serological tests. Major transplant centers now use more sensitive DNA typing techniques (molecular or high-resolution typing) to refine the search for the most closely matched donors. These DNA tests show that several of the HLA genes have additional variations at the molecular level, which the old serological testing would not have detected. These genetic variations and the cell surface proteins they express play a role in the development of graft rejection and GvHD. In 30 to 48 percent of donor-recipient pairs who match serologically, researchers have detected these molecular differences. The newer molecular HLA typing methods are therefore especially important in best matching unrelated or extended family donors of patients.
Studies are currently under way at Memorial Sloan-Kettering to determine how much information is needed to make a good match -- in other words, which antigens and which molecular variants of those antigens are important to match so that a graft will take without causing GvHD and to achieve an anti-tumor effect.
Donor Registries
The National Marrow Donor Program facilitates transplants between patients and unrelated donors. It maintains a database of potential marrow donors and is linked with other national and international registries, creating a combined pool of 4.5 million potential donors. Memorial Sloan-Kettering is a founding member of the National Marrow Donor Program.
Harvesting Stem Cells
Hematopoietic stem cells, the immature cells that develop into the full range of blood cells, are produced in the bone marrow, the spongy tissue found inside many bones (for example, the breastbone, skull, pelvis, ribs, and spine). Stem cells are also found under normal circumstances in smaller numbers in the circulating blood -- the peripheral blood. In either case, these are the cells that physicians collect during a bone marrow or peripheral blood stem cell harvest.
Physicians harvest bone marrow from the pelvic bones or hip in an operating room while the donor is under general anesthesia. The physician inserts a hollow needle into the rear and sometimes the front hipbone, both of which contain a large quantity of bone marrow. The breastbone is another accessible site that is rich in marrow, but this is very rarely used for harvest. The physician often must pierce the bone in several spots to obtain enough marrow for a transplant. The donor will not need stitches but will have some pain and tenderness at the site of the harvest for about a week.
Apheresis
Until the past few years, physicians harvested stem cells only from the bone marrow. Using a newer procedure, apheresis, physicians may collect stem cells from the circulating blood. This procedure, unlike a bone marrow harvest, does not have to be done in an operating room, and the donor does not have to be under general anesthesia.
A few days before the procedure, donors are generally given a medication (G-CSF [filgrastim], GM-CSF [sargramostim], or a combination of the two) to mobilize or force stem cells from the marrow into the circulating blood. These agents can cause flu-like symptoms and bone pain in the days before and after the procedure. The donor then spends several hours on each of two or three days for the apheresis process. The blood passes through a tube inserted in one of the donor's veins and then through a machine that separates stem cells from other blood cells, which are then returned to the patient. The stem cells collected during the procedure are used immediately or can be frozen and stored.
Researchers are comparing the outcomes of transplants using stem cells from bone marrow versus peripheral blood, weighing factors like the time it takes for the stem cells to engraft, the donor's comfort and well-being, and his or her need for hospitalization. Some early studies indicate that peripheral blood stem cell transplants are more likely to engraft and to induce a more rapid recovery of white blood cells called platelets and neutrophils. They may also result in a greater incidence of chronic GvHD, however.
Cord Blood Transplants
Another potential source of stem cells is cord blood. This is blood collected from the umbilical cord and placenta of newborns. Cord blood transplants have been shown to be very successful between some matched siblings in the treatment of both genetic and acquired hematopoietic disorders. Some transplant centers are also using them for stem cell transplants to unrelated recipients. Ensuring an adequate cell dose, especially for adult recipients, however, can prove problematic.
Donating cord blood to an unrelated donor bank is an option that parents may want to discuss with their obstetrician. We do not routinely recommend collection and banking of cord blood for future use by the child from whom the cord blood was obtained.
Autologous Collection
For autologous stem cell rescue physicians usually collect stem cells from the peripheral blood of the patient, rather than from the marrow. This procedure is easier -- unlike a bone marrow harvest, it can take place outside of an operating room and the patient does not have to be under general anesthesia. On the other hand, a few days before the procedure, donors are generally given a medication to mobilize or force stem cells from the marrow into the circulating blood. These agents can cause flu-like symptoms in the days preceding and following stem cell harvest. Patients can also have bony aches and pain from the growth factor(s). The collection additionally requires several hours during a day on the collection machine. Patients tend to recover more quickly when transplanted with stem cells from the peripheral blood, to require fewer red blood cell and platelet transfusions. Their hospital stays are sometimes, but not always, shorter and less costly.
At Memorial Sloan-Kettering, stem cells are collected in the blood donor room with an apheresis or leukopheresis machine, a machine that separates the stem cells from the other components of the blood. Over the course of three to five appointments, blood is withdrawn from a vein and circulated through the machine, which collects the stem cells; the other components are then returned to the patients. The stem cells are cryopreserved or frozen until they are readministered to the patient.
Preparing for a Transplant
Allogeneic Transplantation
The high-dose chemotherapy and/or radiation therapy that physicians use as the first step in an allogeneic transplant has two purposes. This cytoreductive therapy destroys cancer cells as well as cells of the patient's immune system. Unless the patient's immune system is eradicated through this myeloablative therapy (treatment designed to destroy the bone marrow), an allogeneic transplant will be unlikely to take and to reconstitute a new immune system for the patient. Some of the agents commonly used for myeloablation include cyclophosphamide, thiotepa, melphalan, fludarabine, and total body irradiation.
