Bone marrow transplantation (BMT).
For almost a century physicians have attempted to cure anemic or leukemic patients by feeding or injecting marrow preparations from healthy individuals or even animals. With the exception of a handful of aplastic anemia patients who recovered after infusions of marrow from their identical twins, the results were dismal. It was not until the 1960s that the importance of tissue matching was understood, and methods to match tissues were developed. In 1968, a child suffering severe combined immune deficiency syndrome was successfully transplanted with marrow from a tissue-matched sibling. After this first success, and with improvements in preparative therapy and supportive care for patients, the door was open for the development of BMT therapy.
The primary focus of this booklet is on BMT for leukemia. Most marrow transplants are done for high-risk leukemia patients, and research into BMT for leukemia has resulted in the bulk of the present knowledge and expertise. The section on Indications touches on some of the other diseases for which BMT may be appropriate. Although BMT is no longer considered an experimental procedure, intensive experimentation and research continue. Because the field is constantly evolving, no two centers have adopted exactly the same treatments or policies. When a particular method demonstrates definitive advantages, it becomes standard. As improvements occur, so do the statistics. More people achieve long-term disease-free survival, and fewer people succumb to the complications and side effects of the procedure itself.
This booklet describes BMT in language that is as nontechnical as possible. It explains the rationale behind the procedure, including biological processes and treatments. It outlines what a patient should expect from the first day of considering BMT, through preparative therapy, marrow infusion, engraftment and recovery periods, to release back into the world.
Many clinical symptoms and complications attending BMT are unpleasant and frightening. In spite of the great strides made, BMT is still a drastic procedure that may make patients very ill and can be fatal. In addition, long-term effects of BMT, especially for children, can be significant. The booklet does not try to soften these facts. It is important that a patient considering BMT, or the parents of a child for whom BMT has been offered, makes the decision whether or not to proceed armed with enough knowledge to adequately weigh the pros and cons.
At the back of the booklet are a list of patient-oriented resources with addresses and telephone numbers, a glossary of terms frequently encountered in the BMT environment, and a list of common BMT-related acronyms. Italicized words in the text are defined in the glossary at the end of the booklet.
WHAT IT IS
BONE MARROW, BLOOD, AND HEMATOPOIESIS
The bone marrow is the spongy meshwork material that fills the cavities of large bones. Red marrow is the site of blood cell production and growth. In the fetus and infants, red marrow is found in almost all the bones of the body As a child matures, the red marrow recedes and is replaced by yellow marrow, which consists of fat cells and connective tissue. In a healthy adult, red marrow is confined to heads of long bones, the pelvis and shoulder girdle, the sternum and ends of ribs, and flat bones of the skull.
Blood Functions and Composition
The blood is a transportation system that carries oxygen, food, vitamins and other vital nutrients, hormones, clotting factors, and necessary chemicals to all the cells of the body It carries away waste materials and poisons, is involved in temperature control, and is an essential element in the body's defense against infection.
Whole blood is made up of many components. Each component has a specific role in the blood functions. The three main groups of blood cells are the red cells, the clotting cells, and the white cells. They circulate through the bloodstream in a clear yellowish fluid known as plasma.
Red Blood Cells (Erythrocytes) give the blood its color. They carry an iron-rich protein known as hemoglobin, which picks up oxygen from the lungs, transports it and releases it to the organs and tissues. When people are short of red blood cells, they are anemic. Anemia causes weakness and lack of energy, dizziness, shortness of breath, headaches, and irritability Platelets (Clotting Cells or Thrombocytes) are tiny disk-shaped cells needed to clot the blood to prevent excessive bleeding after injury to blood vessels. A deficiency of platelets (thrombocytopenia) can cause spontaneous bleeding of gums or nose and bleeding into other tissues. Unexplained or excessive bruising of the skin is also characteristic of thrombocytopenia.
White Blood Cells (Leukocytes) defend the body against disease-producing bacteria, viruses, parasites, and fungi; and against foreign substances and tumor cells. There are three main types of leukocytes:
* Monocytes defend the body against bacterial infections, and also ingest aging and degenerating blood cells.
* Granulocytes combat infection by rapidly increasing in number in response to the presence of bacteria or foreign substances. They congregate around, engulf, and destroy the offending object. This process is called phagocytosis. They then die and are ingested by monocytes. When the infection is under control, their rate of production returns to normal.
* Lymphocytes patrol the bloodstream, the lymph system, and the lymphoid organs -- which include the spleen, thymus, thyroid, and lymph glands. The lymph system is a filtering and drainage system connected to the bloodstream. Lymph itself is a clear fluid. White blood cells suspended in it give it a milky appearance. Lymph circulates through a network of glands and vessels, picks up waste material, and deposits it into the bloodstream for removal from the body By complex interactions, the two main types of lymphocytes -- B cells (Bone-marrow derived lymphocytes) and T cells (Thymus-derived lymphocytes or thymocytes) -- combine forces to regulate the immune response.
* B cells are responsible for humoral (liquid) immunity Antigens are substances capable of stimulating an immune response and may be foreign chemical substances; or proteins on the surfaces of infectious agents, tumor cells, or foreign tissue cells -- cells that are not "self" such as those that may be introduced by blood transfusions or organ transplants. B cells respond to the presence of antigens by dividing and maturing into plasma cells. Plasma cells produce antibodies, which are proteins (immunoglobulins), and are released into the circulation. An antibody may be thought of as an exact mirror image of a specific antigen.
* T cells are responsible for cellular immunity. They attack and destroy virus-infected and malignant cells. There are several different kinds of T cells and they interact with each other and regulate each other. They also regulate the response of B cells. Helper T cells signal the B cells when to begin the process of maturation into plasma cells and production of antibodies; suppressor T cells signal them to stop this process. Antibodies neutralize or mark infectious agents or foreign substances so that they can be destroyed by cytotoxic T cells, natural killer T cells, granulocytes, or monocytes, in combination with other complex defense mechanisms of the body.
Blood cells grow in the same general manner as other cells of the body. Most tissues and organs of the body contain a pool of immature -- or undifferentiated -- cells known as stem cells. In response to the needs of the body -- such as the need to replace worn-out or damaged cells, stem cells divide and mature and become fully developed and functional, i.e., differentiated. When the need is satisfied, the production of new cells slows or halts.
The process of blood-cell growth and development is called hematopoiesis. In the bone marrow are found pluripotent stem cells. These cells contain the genetic information that controls the development of the characteristics of all the types of blood cell. Depending on which type of cell is needed by the body to replace old cells, or to respond to an immediate need such as an infection, the pluripotent stem cells divide and begin to differentiate into that particular cell line. The erythroid line forms red blood cells; the myeloid line forms monocytes and granulocytes; the lymphoid line gives rise to the lymphocytes, and this line splits quite early in the process into separate T-cell and B-cell lines. The various blood cells are not released from the marrow into the bloodstream until they are fully differentiated, mature, and ready to function efficiently. It takes many cell divisions for this to occur. Most B cells remain in the bone marrow and are not found circulating in great numbers in the bloodstream in the healthy state. It is believed that T cells migrate to the thymus gland where they are "educated" into becoming the specific type of T cells for which there is current demand.
During the process of embryonic development, hematopoiesis occurs first in blood cell islands, and then in the fetal spleen, liver, and bone marrow. At birth, blood cell formation is almost entirely confined to the bone marrow; however, the "memory" remains in the other organs and in certain diseases, when the body is under pressure to produce more blood cells, blood-forming tissues reappear in those organs. In addition, yellow marrow; be replaced by red under the stress of demand for more blood cells.
Peripheral Blood Stem Cells
A certain number of peripheral blood stem cells (PBSCs) circulate in the bloodstream. These appear to be the same as the pluripotent stem cells found in the bone marrow and are capable of repopulating a damaged marrow and restoring hematopoiesis. In a newborn infant, the number of PBSCs is almost the same as the number of marrow stem cells. With increasing age, the number of PBSCs decreases.
Bone Marrow Stroma
The stroma is the supporting tissue framework for the bone marrow. It is comprised of several different types of cell. Its supporting function is not only physical; it is also physiological and chemical. The health of the stroma is vital for the healthy functioning of the hematopoietic cells.
Normal Blood Cell Values
Normal total white blood cell counts are between 5,000 and 10,000 cells per cubic millimeter, and normal platelet values are between 150,000 and 300,000 cells per cubic millimeter.
The hematocrit value is obtained by spinning a blood sample in a centrifuge to pack the red cells. The packed red cell volume is measured and expressed as a percentage of the total blood sample volume. Normal hematocrit values are 37-47, percent for women, 40-54 percent for men, 35-49 percent for prepubescent children, 45-70 percent for normal-term newborn babies.
RATIONAL FOR BMT
Chemotherapeutic agents and ionizing irradiation attack actively dividing cells. For this reason, they are used to treat cancer because cancer cells divide frequently. Normal bone marrow hematopoietic cells also actively divide, and are therefore susceptible. Without a functioning bone marrow, a person has no defense against infection, and also rapidly develops anemia and platelet deficiency Therefore, with conventional chemotherapy and/or radiotherapy doses are limited by marrow toxicity; i.e., the dose must not be so high that the marrow cannot recover from it. Often the dose needed to destroy a tumor is greater than the bone marrow can tolerate.
With BMT therapy a dose potentially high enough to completely wipe out a malignancy can be administered. After the high-dose chemotherapy and/or irradiation, the patient is rescued by infusion of healthy marrow. This marrow makes its way into the bones, engrafts (attaches and begins cell division), and produces a new population of blood cells.
The treatment doses must be high enough to completely eradicate the patient's own marrow. If this is not done, surviving T cells recognize the new marrow as foreign tissue and reject it.
In addition, the new marrow requires "space" to engraft. Physical room is important, but eradication of the host marrow also affects the bone marrow stroma physiologically so that it is ready to accept a graft.