Researchers at Memorial Sloan-Kettering have developed a less toxic radiation therapy regimen called hyperfractionated total body irradiation, which reduces many of the side effects of intensive radiation therapy. Normal tissues recover more readily, fewer patients get cataracts, and children who are treated with this form of therapy are more likely to grow to their full stature. In hyperfractionated irradiation patients receive the total dose of radiation divided into smaller fractions, or doses two or three time daily over several days.
Myeloablative or cytoreductive therapy may last several days or a week or more. A day or two after the completion of treatment, patients generally receive their stem cell transplant.
Autologous Stem Cell Rescue
The high-dose chemotherapy and/or radiation therapy patients receive before an autologous stem cell rescue is called a preparative regimen or cytotoxic therapy. In the most successful cases it will eradicate the patient's cancer cells. Physicians design a treatment regimen that includes the chemotherapeutic agents to which the patient's cancer should be most sensitive.
Some patients will receive radiation therapy in addition to chemotherapy. Memorial Sloan-Kettering researchers have developed a less toxic radiation therapy regimen called hyperfractionated radiation, described above, which reduces many of the side effects of more intensive radiation therapy.
Cytoreductive therapy may last several days or a week or more. A day or two after the completion of treatment, patients generally receive their stem cells.
The Transplant & Recovery
Physicians usually transplant the harvested marrow or stem cells intravenously, in the same way that they would administer a blood transfusion. Over the following days and weeks, the transplanted stem cells in the graft migrate to the marrow space in the patient's bones, where they gradually begin to produce blood and immune system cells.
Between two and three weeks after the transplant, physicians should begin to detect cells of the donor's type in the patient's bloodstream. As time passes, a successful graft is able to produce the full range of blood components including red blood cells (erythrocytes), white blood cells (leukocytes, including polys or neutrophils), and platelets.
During the days just after transplantation, patients need a great deal of medical support including transfusions of irradiated blood products like platelets and red cells. Patients also receive antibiotics to prevent and treat infections. These include bacterial, viral, and fungal infections, which are most likely to occur in the first three months after transplantation. Patients are also vulnerable to complications of the preparative regimen, which may require specific treatment.
Patients generally remain in the hospital for several weeks after the transplant. During this time precautionary measures protect the patient from infection by requiring people who enter the room to wear protective gloves and masks, and to wash their hands with antiseptic soap. Sometimes people entering the room need to cover their clothing with clean, disposable gowns. Fresh fruit, flowers, plants, or cut flowers are barred from the patient's room, as these can carry disease-causing molds and bacteria.
Management of Complications
Graft-versus-Host Disease
Graft-versus-host disease (GvHD) can develop after an allogeneic transplant if the immune cells from the donor recognize the recipient's tissues as foreign and attack them. GvHD can arise even when the transplant comes from a matched related donor. Up to 70 percent of transplant patients develop some degree of GvHD, unless effective preventive measures are used.
The incidence and severity of GvHD increase with greater mismatching between the patient and donor's HLA typing. Patient and donor characteristics like age and gender, as well as the intensity of the cytoreductive regimen, all play roles in the likelihood that a patient will or will not develop GvHD.
GvHD can be either acute or chronic. Symptoms of acute GvHD include a skin rash and intestinal and abdominal discomfort caused by an inflammation of the liver and the lining of the intestine. In patients with this condition, the rebuilding of the immune system may be delayed. Treatment to prevent acute GvHD can include methotrexate, cyclosporine, or related drugs. Agents used to control the condition when it develops include steroids.
Graft Failure
A bone marrow or stem cell graft "fails" when the patient does not recover marrow function after the transplant. Most cases of graft failure occur within the first two months after transplant. Grafts generally fail because the patient rejects donor cells. Researchers have therefore developed improved regimens to reduce substantially the incidence of graft rejection. Infections, especially from certain viruses, can also cause graft failure. Improved methods for prevention, as well as early detection and treatment of these infections, are reducing graft failure caused by viral infections.
Complications of High-Dose Therapy
Patients who have received very high doses of chemotherapy and radiation therapy can develop both acute and chronic complications, including infection, bleeding, and anemia during the period before blood cell production returns to normal. Liver and lung problems can develop after transplant. Physicians have developed treatments for both acute and chronic effects of treatment that are effective for many patients.
Another possible complication is mucositis, a condition in which the cells that line the mouth and intestinal tract are destroyed by the high-dose chemotherapy and/or radiation therapy. Symptoms include mouth pain and ulcers, abdominal pain, diarrhea, and infection. A new drug called recombinant human keratinocyte growth factor (rHuKGF) is under study in clinical trials, but is believed to reduce the duration of mucositis in transplant patients.
In some patients, cancer can recur after either autologous rescue or allogeneic transplantation if the high-dose chemotherapy and radiation given before the transplant did not eliminate all the malignant cells, or if the autologous stem cells harvested before the cytotoxic therapy contained some cancer cells. In the allogeneic setting the graft-vs-leukemia process does not always protect the patient against relapse, especially if the patient were transplanted with relapsed or advanced disease. When a patient's cancer recurs, physicians shift their treatment strategy to the next-line therapy. In rare instances, patients can develop a secondary cancer or condition such as a myelodysplastic syndrome as a result of the high-dose treatment.