After engraftment, if the new marrow is from another person, the donor T cells may react against tumor antigens on residual cancer cells and eliminate them. This is known as the graft-versus-leukemia effect.
TYPES OF TRANSPLANTATION
The three different types of transplantation are allogeneic, syngeneic, and autologous. These words refer to the source of the infused marrow. In allogeneic transplantation, marrow is donated by an individual whose bone marrow genetically "matches" that of the patient as closely as possible; i.e., the donor and recipient are histocompatible. In syngeneic transplantation, the donor is an identical twin of the patient; by definition, identical twins share identical antigens, and the genetic match is perfect. In autologous marrow transplantation, the patient's own marrow is used.
Choice of type of transplantation is dictated by the disease in question, the availability of a donor, and the state of general health and age of the patient.
Human Leukocyte Antigens and Tissue Typing
Most cells of the body including white blood cells, have proteins on their surfaces called human leukocyte antigens (HLAs). Any antigenic difference is capable of causing T cells to cry "stranger!" but HLAs are the major antigens which stimulate immune cells into action when foreign tissues meet. If donor T cells attack antigenically different cells of the graft recipient, the result is graft-versus-host disease (GVHD), which can be life-threatening. Fortunately for BMT patients, donor T cells usually become tolerant after about six months and learn to live with the cells of the recipient. (This is in contrast to solid organ transplants; host T cells never learn tolerance, and recipients of solid grafts must take immunosuppressant drugs for the rest of their lives to prevent rejection.) HLAs were first described in 1965 and their discovery opened the door to allogeneic transplantation. The genes that program cells to produce HLAs are found at one end of the sixth chromosome. Chromosomes come in pairs. An individual inherits one half of the pair (one haplotype) from each parent. The HLA genes arc inherited as an intact group by classical Mendelian inheritance. This means that a patient's sibling has a theoretical one in four chance of carrying exactly the same HLA antigens as the patient, i.e., of being HLA identical. The following diagram makes this clear:
Molecular biologists have mapped the HLA genes and identified four separate major gene loci or sites: A, B, C, and D/DR. Tests similar to those used for determining ABO blood groups define the groups. Antisera (sera containing antibodies) have been developed to identify more than 90 antigens coded for by specific sites on the A and B loci. The C locus lies between A and B on the chromosome, and so an A- and B-HLA-identical sibling can be safely presumed to be also C-HLA identical.
The D/DR locus antigens (also known as Class 11 antigens) are defined by a similar process -- DR typing -- that uses designated typing cells. The match is confirmed by mixed leukocyte culture (MLC) tests. Donor leukocytes are mixed and cultured with recipient leukocytes that have been tagged with a radioactive label so that they can be followed and distinguished from the donor cells; at the same time, radioactive-labeled donor cells are cultured with unlabeled recipient cells. The two cultures are observed for reactions between the cell populations. If the cultures are mutually unresponsive, the D/DR loci of the two populations are identical, or at least nonreactive. At some centers reliance on MLC tests has been supplanted by sensitive molecular-biological techniques.
In search for a donor. if an HLA-identical sibling is not available, a sibling with one antigen mismatch is usually acceptable; two-antigen mismatches are occasionally used, but severe GVHD becomes virtually certain with less good matches. In the absence of a suitable sibling donor, the logical first place to look is in the extended family Relatives with one identical haplotype will exist. Occasionally a match may be found, especially if the family has lived in the same area for some time and gene groups are concentrated.
Although the odds are estimated to be 1 in 20,000, it is sometimes possible to find an unrelated individual whose HLAs match those of a patient. The first unrelated donor transplant was done in 1973 in New York. The patient was an infant with severe combined immune deficiency syndrome. The donor was found in Copenhagen, Denmark.
National Marrow Donor Program
The National Marrow Donor Program (NMDP) was established in 1986. This program administers the various collection, transplant, and donor centers around the country and requires these centers to meet stringent standards. Lists of potential donors were initially formed from family members of BMT patients who had been HLA-typed in the search for a donor for those patients. Active recruitment was at first largely from platelet donors; now it has expanded to include the general populace, with special efforts being made to recruit donors among ethnic minority groups. Numbers of volunteer donors rise daily; there are now approaching 700,000 registered potential donors at 102 centers in the United States. Efforts are ongoing to expand donor searches worldwide. The United Kingdom, Canada, and Australia already exchange lists; Western Europe, Brazil, India, Japan, and New Zealand have informal connections.
It takes an average of 120 days from the first request for an unrelated donor search until the marrow is delivered. Goals of the NMDP are to expand the pool of donors and thus improve the odds of finding matches, and to shorten the search time. If patients are referred early in the disease process, the search can begin long before the marrow is needed.
Transplantation with healthy marrow from an identical twin would seem to be ideal. Since all the genes are identical, histocompatibility is perfect and there is no danger of GVHD. However, few people have identical twins. An additional disadvantage is that without the stimulation of antigenic difference, syngeneic T cells apparently accept the tumor antigens on residual cancer cells without question. Thus, there is no graft-versus-leukemia (GVL) effect and relapse rates are higher in patients who have received syngeneic transplants than in those with allogeneic transplants.
The advantage of autologous BMT is that, as with syngeneic, the patient is in no danger of GVHD. Thus, the recovery period is easier. This means older patients may be eligible for BMT, and autologous transplants have been done on persons as old as 60. As with syngeneic transplantation, a disadvantage is that the GVL effect is missing. More importantly, the marrow and marrow stroma are often battered by previous chemotherapy. It can be difficult to harvest adequate numbers of healthy stem cells and engraftment may fail to occur or be significantly delayed.
Marrow is harvested when it is as disease free as possible and is stored frozen at -- 70 C until the patient is ready for transplantation. In the freezing process, dimethyl sulfoxide (DMSO) is added to the marrow to stop ice crystals forming inside cells and bursting them. Marrow can be stored in this state for many years.
Peripheral blood stem cells (PBSCs) are frequently collected and added to the bone marrow infusion. This increases total stem-cell count and speeds up engraftment. Peripheral stem cell harvests and transplants have been used instead of or in addition to autologous bone marrow harvests when transplanting patients with acute non-lymphocytic leukemia, acute lymphocytic leukemia, Hodgkin's disease, non-Hodgkin lymphoma and a variety of solid tumors. Extracting stem cells from the peripheral blood is called a "peripheral stem cell harvest" or PSCH.
PBSCs are collected by apheresis, a process of separating blood into its different components. The patient is connected to the apheresis machine for two to four hours. PBSCs are removed and the rest of the blood returned to the patient. Several or many, collections are made over a period of time, and the cells are frozen in DMSO, and stored at -- 70 C. Typically several sessions are required to collect sufficient stem cells from the bloodstream for transplantation.
The PSCH is painless. Patients occasional experience lightheadedness, coldness, numbness around the lips, or cramping in the hands during the harvest.
In patients whose bone marrow is too severely compromised with tumor, or too badly damaged by previous therapy, transplants have been successfully accomplished using PBSCs only. After achieving remission following induction therapy, leukemic patients have few malignant cells in the circulation, but increased numbers of PBSCs. Therefore, chemotherapy, is now often used specifically to stimulate PBSC numbers. Other factors that stimulate these numbers are exercise, corticosteroid injections, repeated apheresis, and administration of growth factors -- naturally occurring substances produced by the body to stimulate pluripotent cells to differentiate into the different cell lines. An advantage of PBSC transplantation is the patient is spared the general anesthesia necessary for marrow harvest.
Even in clinical complete remission, a few malignant cells may lurk in the bone marrow. Marrow and/or PBSC suspensions are usually purged after harvest to eliminate possible contamination. The value of purging is somewhat controversial. The additional handling of the marrow reduces the number of viable stem cells, and increases the possibility of contamination with infectious agents. Some believe cancer cells do not survive freezing and therefore purging is superfluous. If relapse occurs after trasplantation, it is presently impossible to determine whether the malignancy came from viable cancer cells in the transfused marrow, or from cancer cells in the body that escaped the BMT preparative treatment. Therefore, most centers "hedge their bets" and purge.
Methods of purging vary from center to center and change constantly as improvements are introduced. The methods take advantage of structural. biological, or antigenic differences between normal and malignant cells. The tumor cells in the marrow or PBSC suspension are either killed or removed. Specific methods of purging are discussed in more detail in the Current Research section.
Because BMT subjects the body to enormous strain, it is an option only for people who, apart from their disease, are in good general health. Transplant centers set their own age limits.
Statistics show that younger patients do better in every way than older patients; i.e., younger patients have swifter engraftment, fewer effects from toxicity of conditioning therapies, less severe complications, and less GVHD. In general, the earlier in the course of a malignant disease the transplant is done, the better. Cancer cells tend to become resistant to chemotherapy or radiation therapy after much exposure, so that it is more difficult to induce later remissions, and more difficult to eradicate the cancer even with the high-dose therapies used as preparation for BMT In addition. repeated courses of chemotherapy batter and bruise the body, including the liver, kidneys, and heart. Damage to the bone marrow stroma reduces the chances for successful engraftment of a new marrow.
Criteria for patient selection vary from center to center, and different biases affect success-rate statistics. At all centers, however, each patient is considered on an individual basis. The ratio of the risks to the benefits of undergoing BMT in the particular case is carefully calculated. Factors that must be carefully weighed in the decision whether or not to perform BMT include the expected behavior of the disease with continued conventional therapy the availability of a suitable donor, the physical condition of the patient, and the probability of success of BMT with the particular disease.
The leukemias are classified under the French-American-British (FAB) system. Thus, myeloid leukemias (AML) are numbered Ml, M2, etc., and lymphocytic leukemias are numbered L1, L2, etc. These numbered categories define which type of cell has become leukemic, and how differentiated and mature the leukemic cells are. Outlooks for success of conventional therapy as compared with BMT vary with each type of leukemia and with the stage of the disease.
Acute Myeloid Leukemia (AML; also known as Acute Non-Lymphocytic Leukemia [ANLL]): BMT is possible for AML patients under the age of 40. Some centers have accepted patients as old as 50. Younger patients have a better chance for a successful outcome than older patients. Leukemic relapse is the most common cause of failure of BMT; risk of relapse is lower if BMT is done in first remission, rather than in second remission or in resistant relapse. BMT currently offers the only chance for cure in resistant relapse. Autologous BMT for AML is done more often in Europe than in the United States, but encouraging results are reported.
Acute Lymphocytic Leukemia (ALL): In general, BMT is the treatment of choice for children with ALL if they are high-risk patients. "High risk" means chances of relapse after induced remission are great. Patients are considered high risk if they are over a certain age (about 17 at most centers); if they have a white blood cell count of more than 100,000 cells per cubic millimeter at diagnosis; or if they have certain cytogenetic abnormalities (i.e., particular abnormalities on their chromosomes). High-risk patients are transplanted after a first remission is achieved with standard chemotherapy
Most standard-risk children respond satisfactorily to conventional therapy. If they relapse, and especially if they relapse soon, BMT is considered. The transplant is sometimes done as soon as possible after relapse occurs. This has the advantage of sparing the patient the chemotherapy needed to induce a second remission.
Children less than six months of age may be high-risk patients, but transplants are technically difficult and the preparative treatments are very hard on tiny infants.
In adult ALL, BMT is considered if the patient is under 40.
Chronic Myelogenous Leukemia (CML): Allogeneic or syngeneic BMT is standard therapy and presently offers the only chance of cure. If a suitable donor is available, the chances of cure are good in the stable or chronic phase of the disease. In accelerated phase of the disease, the odds for success are less good, and in blastic phase the odds are poor. Autologous transplantation in blastic phase sometimes returns patients to stable, long-lasting chronic phase.
Other Hematologic Malignancies
BMT is indicated in certain cases of preleukemia, multiple myeloma, Hodgkin's disease, and non-hodgkin's lymphomas.
Multiple Myeloma: Allogeneic BMT is an option for patients under the age of 50 to 55; autologous BMT has been performed on 60-year-old patients. Risk of relapse is high. However, recent results are encouraging and some patients have survived several years; a few recipients of syngeneic grafts have survived free of disease for more than a decade.
Hodgkin's Disease: BMT is an option in Hodgkin's disease patients who have relapsed after several courses of conventional therapy. The tumor must, however, be responsive to chemotherapy and/or radiotherapy. Autologous transplants are usually preferred. The prognosis is significantly improved if the procedure is done early in the disease process before the malignant cells have become resistant to chemotherapy
Non-Hodgkin's Lymphomas: Allogeneic or autologous BMT may be an option for patients with intermediate to high-grade disease (Stage 11-111) if their cancer is responsive to chemotherapy. Usually the bulk of the tumor is reduced with radiotherapy or chemotherapy before BMT. Chances of BMT curing patients with Stage III-IV disease are not good.
BMT is used to treat certain solid tumors, including cancers of breast, testicle, and ovary; and pediatric solid tumors including neuroblastoma, rhabdomyosarcomas, Ewing's sarcoma, and Wilms'tumor. The tumors must be responsive to chemotherapy and/or radiotherapy.
Ideally, if BMT is to be used in the treatment of solid tumors, it should be an integral part of the scheduled therapy rather than a "last ditch" rescue operation after recurrence of the disease and/or the appearance of new metastases. Allogeneic BMT is possible if there is an HLA-identical sibling, but autologous BMT is more frequently the treatment of choice for solid tumors. When a patient is first diagnosed, it is impossible to be certain that the cancer is not already in the marrow; therefore, immediate harvest of the marrow is not advisable. In adults, the primary growth is removed surgically and the patient is given a course of chemotherapy and/or radiation; in pediatric cases, tumor bulk is commonly reduced with three to four months of chemotherapy before surgical removal. Then the marrow is biopsied and if it looks clean, it is harvested, purged in most cases, and stored frozen until the planned date for transplantation. Encouraging results with various adult and pediatric solid tumors have been obtained.
Acquired Hematologic Diseases
The bone marrow of patients with hematologic disease is defective, with no normal cells to salvage, and so transplants must be allogeneic. Nonmalignant hematologic diseases that have been treated with BMT include aplastic anemia that has not responded to treatment with immunosuppressant drugs, and other more rare conditions such as Fanconi's anemia, and Diamond-Blackfan syndrome.
Severe aplastic anemia: BMT is the treatment of choice for patients less than 20, and in certain cases up to the age of 30.Chance of failure to engraft (FTE) are high in aplastic anemia because T cells remaining in the circulation after preparative therapy for BMT are functional and capable of rejecting the donated marrow. Multiple transfusions prior to BMT tend to sensitize patients and increase the chance of FTE because each transfusion introduces foreign antigens. The chances rise for these antigens to occur in the donor marrow; host T cells recognize such antigens and rejection ensues. Therefore, BMT should if possible be performed before many transfusions have been necessary.
Preparative treatment is often less rigorous than with malignant disease; it may consist of cyclophosphamide alone, or cyclophosphamide with total lymphoid irradiation (TLI; a process in which just the major lymphoid regions of the body are irradiated). This means the toxic effects of the treatment are less; however, rates of FTE are higher. TBI conditioning reduces the rate of FTE, but increases the incidence and severity of GVHD. Therefore, for each case., the risks of TBI versus those of less rigorous conditioning must be weighed.
Genetic and Immunodeficiency Diseases
All cases are pediatric because afflicted children generally do not live into adulthood. At present, BMT is the only known curative therapy for any of these diseases, which include severe combined immunologic deficiency syndrome (SCIDS), thalassemia, sickle cell disease, mucopolysaccharidosis and other metabolic storage diseases, osteopetrosis, Wiskott-Aldrich syndrome, Lesch-Nyhan syndrome, and Niemann-Pick disease.
SCIDS: Children with SCIDS have virtually no functional immune cells capable of rejecting a graft and some transplants have been performed successfully without preparative treatment to eradicate the patient's marrow. However, most centers have more success using cyclophosphamide with busulfan or sometimes TBI.
Thalassemia: As with aplastic anemia, multiple blood transfusions prior to BMT may sensitize the patient and increase the possibility of FTE. BMT as early as possible is therefore desirable.
Mucopolysaccharidosis: This group of metabolic storage diseases tends to produce irreversible central nervous system damage and mental deterioration. BMT at an early enough stage in the disease may prevent this.
PRE-EVALUATION OF BMT CANDIDATES
Once a patient is considered a candidate for BMT, a process swings into action to ensure that the procedure is appropriate, and that the proposed center can offer optimal treatment for the case. Preevaluation procedures and consultations are usually conducted through the ambulatory BMT care clinics associated with most transplant centers.
The first step is usually tissue typing of the patient. Siblings are also typed and if no HLA-identical sibling donor exists, the search for an alternative donor may begin and/or the option of autologous transplantation is considered.
It is important that patients or, in the case of small children, parents know what to expect of the transplant procedure, and are actively involved in the final decision. This is the purpose of informed consent. The transplant team and/or the referring medical team explain and discuss with the patient and family the rationale, risks, and benefits of BMT; the expected symptoms of toxicities from the procedure; and the risks and benefits of alternative treatment. These consultations may take several hours and patients are encouraged to bring notebooks and pencils or tape recorders in order to review what has been discussed. They should then feel free to ask any question and clarify any point before finally signing the informed consent form. The following list gives examples of questions patients or families may, want to ask before signing informed consent at the proposed BMT center:
* How many procedures has the center done, and how long has it been
* What other centers perform the proposed specific type of bone
* Does the nursing staff have specialized BMT training?
* What type of isolation procedure does the center employ, and is it
possible to visit the unit and meet the staff?
* What are the visitor restrictions?
* How is it possible to exercise in the confines of isolation rooms?
* What are the statistics of cure and relapse for the specific disease?
* At the proposed center, what are the main causes of morbidity and
mortality from BMT for the specific disease, type of transplant,
and age group?
* What are the acute and chronic long-term effects of BMT?
* What are the possibilities of prior sperm banking?
* What are the costs, how much coverage can be expected from insurance,
and what other financial help is available?
* What support services are on hand for support persons or family
members, and is help available for temporary housing in the area?
If the patient is a child, a psychologist or social worker on the BMT team interviews both parent(s) and child. The procedure is explained in terms simple enough for the child to comprehend. Videotapes are sometimes shown. Often parents are put in touch with another family whose child has gone through BMT Up to and including preschool age, children are usually not part of the consent process. After that, if they wish, they should be given the opportunity of an interview without the parent present in order to express their own concerns.
A complete medical history is taken. This includes confirmation of diagnosis, and a detailed description of previous treatments and the results and/or reactions of the patient to such treatments. Any other existing medical problems are evaluated, including the patient's history of allergies and infectious diseases.
Patients usually go home for the waiting period until the appropriate time for transplantation, or transplant unit waiting lists are cleared, or a donor is found. During this time, patients are encouraged to build up strength in any way possible. They should feel like athletes training for competition, with the proviso that they consult their physicians to check that chosen activities are suitable and safe for them. Exercise and excellent nutrition not only prepare the body physically, but also often improve outlook, attitude, and hope.
Shortly before the patient is admitted into the transplant unit, a battery of tests is run. These include assessments of kidney, liver, heart, lung, and hormone functions; bone marrow is biopsied, and X-ray- and computer-assisted-tomography (CAT) scans run to check progression and stage of disease; lumbar puncture is performed to see what cells are present in the cerebrospinal fluid.
It is vital that no existing infection, however minor, is present. Blood tests check for evidence of bacteria, fungi, or parasites. Examinations of mouth and teeth, anus and rectum check for sores or abscesses. Any infection must be treated and eradicated before BMT can be done.
Viral infection is a further hazard. Thus, blood is tested for antibodies to hepatitis viruses, cytomegalovirus (CMV), herpesviruses, and human immunodeficiency virus (HIV; the virus that causes AIDS). Liver enzyme and function assays check for hidden hepatitis.
Finally, an evaluation is made of the patient to determine, as far as is possible, that no psychological factors could preclude transplantation. The patient must be considered likely to be able to cope with the rigors and isolation that are unavoidable aspects of BMT. The stability of the patient's support system is also evaluated, i.e., spouse, parents, or other persons able to provide necessary emotional and psychological support.
A peripheral intravenous central catheter (PICC) is placed to provide ready access to the blood system and to avoid the misery of repeated needle sticks or intravenous insertions. This indwelling catheter consists of a bundle (similar to a coaxial cable) of at least two, and usually, more (as many as five) flexible silicone tubes that can be left in place for months. Under local or general anesthesia, a small incision is made in the neck or upper chest. The PICC is led under the skin for several inches and then threaded via one of the major veins into the right atrium of the heart. The reason for leading it for a distance under the skin is that infection at the entrance site is rather common. If a catheter leads directly into a vein, infection may swiftly reach the bloodstream and become generalized. The indirect route provides time to control it before it does so. The PICC is used for drawing blood for tests, and to infuse medications, nutrients, fluids, blood and platelet transfusions, and the bone marrow itself; multiple tubes make it possible to perform different functions simultaneously Patients are instructed in routine care and cleansing of PICCs to avoid infection or blockage. Catheters leave minimal scarring, but if scars are a concern, it is usually. possible to position them so that the scars are not noticeable.
ABO blood types of donor and recipient are determined. If they, are incompatible, red blood cells are removed from the donor marrow before it is infused. This avoids the dangerous transfusion reaction that could occur if recipient antisera clumped and lysed (burst) donor red cells. After engraftment, the patient's blood type is that of the donor.
EVALUATION OF DONOR
Donation of bone marrow poses virtually no danger to the donor. However, the harvest is done under spinal or general anesthesia. Any anesthesia poses some risk and the donor must be aware of this, and aware of what the procedure will involve. After a detailed explanation, the donor is given time to consider before committing irrevocably to the process. Like the recipient, the donor signs an informed consent.
A medical history is taken, followed by a thorough physical examination including electrocardiogram and chest X-ray. In the laboratory, blood chemistry tests are run, and the donor's CMV hepatitis, HIV and other sexually transmitted disease antibody status is determined. The donor receives psychological counseling if necessary or appropriate.
Donors are often asked to make several donations of blood and platelets to the patient during the recovery period.
It is common practice to take a unit of blood from the donor a week or two before marrow harvest and this is usually reinfused after the procedure.
On the day of donation or the day before, the donor is admitted to the hospital. Marrow is taken from the anterior and posterior iliac crests of the pelvis. The physician uses a large syringe with a wide-bore needle and aspirates (sucks out) the marrow. Many aspirations are needed because only about 5 ml can be aspirated at a time. The number of marrow stem cells needed depends on the size of the recipient. The total amount taken varies with the size of the donor and averages 10- 1 5 ml per kilogram of body weight. This quantity is between 3 and 5 percent of the donor's total bone marrow and is restored within two or three weeks. The donor stays in the hospital usually for one or two days for observation, and for care through initial soreness in the pelvic area. Soreness is usually the only side effect, and most donors profess willingness to donate again in the future.
The harvested marrow is filtered if necessary to remove tiny bone fragments and other debris, sieved through a stainless steel screen to break up clusters of cells, and transferred immediately to a blood transfusion bag. It is infused within 24 hours of harvest, or frozen for later use.
If an autologous transplant is planned, the process is the same except that the timing is different. Marrow is harvested at least seven to 10 days before transplantation day, treated, and frozen. It may be stored for several years until needed. Because the marrow is often depleted by prior courses of chemotherapy more aspirations and a greater volume of harvested marrow may be necessary than from a donor. As noted earlier PBSCs are now commonly used to augment stem cell numbers.
The preparative regimen preparation is also called marrow ablation or conditioning. Whichever term is used, it refers to the regimen (treatment system) employed to destroy the patient's own marrow and tumor cells. Conditioning agents include total body irradiation (TBI), and high doses of a selection of chemical agents including cyclophosphamide (Cytoxan), cytarabine (ARA-C), etoposide, and busulfan (Myleran). The best regimen has not been established. Each center employs its own tried and true protocol. What is known to be important is that more than one agent must be used; i.e., either more than one chemical agent; or TBI plus at least one chemical agent. The reason for this is not clearly understood, but when only one agent is used, the probability of relapse is much increased. It is also not established whether it is better to treat with chemicals first, followed by TBI, or vice versa.
The patient is admitted to the transplant unit for preparation. The number of days until transplantation will depend on the preparative regimen. Marrow infusion day is called Day 0, and the days before are given negative numbers like a countdown. For example, if the regimen consists of cyclophosphamide plus TBI, the drug is probably given for four days, on Days -8 through -5. TBI is given over three days, on Days -4 through -2. If ARA-C is the drug of choice, six days may be required for its administration, so the countdown would start on Day -10. Day -1 is almost always a day of rest.
The total dose of TBI is usually between 1,200 and 1,350 rads (or Gy). TBI is fractionated or hyperfractionated; i.e., it is given in several small doses, rather than all at one time; e.g., 125 rads at a time, three times per day for three days. The more it is fractionated, the less the danger of developing severe lung disease. Fractionation also largely eliminates the intractable nausea and vomiting that may occur if a dose of more than 300-400 rads is given at one time.
TBI has been favored as part of the regimen in most centers, but busulfan may be as effective and is under investigation in clinical trials to check long-term results. Since it is less toxic than TBI, it increases the pool of eligible candidates, particularly among older persons and infants. At present, it must be taken orally and the dose consists of a large number of pills. Antiemetics (drug to suppress vomiting) such as Adivan are sometimes necessary. For infants, the drug is administered via a stomach tube.
Reactions to preparative therapy vary just as they do to conventional chemotherapy Most people lose their hair and their sense of taste. Most people suffer nausea and vomiting as a reaction to the chemicals; however, many drugs are now available to help control this side effect. It is vital that patients maintain good nutrition; therefore, if the appetite is lost and food by mouth becomes problematic because of nausea and vomiting, patients receive hyperalimentation, also known as total parenteral nutrition; i.e., they arc fed a carefully balanced mix of all nutrients, vitamins, and trace elements intravenously via the central catheter.
Specific drugs have specific concomitant problems. Thus, high-dose ARA-C may produce a degree of ataxia (defective muscular coordination); it also sometimes induces painful conjunctivitis or severe dermatitis. All these symptoms are temporary and reversible. High-dose cyclophosphamide is notorious for producing hemorrhagic cystitis (irritation of the bladder wall, which can lead to severe bleeding). Patients on cyclophosphamide are given extra fluids to increase urine flow; and are usually given mesna, a drug which combines with the by products and renders them relatively harmless. Sometimes a three-way catheter is inserted, which continuously irrigates the bladder, swishing away destructive byproducts of the drug in the urine before they can attach to the bladder wall; however, most centers prefer to avoid insertions of catheters because of the risk of infection. Thus, the immediate effects of conditioning chemicals may be unpleasant, but are controllable and temporary if not preventable.
The actual process of TBI is described by patients as ranging from uncomfortable to frightening. Depending on the equipment available at the center, the patient may have to assume a contorted position, and be held motionless in that position for the duration of the administration of the dose fraction in some kind of a box or frame. This can be claustrophobic, and also miserable when a patient is nauseated from preceding high-dose chemotherapy Small children are sedated or even lightly anesthetized for TBI since they cannot be expected to remain still. Usually, the only immediate physical reactions to TBI are warmth and tingling of the skin.
Tumor cells sometimes hide in the central nervous system (CNS; the brain and spinal cord) and escape the conditioning regimen In many centers, intrathecal chemotherapy is routinely administered; i.e., drugs are injected into the spinal canal from whence they travel throughout the CNS. In male patients, tumor cells often lurk in the testicles. Therefore, it is customary to irradiate the testicles separately a day or two before TBI.
If a patient has had previous extensive irradiation of the head because of an episode of CNS leukemia, it is sometimes decided to shield the head because too much irradiation of the brain can cause encephalomalacia ("softening" of the brain), which results in permanent functional deterioration of the brain. Either the dose to the head is decreased, or eliminated altogether.
The patient's defenses against infection are rapidly eroded by the conditioning regimen. From the beginning of preparation, patients are isolated to minimize risk of infection; they remain isolated until engraftment occurs and some degree of immunity returns. The form of isolation varies from center to center. Most centers use rooms in which the air is filtered with high-efficiency particulate air (HEPA) filters; these filters screen out all particulate matter, which could contain infectious agents (bacteria, fungi, parasites). Some centers employ specially designed laminar air flow (LAF) rooms. In these, the patient's bed and a tiny area of living space is surrounded by unidirectional moving curtains of air. Some centers employ regular isolation rooms, with strict reverse isolation procedures. Whichever type of room is used, nursing staff and visitors must "scrub" before entering the patient area, and wear ultra-clean clothing, masks, and gloves. Until the new marrow has successfully engrafted and some immunity is restored, physical contact with other people is kept to an absolute minimum. Usually, patients are only touched by the two or three nurses assigned to them. However, parents of small children take over many routine procedures from the nursing staff. Thus, children are usually not deprived of the psychologically vital physical contact with a parent.
Rigorous personal cleanliness is necessary The patient is instructed how to accomplish this in the confines of tiny rooms and personal bathroom areas. Special instructions are given for tooth and mouth rinsing and for cleaning around the anus and genitals.
MARROW INFUSION: DAY 0
Many patients describe the actual process of transplantation as an anticlimax. It is no more complicated than a blood transfusion. The marrow is dripped in slowly from its transfusion bag via the PICC. The process takes several hours. Reactions are very uncommon. Occasionally, some shortness of breath, hypotension, chills, fever, or mild skin rashes and hives occur; however, necessary equipment and medications are at hand to deal with such eventualities.
For patients undergoing autologous transplantation, Day 0 is describe as "twenty-four hours of garlic" The DMSO in which marrow is frozen smells strongly and persistently of garlic.
After transplantation, the wait begins for the new marrow to engraft. The signal that this has happened is the appearance of new white blood cells in the circulation. On average, this happens between Day 14 and Day 30.
For the first day or two after marrow infusion, patients usually feel reasonably well. Some are still able to eat. However, within a short time, the toxicity of conditioning takes effect. In addition, patients have no defense against infection. Getting patients through this crtical phase is a balancing act that requires skills and the cooperation of everyone involved, including the patient. Nursing care assumes paramount importance. BMT nurses arc highly specialized, and trained to pick up the most subtle hints of trouble. To do this, they monitor patients around the clock and subject them to a barrage of tests.
Status of the blood is frequently checked. Transfusions of red cells and platelets are given regularly to avoid anemia and bleeding problems; the aim is to keep platelets at more than 20,000, and the hematocrit above 30 percent. To achieve this, patients may require daily platelets; red cells are given once or twice per week or when needed. Any blood products given to BMT patients are irradiated to destroy functional lymphocytes that could trigger or exacerbate GVHD.
Kidney function is constantly monitored by checking serum levels of carbon dioxide, potassium, blood urea nitrogen (BUN), and creatinine. The job of the kidney is to cleanse the blood. Drug-induced toxicity, infections, and circulatory problems can all affect this vital operation, Damage is usually reversible, but it may be necessary to adjust doses of certain drugs in order to maintain sufficient kidney function.
The many functions of the liver include important roles in digestion and utilization of food, in blood clotting, in storage of vitamins, and in the regulation of blood volume. Altered serum levels of bilirubin and liver enzymes signal the possibility of trouble in the liver.
Periodic X-rays screen the chest for incipient lung problems.
Nutritional balance is important, particularly when patients are on hyperalimentation, and is watched. Fluid and electrolyte balance is also monitored; this is particularly delicate in children.
In order to wipe out the host marrow and cancer cells, conditioning is toxic. If marrow ablation is insufficient, FTE or relapse is virtually certain. Methods to reduce overall toxicity while increasing bone marrow and tumor toxicity have been developed (e.g., fractionation of TBI, and replacement of TBI with busulfan) and research continues in this area. Meanwhile, normal cells still do not escape unscathed. As with conventional chemotherapy, any cells that are normally in a state of active multiplication are destroyed. This is the reason for hair loss. The lining cells of the gastrointestinal system are also susceptible and patients often develop mouth sores, and pain in the esophagus and stomach, and in rectal and anal regions. This pain is sometimes severe enough to require morphine, and patients are supplied with self-regulated pain-control pumps. Nurses usually give a booster shot before they clean mouth sores; this reaming out is necessary to prevent necrosis (tissue breakdown), which could provide breeding territory for bacteria or other infectious agents. Patients are likely to develop diarrhea; the anal region is sore and raw and must also be kept scrupulously clean.
Interstitial pneumonitis (IP) is an inflammation of the tissues surrounding the air passages of the lungs. It can be caused by infection, but is often a result of conditioning toxicity, and particularly of TBI.
Exercise helps prevent secondary lung infections superimposed on IP, as do deep breathing and coughing every 2-4 hours. Exercise can be hard for patients in the first week or two post-transplant. It is also awkward in the confines of isolation rooms. Usually, however, an exercise bicycle or rowing machine is installed in the room and suitable exercise regimens are instituted and strongly encouraged.
Veno-occlusive disease (VOD) occurs in about one in five patients. This condition can occur in most organs, but it shows up predominantly in the liver. Liver cells try to clear the system of conditioning toxins and become poisoned and swollen. The swelling physically narrows blood vessels. To try and heal the damage, the body deposits fibrin within the veins, which further narrows them. The vessel walls get thicker and thicker until the veins are occluded (blocked). This results in fluid build up and patients develop edema (excess fluid in the tissues) and ascites (fluid in the peritoneal cavity). They become jaundiced because bile flow is also obstructed. If the liver is not functioning well, the brain may be affected, producing confusion, lethargy, and disorientation. Treatment involves relieving symptoms with medication, and adjusting and maintaining fluid and electrolyte balance while the liver heals itself.
Leaky-vessel syndrome also results in accumulations of fluid in tissues. Certain lymphokines, which are substances released by antigen-sensitized lymphocytes, cause blood vessel walls to lose resilience and elasticity so that they leak. Pulmonary edema in BMT patients is usually caused by leaky-vessel syndrome.
Because conditioning suppresses the bone marrow and the immune system, and breaks down the natural barriers to infection (e.g., skin, and mucous membrane linings of mouth, gut, nose, etc.), most patients develop infections. The first sign is high fever. Most centers wait until a fever develops to administer antibiotics; others start on Day 0, infusing antibiotics with the marrow. The antibiotics include broad-spectrum antibacterial agents; the antimycotic (anti-fungal) drug, amphotericin; and antiparasitic medications. This chemistry set of antibiotics must be managed with care because it adds to toxicity and may cause kidney damage. Some centers administer antiparasitic medication as a prophylactic from Day -7 until Day 0, and then stop it until engraftment has occurred. Even if patients respond to antibiotics, the drugs are usually continued until the white blood cell counts are back up to between 300 and 500.
Infections are usually opportunistic. This means they are caused by nonpathogenic organisms (organisms that normally cause no disease). These organisms may have been members of the patient's natural flora (i.e., they may have been living on the patient without symptoms before BMT), or they may be hospital organisms. Bacteria that may cause problems include Pseudomonas species and Escherichia coli. Fungal infections include Candida, and the more dangerous Aspergillus. Parasites include Pneumocystis carinii and Toxoplasma.
When fevers occur, multiple cultures are made from blood and suspect tissues to try and identify the causal organism. The lungs, gastrointestinal tract, kidney and bladder are common sites for infection. Occasional CNS infections also arise.
Sites of local infection in BMT patients are red and painful, but do not develop pus or abscesses. Patients lack the granulocytes that form pus in healthy individuals. Points of insertion of central venous catheters must be particularly watched for these atypical signs of infection. Local infections are treated with appropriate topical antibiotics.
In an effort to reduce the incidence of infection, some centers employ gut sterilization and strict total isolation. This involves treatment with oral antibiotics that sterilize the gut but are not absorbed into the bloodstream. Any food taken by mouth must be sterile. Patients are washed at least twice per day from head to toe in bactericidal solutions. The strict isolation involves enclosure in a plastic "bubble" This is hard on patients. It is also difficult for attending physicians and nurses to conduct examinations and administer treatments through plastic. The treatment is usually reserved for patients at high risk of severe GVHD. Some reports show that severity of GVHD is minimized if bacterial content of the gut is controlled. Patients at high risk for GVHD include those who have received unrelated matched, or related mismatched transplants.
Even without gut sterilization, any food the patient is able to take by mouth until the blood counts return to normal is carefully prepared to keep bacterial or fungal content to a minimum. This precludes fresh fruits, vegetables, and salads. Foods are bland to avoid any further irritation of the mouth and gut, and soft to make swallowing a possibility
If fevers do not respond to antibiotics, a virus is probably responsible. Little can be done apart from nursing the patient through the symptoms. Several viruses are normally carried in a latent (inactive) state; because of the suppressed immune system, these may prove highly pathogenic (capable of causing disease) or even lethal. Herpes simplex and Herpes zoster are often present in a latent state in healthy individuals. If patients test herpes positive before transplant, acyclovir (an antiviral drug) is given immediately (before Day 0). Passive immunity may be boosted by infusions of gamma globulin preparations containing antibodies to herpes.
Many people test positive for CMV This virus can cause serious infection in almost any site. CMV interstitial pneumonitis is still often fatal. If patients test CMV-negative before transplantation and receive CMV-negative transplants, every effort is made to ensure that any transfused blood products are also CMV-negative. Most patients are given infusions of gamma globulin containing CMV antibodies prophylactically; these are continued until after engraftment. These measures have decreased the incidence of CMV IP.
Gancyclovir is a new antiviral agent. It is effective as a prophylactic against CMV and, in combination with CMV-immune gamma globulin is the only drug that is effective against established CMV infection. It has the disadvantage of reducing white blood cell counts.
Unfortunately immunosuppressive agents used to control GVHD increase incidence of viral infections, particularly of CMV.
Failure to engraft
Infused marrows rarely fail to engraft if marrow ablation and immunosuppression have been sufficient. Occasionally engraftment failure or delay occurs in autologous transplants when stem cells are too few or too battered by previous chemotherapy Failure or delay are also possible in both autologous and allogeneic transplants if bone marrow stroma is heavily damaged. The stroma must heal from toxicities of previous therapy and conditioning before it can support new marrow. Prior blood transfusions may sensitize the recipient to antigens present on an allogeneic marrow; if sufficient functional host T cells survive conditioning, they may be capable of rejecting the graft.
After engraftment and the appearance of new white blood cells, graft-versus-host disease (GVHD) may develop. It afflicts approximately 50 percent of allogeneic transplant patients, and is fatal in about 30 percent of patients whose GVHD is clinically significant. Two forms are recognized: acute, and chronic.
Severity of GVHD depends on the degree of difference between donor and recipient HLAs, and on the ability of donor T cells to recognize non-HLAs antigens. Donor T cells respond to antigens they "perceive" as foreign and attack the host cells expressing them. The injured host cells release chemicals that signal other donor immune cells (e.g., monocytes and granulocytes) to join the battle. These summon yet more T cells to the fray, and thus the disease progresses.
Incidence and severity of GVHD, both acute and chronic, increases with increasing age of patients. Tolerance of host cells by donor T cells is mediated by donor suppressor T cells. The thymus gland "educates" immature T cells to become suppressors. In older people the gland shrinks and its function is much reduced. This may explain the delay in development of tolerance in older patients. To corroborate this theory, thymus glands of children who develop chronic GVHD are often found to be damaged.
Microorganisms share antigens with gut epithelial cells, and their presence may trigger GVHD. Similarly, intracellular latent viruses cause expression on cell surfaces of viral antigens, to which T cells react.
Acute GVHD primarily affects the skin, liver, and gastrointestinal tract. Median time of onset is 25 days post-transplant, but has been known to occur as early as Day 9. The first symptom is often burning and redness of palms of hands and soles of feet. Within about 12 hours, a fine maculopapular (measles-like) rash develops over the trunk, and ears and then all over the body In severe GVHD, blisters and ulcers develop that may progress to general desquamation, when large areas of skin die and peel off.
A rise in blood levels of bilirubin and liver enzymes signal liver involvement. Jaundice, sometimes accompanied by pain in the right upper abdomen and by enlargement of the liver are further symptoms. Without a biopsy, it is not always possible to distinguish between liver GVHD and VOD.
Patients who develop acute GVHD always have skin involvement and, usually, liver involvement. Gastrointestinal GVHD causes nausea and vomiting, pain, and loss of appetite and ability to eat. Severe watery diarrhea and sloughing of intestinal mucosa (mucous membrane lining) causes electrolytes and fluids to be out of balance. Especially if associated with infection, vomiting and diarrhea may cause bleeding that can be dangerous if patients? platelet counts are low.
A risk factor associated with development of acute GVHD is a sex-mismatched donor, especially if the donor is female and the recipient male. Donor cells may react to Y-chromosome antigens on male cells. Prognosis depends on the severity of the attack. It is favorable if symptoms are mild. In moderate to severe acute GVHD, prognosis is poor.
Statistically, the fewest relapses in leukemia are noted in patients who develop chronic GVHD.
Chronic GVHD develops any time after about three months and has been known to appear up to two years post-transplant. Overall incidence is about 27 percent (10-20 percent in patients less than 20 years old; more than 50 percent in those over 40). A previous episode of acute GVHD increases the likelihood of contracting chronic GVHD.
Chronic GVHD mimics autoimmune diseases such as scleroderma, systemic lupus erythematosus, and rheumatoid arthritis. Inflammation in chronic GVHD lasts longer and is more pronounced than in acute GVHD, and may result in fibrosis (i.e., fibrous tissue, which is hard and inelastic like scar tissue, appears in the skin and in joints).
Skin is the most frequently affected organ. Itching is an early symptom. A lichenoid rash develops. This is a scaly condition that looks like lichen. In severe cases, the basal epidermis (bottom layer of the skin) is destroyed and large areas of skin die. Fibrous tissue takes over with extensive scarring and loss of pigment. Hair follicles are destroyed, and hair falls out in patches. Sometimes, at least temporarily the ability to sweat is lost. If the disease persists for months, the skin becomes pigmented and very hard and hidebound; i.e., it does not move independent of the underlying subcutaneous tissues. Crippling contractures may occur because fibrous tissue surrounding joints stops muscles working correctly
In most patients, lichenoid growths appear in the mouth and throat. The lesions are white patches resembling oral candidiasis (thrush). Mouth and esophageal mucosa are destroyed and become very dry This makes eating and swallowing difficult. The dry mouth predisposes patients to tooth decay and gum disease.
Most patients also have reduced tear flow. Eyes become dry, sensitive to light, sore, and susceptible to infection.
Liver involvement occurs in almost all cases. As with acute GVHD, liver enzymes and bilirubin are elevated in the blood; chronic hepatitis and cholestasis (bile-flow failure) may follow.
In a few cases, the small airways of the lungs are attacked by the disease; fibrous tissue builds up and obliterates them, causing permanent respiratory impairment.
Vaginitis and vaginal dryness, or vaginal strictures (tightness) are also sometimes associated with chronic GVHD.
As with acute GVHD, prognosis depends on severity If skin and liver only are involved, prognosis is favorable. Outlook is not good when disease is widespread and involves many organs. Prognosis is also less good if the patient has previously had acute GVHD, especially if the acute form phases straight into the chronic form.
Approaches to prevention of GVHD are either pharmacological or immunological. The trick is to prevent GVHD or reduce its severity while preserving the graft-versus-leukemia (GVL) effect. Cyclosporine is a substance produced by a fungus. It revolutionized solid organ transplantation in the early 1980s because it suppresses host cytotoxic cells and thus prevents organ rejection. In BMT patients it induces donor-T-cell tolerance of host cells by inhibiting development of cytotoxic T cells, but sparing suppressor T cells.
There is evidence that prophylactic administration of cyclosporine reduces the incidence of severe GVHD and many centers now use it as a preventative, alone or with methotrexate and/or adrenal steroids.
If the marrow is depleted of T cells before it is infused, incidence of GVHD is much reduced. Depletion methods are similar to those used to purge tumor cells from marrow; they make use of structural, biological, or antigenic differences between T cells and other cells in the marrow. However, if no T cells are present, the new marrow may fail to engraft. In addition, because the GVL effect is absent, incidence of relapse rate is significantly increased. Thus, overall survival of leukemic patients given T-cell-depleted marrows is no different from those given untreated marrow because the smaller number of patients that succumb to GVHD is counterbalanced by a greater number of relapses.
Molecular biologists are now able to distinguish the specific T cells responsible for the antitumor effect; they are designated "CD4" cells, because of a specific antigenic marker. "CD8" T cells are apparently the culprits in the development of GVHD. Theoretically, elimination of CD8s from marrow while sparing CD4s should result in an ideal graft. Preliminary results are promising; selective removal of CD8 cells from marrow appears not to impair engraftment, but does reduce GVHD incidence or severity The relapse rate is not increased over that obtained with untreated marrows, which indicates that the GVL effect is satisfactorily retained.
Treatment of GVHD is difficult because the condition impairs any fragile immunity patients have regained. Drugs used to treat GVHD are also immunosuppressant. Therefore, infections are almost invariably involved; these are frequently severe and sometimes fatal.
Cyclosporine is the primary treatment if GVHD develops. A high dose is given at first and this is reduced very slowly over several weeks if the patient responds. Cyclosporine works best in combination with methotrexate, or with steroids such as methylprednisolone. Some centers start treatment with cyclosporine alone and add other drugs if response is inadequate; other centers treat immediately with two or all three agents. If the disease still does not respond, antilymphocyte antibodies are sometimes tried, or an immunotoxin (e.g., an anti-T-cell MoAb attached to a cellular poison such as the plant alkaloid, ricin).
To treat skin and joint fibrosis that occurs in chronic GVHD, PUVA (for Psoralen-Ultraviolet A) therapy is effective. This treatment was first used for psoriasis. Psoralen is a plant extract that increases the sensitivity of cells to ultraviolet light. It is taken by mouth and patients are subsequently exposed to the A wavelength of ultraviolet light in tanning booths.
GVL Effect in Autologous and Syngeneic Transplants
Because of the lack of the GVL effect, relapse rates are higher in autologous and syngeneic transplants than in allogeneic transplants. Low-dose cyclosporine administered after engraftment tricks T cells to become autocytotoxic; i.e., to attack cells carrying their own antigens. A mild GVHD-like skin rash appears that rarely requires treatment. It may be sufficient to confer the desired antileukemic effect in these patients.
Very occasionally, a condition resembling chronic GVHD occurs spontaneously in patients who have received autologous or syngeneic transplants. Possibly this occurs when T cells react to cells containing latent virus. This too may confer the GVL effect.
RECOVERY AND RELEASE FROM HOSPITAL
If no complications arise, engraftment is swift, and the first new white cells appear as early as Day 14. It is not unusual, however, to wait for a month. Engraftment may be accompanied by aching bones and joints but in general, as engraftment occurs, patients begin to feel better. Mouth and gut tissues heal and eating may be possible; if a sense of taste recovers, even the appetite may return.
The possibility of GVHD unfortunately accompanies engraftment. Mild GVHD does not significantly delay release from the hospital. Moderate to severe attacks, however, signal a longer stay.
Discharge criteria vary somewhat from center to center. First, suitable family or other support and living arrangements must be available nearby Patients are not released before absolute white cell counts reach between 500 and 1,000. Other criteria include no episode of fever after being off intravenous antibiotics for at least two days; and nausea, vomiting, and diarrhea absent or controlled with oral medication. If possible, patients should be blood and platelet transfusion independent, and should have (usually) a self-sustaining platelet count of at least 30,000, and hematocrit of more than 30 percent for adults and 25 percent for children.
What often delays departure is continuing inability to eat. Attempts are made in the hospital to train patients to eat but if all other criteria are satisfactory, some patients are discharged before they eat because eating only becomes possible for them away from the hospital environment. They are readmitted if they still cannot eat because nutritional and fluid balances must be kept in order.
The ambulatory care clinics attached to most BMT centers make it possible for patients to be discharged early Not only does early release reduce costs, but also patients do better when they are at least sleeping in a home environment. Prior to release, patients are instructed in how to continue stringent hygiene in the home setting. They are taught which symptoms warrant immediate emergency-room help, and which can wait until clinic doors open.
Close monitoring at ambulatory BMT care clinics is necessary at least until Day 100. Blood chemistry, fluid balance, and hematologic status are checked frequently Lumbar punctures to check for cells in spinal fluid, bone-marrow biopsies, and chest X-rays are also performed on a regular basis.
Ambulatory BMT care clinics are equipped with emergency facilities, and patients? records are kept there. They are carefully designed so that patients never encounter crowded areas that would pose risk of infection. For the first days postdischarge, patients are likely to spend most of each day at the clinic. By Day 100, visits have generally been reduced to once a week. Central venous catheters are usually removed three to four months post-transplant. If all has gone smoothly, at about Day 100, patients can truly go home. They are instructed in precautionary measures that must still be observed, and are discharged into the care of their primary physicians.
An understanding of why immunity is still compromised is important. Rates of immune recovery are influenced by age, conditioning regimens used, and GVHD presence and severity; thus, the following numbers are "best-case scenarios" and should not be considered absolutes.
Lymphocyte numbers return to normal in about three months, but mature T-cell functions are impaired for more than a year. T-cell depletion of marrow further delays this recovery Normal production of antibodies by B cells takes up to a year. Granulocytes appear 15 to 45 days post-transplant, but are also functionally impaired for at least four months.
Platelet numbers are usually normal after one to three months.
First red blood cells appear after two to three weeks, but patients must expect some degree of anemia for several months.
Because immune status remains fragile, patients must avoid crowds for the first six months post-transplant. This means no malls, no theaters, no football games, no churches or synagogues. For school-age children, telephone hookups can usually be arranged so that they maintain contact with school. Visitors are limited to one or two people at the same time.
In the following six months, the rules are relaxed somewhat. Return to work or school part time is possible in most cases. At the end of a complete year, full-time work or school is usually possible and a normal lifestyle can be resumed.
For up to a year, patients should avoid contact with people who have recently received live-virus vaccinations. This avoidance must continue if patients have chronic GVHD.
Even if a donor has been immunized against childhood diseases, the immunity is usually not transferred with the graft. Therefore, inoculation with tetanus toxoid, and diphtheria and inactivated polio vaccinations are advised.
PSYCHOLOGICAL AND SOCIAL ASPECTS
It is impossible to anticipate how an individual will react to the ordeal of BMT. Many patients cope wonderfully well. Asked how it was, patients acknowledge that it was tough, that they felt terrible, that they were in another world -- cut off from reality But they also say the bad parts were over quickly Some recall the boredom and claustrophobia of LAF rooms, rather than pain or fear. Many express appreciation for the extraordinary support they received from physicians and staff of the BMT centers. And all recovered patients express the joy of being given back a future.
Each patient approaches BMT in a different way but many feel that knowing what to expect before the event was very helpful. Knowledge of what was happening and why symptoms occurred imparted a sense of control to a situation in which otherwise they might have felt totally helpless and dependent.
When a cancer patient approaches transplantation, it is part of the whole picture of having the disease. Such a patient has faced the fact of having an intractable disease, the probability of early death, the trauma of relapse after therapy. Disruptions of family life, work, or school are familiar. The patient has encountered the unfortunate reactions of some friends and relatives: the withdrawal and avoidance because they "don't know what to say," and because they fear cancer as if it were leprosy and contagious.
However, the "all-or-nothing" aspect of BMT is unique and psychologically daunting. The patient is offered two choices:
1. To continue with conventional therapy and face inevitable but not necessarily imminent death from the disease.
2. To go for BMT, which offers a reasonable chance of cure, but via a painful and frightening procedure that may be fatal.
Whichever choice is made, unusual courage is required to make it. Frequently the decision must be made when the patient and family are already under stress. Time is often of the essence and the decision cannot be deferred. Most BMT teams include counselors, psychologists, psychiatrists, and social workers ready to help patients and family members or other support persons make this vital decision. If the BMT option is chosen, these team members are equipped to offer practical and psychological support through the particular stresses and problems that accompany the procedure. Patients and families should feel comfortable making use of their expertise.
If the BMT center is a long distance from home, the patient and at least the person providing emotional and physical support must relocate to be nearby To an already stressful situation, this adds the hassle of living away from home, and also the expense of maintaining two homes for at least six months.
The cost of BMT is enormous and families often incur large debts. Patients ask: "How can I ask my family to make this sacrifice -- especially when the outcome is uncertain?" The BMT team is equipped to listen to these concerns and to advise on obtaining financial help.
Once in the hospital, as well as the ordeal of a long stay and distressing physical symptoms, patients must cope with isolation. Isolation removes many of the normal means of dealing with bad situations. Patients are deprived of friends or fellow workers with whom they are accustomed to discussing problems. Even though physical contact is usually impossible, the presence and support of a loved one is more than comforting; it is invaluable. Many patients say the presence of their spouse or other support person was their lifeline.
Patients -- particularly older children and adolescents -- may be upset by body-image changes: hair loss, loss or gain of weight, the long-term presence of central catheters and the scars they leave. Reassurance about the temporary nature of most of these changes is important.
Acute anxiety exacerbates nausea and vomiting. BMT team members at many centers teach relaxation techniques. At some centers, hypnosis has been used for pain control. Biofeedback systems are being tried with some success; electronic machines detect physiological responses and convert them to signals, such as audible tones; by recognizing how they are doing by the signals, the patient learns to control the responses. Biofeedback has been used for pain, and for nausea and vomiting.
Drugs are available to help patients through periods of extreme anxiety or depression but since the patient is already taking a multitude of medications, some of which may already be changing mental states, such drugs are used with great caution and only as a last measure. Drugs are available for occasional cases of delirium, because the patient is then at risk of inflicting damage by struggling or pulling out catheters.
Family-Member or Other Support-Person Issues Issues
The stress on support persons is enormous. It is hard to watch a loved one suffer, and feel unable to help; hard to be positive but realistic; hard to hide fear and anxiety; very hard not to be able to do the natural thing, which is to touch or hold the patient to give comfort. Some are uncomfortable with role-reversal situations. A spouse must often leave children at home for the duration; the guilt and worry about this predicament can be overwhelming.
Patients' frustration with their plight sometimes results in noncompliance with instructions: refusal to do obligatory mouth rinsing, or to take showers; refusal to exercise or to eat. Support persons feel they have become "ogres" as they urge and nag in the face of patients? sometimes bitter opposition. Conditioning regimens may temporarily affect the central nervous system and irrational noncompliant patient behavior can be caused by these effects. Understanding that a physical explanation may exist for such behavior is helpful.
Support persons should not underestimate the stress and tension they are subjected to, and should not hesitate to seek counseling as soon as a need arises. Support groups are also available. Mutual sharing of problems eases tensions and anxieties. The discovery that difficulties arc not unique is always helpful.
Children tolerate BMT better than do adults and their prognosis is better. The effects of preparative regimens are generally less severe, and the incidence of GVHD is less in children than in adults. However, in spite of the hope BMT gives to an otherwise doomed child, it is very hard on parents to watch their children going through the procedure.
Very young children certainly experience pain and discomfort, but they are spared the fear and anticipation that older children and adults must deal with; they do well as long as a parent is with them and physically taking care of them. Children can bring favorite toys or "security blankets" with them into the BMT unit. These must be sterilized, but such personal belongings add immeasurably to a child's comfort.
Surprisingly young children understand the concept of death, and know they are at risk. They often try and protect their parents from this knowledge. Pediatric counselors are people to whom they can turn when they need to share thoughts, or need reassurance. Reassurance is very important, but so is honesty If children ask straight questions, they deserve straight answers.
Visits by friends and siblings in the later stages of the procedure are valuable if they are possible. However, some centers do not permit visits to the unit by children under the age of 12.
When for any reason a graft fails, especially if the patient was a sibling, a donor may feel inadequate and responsible for the failure, in addition to suffering grief. The BMT team can offer professional reassurance and an explanation of what went wrong.
Confidentiality of unrelated donors and recipients is maintained until several months post-transplant. They are permitted to write to each other using first names only, but the letters are screened.
BMT conditioning regimens often result in sterility, which, depending on the age of the patient and the type and doses of agents used, may be permanent.
Treated with high-dose chemotherapy alone, most prepubertal children -- both boys and girls -- develop normally Young women, below the age of 26 years, recover at least to have normal periods; a small number have borne children. Older women develop premature menopause. Men usually recover fertility and are capable of fathering children; however, sperm counts often remain low.
Virtually all patients treated with TBI are permanently sterile. Ovaries fail and testicles cease to produce sperm. Most girls who receive TBI conditioning before puberty never menstruate or develop secondary sexual characteristics. A few prepubertal boys develop secondary sexual characteristics but late. Prepubertal boys who have had testicular irradiation before conditioning are particularly affected.
Although sterility is probable, adults can expect to retain sexual functions. Problems that arise are often of psychological origin and can be helped.
Women with early menopause are given estrogen-replacement therapy Adolescents and children treated with TBI before puberty may need hormone replacement therapy for the development of secondary sexual characteristics.
The total cost of BMT now varies from $75,000 to more than $200,000. Information about financial risks and obligations is part of the informed consent process. Most centers require guarantees of payment before admitting patients to the program. Prior approval for the procedure must be obtained from a third party payer, preferably in writing.
A typical total hospitalization insurance benefit is $500,000. Prior conventional therapy may have used up a substantial proportion of this lifetime allowance, and expanded coverage to encompass BMT is difficult or impossible to obtain. If transplants are successful and done early in the course of disease (i.e., before patients? resources are decimated by conventional therapy), BMT may ultimately be cost effective.
BMT for some conditions is standard therapy insurance companies will usually cover standard therapy, but will not pay for a procedure that is investigational. There are no industry standards for third-party insurers to determine reimbursements. A recent survey of transplant centers found that autologous BMTs are frequently not reimbursed by insurance companies. Patients often can enlist help from the BMT team on how to approach insurance companies. Many BMT centers report that they are able to reverse insurers' initial denial of coverage when the transplant physician intervenes.
The BMT team can provide information about sources of financial aid such as charitable funds administered by churches and service organizations. Social security programs provide some aid. The Children's Organ Transplant Fund, National Children's Cancer Society, Cancer Fund of America and Children's Transplant Association also provide funds and other special services. The National Cancer Institute Cancer Information Service, the Leukemia Society of America, and the American Cancer Society are additional sources of information. Corporate Angels Network may be able to help with transportation; this New York-based group organizes use of available space on company jets to transport patients free of charge. Addresses and telephone numbers of these and other organizations are found at the back of this booklet.
"It is as if we have invented sophisticated techniques to save people from drowning, but once they have been pulled from the water, we leave them on the dock to cough and splutter on their own in the belief that we have done all we can" This was written in 1985 by a cancer survivor, Fitzhugh Mullan, M.D. It is a feeling that some people have when they have undergone BMT and returned to the "real" world. Unforeseen problems occur, and the intense and supportive care they received through the months of their therapy is no longer readily available.
People who survive cancer and/or BMT do not return to life exactly as it was before illness struck. The reasons are psychological, physical, and social. In general, patients under 30 have less trouble readapting than older patients. However, even young patients are likely to be afraid when they first go home. Being cut off from the reassurance of regular monitoring is frightening, both for patients and support persons. Patients inevitably grow dependent on BMT team members; breaking these bonds is hard. Thus, the joy of release is tempered with fear.
First, the real world seems full of germs. Most patients are very afraid of infection when they first leave the BMT center. Fear of recurrence of disease may never go away completely Statistically 30 percent of leukemia patients relapse in the first two years; toward the end of the second year, the curve flattens so that at two years, only 10 percent relapse. At 5 years, the number is down to less than 2 percent.
Almost everyone who has been through a life-threatening situation finds their outlook on life has changed. Sometimes difficulties are encountered with personal relationships because friends and family members have stayed the same and cannot psychologically "follow where the patient has gone." This means that hoped-for resources for emotional support may be stripped away.
Some physical effects of BMT are almost always present, and some of these are permanent. Chronic GVHD has usually cleared up by the end of two to three years; however, occasional patients are plagued up to five years post-transplant. Physical strength and stamina may be reduced. Some patients have reduced pulmonary function because of lung damage incurred during the BMT therapy Cataracts caused by irradiation may develop between 3 and 6 years post-transplant, although incidence of these has been reduced by fractionation of TBI. Because of such factors, people who have undergone BMT may be physically unable to return to their old jobs and must adjust to alternative employment. In common with other cancer survivors, they may well encounter active discrimination in job searches because of their medical history In addition, health and life insurance are difficult, if not impossible, to obtain.
Long-term problems encountered by children after BMT conditioning in early years are severe. They include thyroid dysfunction, and stunting of growth. Replacement therapy with thyroxin is usually effective, but growth hormone is used with only limited success. Continued small stature can be problematic in later life, both in terms of job discrimination and of acceptance by peers. Cranial irradiation and intrathecal therapy can cause neurological deficits in young brains, particularly in very young brains. Thus, some children come through BMT with various learning disabilities and need specialized education. Problems of sexuality and sterility when BMT children reach adolescence and young adulthood are extreme and require especially sensitive handling.
Organizations such as the National Coalition of Cancer Survivorship, the American Cancer Society, and the Leukemia Society of America are able to offer practical advice. A national newsletter started by a former BMT patient offers contacts with other former patients who can share concerns and experiences. The addresses and telephone numbers of these organizations are found at the back of this booklet.
BMT patients are frequently candidates for clinical trials. These are the means by which researchers learn which approaches are more effective than others. After extensive laboratory research, networks of physicians and scientists across the country test new regimens and protocols in hundreds of volunteer patients. During the trial, patients are carefully monitored and followed up later for long-term effects. Before entering the trial, patients are fully informed of its nature and rationale, and are at liberty to decline; if the nature of the trial permits, they may also withdraw at any stage. Specific trial criteria are set that bar some patients from entering. Some patients hesitate to enter trials because they do not want to be "guinea pigs" However, if the treatment proves efficacious, they are the first to benefit, as well as having provided incalculable service to later patients and to the medical community
Clinical trials and research programs are in progress on all aspects of BMT, and a comprehensive list of all that is going on would be overwhelming. Projects include tests of new preparative regimens, and manipulations of tried and true ones; techniques of prevention and control of GVHD; prevention and control of infection; improved drugs to prevent nausea and vomiting; methods for early detection and treatment of VOD.
On an experimental basis, BMT is being used as therapy for several tumors not yet on the "standard" list. For example, attempts have been made to treat lung and colon cancers, and pediatric glioma and retinoblastoma. So far, results have not been very encouraging with these tumors, but efforts continue.
Purging Mechanism in Autologous Transplantation
Since the possibility of tumor cells remaining in autologous marrows is of great concern, much research has been performed on different purging mechanisms. Methods include the following:
In pharmacological purging, the marrow is treated with the same cytotoxic agents used in chemotherapy
Biophysical purging uses substances such as cytotoxic radioisotopes that selectively destroy certain tumor cells; or fluorescent dyes, which, on exposure to light, become toxic to certain tumor cells (such as leukemic and neuroblastoma cells) but not to normal cells.
Elutriation is a physical approach to purging. A centrifuge spins the marrow suspension gently, and the cells are separated on the basis of size and sedimentation characteristics into different fractions. The fraction containing cancer cells is discarded.
Immunological purging takes advantage of monoclonal antibodies (MoAbs). MoAbs have been developed for all the different hematopoietic progenitor cells, and for some tumor cells, including those of neuroblastoma, breast cancer, multiple myeloma, melanoma, and some lung cancers. MoAbs home in on their target cells and attach. Antibodies themselves do not kill cells, but they set them up for the killing. Complement is a naturally occurring enzyme system, and if added to the marrow suspension, it lyses cells that are sensitized or "marked" with antibodies. Alternatively, immunotoxins (MoAbs conjugated with powerful cytotoxins such as the plant alkaloid ricin) are employed to selectively kill tumor cells.
MoAbs are also used in techniques that remove tumor cells from the marrow suspension rather than killing them in situ. These include coating magnetic microspheres (microscopic iron balls) with Moabs. The target cells attach to the microspheres and when the suspension is passed over a magnetic field they are drawn out. Immunorosetting is a method in which sheep erythrocytes, which are coated with tumor-specific antibodies, are added to the marrow suspension. The tumor cells congregate around the erythrocytes and the resulting clumps are easy to remove.
All the above purging methods are negative stem-cell selection techniques. Positive stem-cell selection involves return to the host of only cells known to be normal. One method is to grow healthy stem cells in a liquid culture in the laboratory until enough are available for successful transplantation. Another approach is to use magnetic-microsphere/ MoAb conjugates directed against normal pluripotent stem cells; passage over a magnetic field draws out the healthy cells, and these are separated from the microspheres before infusion.
T-cell depletion of allogeneic marrows to prevent severe GVHD uses some of the same technologies as purging. Soybean agglutinin is a pharmacological agent that selectively destroys T cells. Elutriation is sometimes used for T-cell depletion; after centrifugation, the small-cell fraction containing T cells is discarded. MoAbs specific for T cells are employed and complement added to the marrow suspension lyses all sensitized cells.
MoAbs have also been developed against different types of T cell. These are the tools that make it possible to separate CD8 cells (which probably cause GVHD) from marrow suspensions, while leaving intact the CD4 cells (which confer the GVL effect). Complement is used to lyse sensitized CD8 cells. Alternatively, CD8 cells in the suspension attach to magnetic microspheres coated with CD8 MoAb; passage over a magnetic field draws them out.
The hope and aim of all BMT-related research is to make the procedure safer and more reliable. As natural corollaries, more patients will become eligible, and the range of diseases for which BMT can be offered as therapy will widen. Much progress has been made in a very short time; much more is promised.
Dowie, M. We Have a Donor, St. Martin's Press, New York, 1988. An accessible book written about solid organ transplantation which contains some material of interest to bone marrow transplant patients, including some history, ethics, and politics of transplantation.
Geier MA. Cancer: What's It Doing in my Life? Hope Publishing House, Pasadena, CA, 1985. A very well-written book by a woman with lymphoma: it deals with how she copes with her disease, and how she deals with other people handling her disease. Includes appendices with practical advice on how to organize one's affairs when cancer strikes, and sources for help.
Leukemia Society of America. Coping with Survival: Support for People Living with adult leukemia and lymphoma A useful and practical booklet on psychological aspects of cancer.
Thompson FM. Going for the Cure. St. Martin's Press, New York, 1989. A young orthopedic surgeon was the first patient at Dana-Farber Cancer Institute to have an autologous bone marrow transplant for multiple myeloma. She tells her own story in this gripping, moving, and very readable book.
Winningham ML, et al. Rhythmic Walking: Exercise for People Living with Cancer. James Cancer Hospital, Columbus, OH. A booklet written by an exercise physiologist and two oncology nurses at the Arthur G. James Cancer Hospital and Research Institute, The Ohio State University; a program to help cancer patients develop a safe, regular exercise program.
Bortin MM. A compendium of reported human bone marrow transplantations. Transplantation 9:571-583,1970.
Buchsel PC, Kelleher J. Bone marrow transplantation. In: Skelley L, Fry ST, eds. Nursing Clinics of North America: Ethics Part II: Applications in Nursing Practice 24(4):907-938,1989.
Champlin R, editor. Bone Marrow Transplantation, Kluwer Academic Publishers, Boston MA, 322 pp, 1990.
Clift RA, Hansen MD. The role of HLA. In: Blume KG, Petz MD, eds. Clinical Bone Marrow Transplantation, Churchill Livingston, New York, pp 313-327,1983.
Gallagher MT Experimental basis. In: Blume KG, Petz MD, eds. Clinical Bone Marrow Transplantation, Churchill Livingston, New York, pp 33-64,1983.
Gross S. Perspectives in marrow purging. In: Gross S, Gee AP, Worthington-White DA, eds. Bone Marrow Purging and Processing: Progress in Clinical and Biological Research 33, Alan R. Liss Inc, New York, pp xxix-xxxiv, 1990.
Juttner CA et al. Peripheral blood stem cell selection, collection and autotransplantation. In: Gross S, Gee AP, Worthington-White DA, eds. Bone Marrow Purging and Processing: Progress in Clinical and Biological Research 33, Alan R. Liss Inc, New York, pp 447-460,1990.
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|Publication:||Pamphlet by: Leukemia Society of America|
|Date:||Jan 1, 1992|
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