BONE MARROW HARVESTBone marrow transplantation (BMT) is a relatively new medical procedure being used to treat diseases once thought incurable. Since its first successful use in 1968, BMTs have been used to treat patients diagnosed with leukemia, aplastic anemia, lymphomas such as Hodgkin's disease, multiple myeloma, immune deficiency disorders and some solid tumors such as breast and ovarian cancer.
In 1991, more than 7,500 people underwent BMTs nationwide. Although BMTs now save thousands of lives each year, 70 percent of those needing a BMT using donor marrow are unable to have one because a suitable bone marrow donor cannot be found.
Bone marrow is a spongy tissue found inside bones. The bone marrow in the breast bone, skull, hips, ribs and spine contains stem cells that produce the body's blood cells. These blood cells include white blood cells (leukocytes), which fight infection; red blood cells (erythrocytes), which carry oxygen to and remove waste products from organs and tissues; and platelets, which enable the blood to dot
In patients with leukemia, aplastic anemia, and some immune deficiency diseases, the stem cells in the bone marrow malfunction, producing an excessive number of defective or immature blood cells (in the case of leukemia) or low blood cell counts (in the case of aplastic anemia). The immature or defective blood cells interfere with the production of normal blood cells, accumulate in the bloodstream and may invade other tissues.
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Large doses of chemotherapy and/or radiation are required to destroy the abnormal stem cells and abnormal blood cells. These therapies, however, not only kill the abnormal cells but can destroy normal cells found in the bone marrow as well. Similarly, aggressive chemotherapy used to treat some lymphomas and other cancers can destroy healthy bone marrow. A bone marrow transplant enables physicians to treat these diseases with aggressive chemotherapy and/or radiation by allowing replacement of the diseased or damaged bone marrow after the chemotherapy/radiation treatment.
While bone marrow transplants do not provide 100 percent assurance that the disease will not recur, a transplant can increase the likelihood of a cure or at least prolong the period of disease-free survival for many patients.
In a bone marrow transplant, the patient's diseased bone marrow is destroyed and healthy marrow is infused into the patient's blood-stream. In a successful transplant, the new bone marrow migrates to the cavities of the large bones, engrafts and begins producing normal blood cells.
If bone marrow from a donor is used, the transplant is called an "allogeneic" BMT, or "syngeneic" BMT if the donor is an identical twin. In an allogeneic BMT, the new bone marrow infused into the patient must match the genetic makeup of the patient's own marrow as perfectly as possible. Special blood tests are conducted to determine whether or not the donor's bone marrow matches the patient's. If the donor's bone marrow is not a good genetic match, it will perceive the patient's body as foreign material to be attacked and destroyed. This condition is known as graft-versus-host disease (GVHD) and can be life-threatening. Alternatively, the patient's immune system may destroy the new bone marrow. This is called graft rejection.
There is a 35 percent chance that a patient will have a sibling whose bone marrow is a perfect match. If the patient has no matched sibling, a donor may be located in one of the international bone marrow donor registries, or a mis-matched or autologous transplant may be considered.
In some cases, patients may be their own bone marrow donors. This is called an autologous BMT and is possible if the disease afflicting the bone marrow is in remission or if the condition being treated does not involve the bone marrow (e.g. breast cancer, ovarian cancer, Hodgkin's disease, non-Hodgkin's lymphoma, and brain tumors). The bone marrow is extracted from the patient prior to transplant and may be "purged" to remove lingering malignant cells (if the disease has afflicted the bone marrow).
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A successful transplant requires the patient be healthy enough to undergo the rigors of the transplant procedure. Age, general physical condition, the patient's diagnosis and the stage of the disease are all considered by the physician when determining whether a person should undergo a transplant.
Prior to a bone marrow transplant, a battery of tests is carried out to ensure the patient is physically capable of undergoing a transplant. Tests of the patient's heart, lung, kidney and other vital organ functions are also used to develop a patient "baseline" against which post-transplant tests can be compared to determine if any body functions have been impaired. The pre-transplant tests are usually done on an outpatient basis.
A successful bone marrow transplant requires an expert medical team - doctors, nurses, and other support staff - who are experienced in bone marrow transplants, can promptly recognize problems and emerging side effects, and know how to react swiftly and properly if problems do arise. A good bone marrow transplant program will also recognize the importance of providing patients and their families with emotional and psychological support before, during and after the transplant, and will make personal and other support systems readily available to families for this purpose.
BONE MARROW HARVESTRegardless of whether the patient or a donor provides the bone marrow used in the transplant, the procedure used to collect the marrow - the bone marrow harvest - is the same. The bone marrow harvest takes place in a hospital operating room, usually under general anesthesia. It involves little risk and minimal discomfort.
While the patient is under anesthesia, a needle is inserted into the cavity of the rear hip bone or "iliac crest" where a large quantity of bone marrow is located. The bone marrow a thick, red liquid - is extracted with a needle and syringe. Several skin punctures on each hip and multiple bone punctures are usually required to extract the requisite amount of bone marrow. There are no surgical incisions or stitches involved - only skin punctures where the needle was inserted.
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The amount of bone marrow harvested depends on the size of the patient and the concentration of bone marrow cells in the donor's blood. Usually one to two quarts of marrow and blood are harvested. While this may sound like a lot, it really only represents about 2% of a person's bone marrow, which the body replaces in four weeks.
When the anesthesia wears off, the donor may feel some discomfort at the harvest site. The pain will be similar to that associated with a hard fall on the ice and can usually be controlled with Tylenol. Donors who are not also the BMT patient are usually discharged after an overnight stay and can fully resume normal activities in a few days.
For autologous transplants, the harvested bone marrow will be frozen (cryopreserved) and stored at a temperature between -80 and -196 degrees centigrade until the day of transplant. It may first be "purged" to remove residual cancerous cells that can't be easily identified under the microscope (see page 30).
In allogeneic BMTs, the bone marrow may be treated to remove "T-cells" (T cell depletion) to reduce the risk of graft-versus-host disease (see page 94). It will then be transferred directly to the patient's room for infusion.
A patient admitted to the bone marrow transplant unit will first undergo several days of chemotherapy and/or radiation which destroys bone marrow and cancerous cells and makes room for the new bone marrow. This is called the conditioning or preparative regimen. The exact regimen of chemotherapy and/or radiation varies according to the disease being treated and the "protocol" or preferred treatment plan of the facility where the BMT is being performed.
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Prior to conditioning, a small flexible tube called a catheter (sometimes called a "Hickman" or central venous line) will be inserted into a large vein in the patient's chest just above the heart. This tube enables the medical staff to administer drugs and blood products to the patient painlessly, and to withdraw the hundreds of blood samples required during the course of treatment without inserting needles into the patient's arms or hands.
The dosage of chemotherapy and/or radiation given to patients during conditioning is much stronger than dosages administered to patients with the same disease who are not undergoing a BMT. Patients may become weak, irritable and nauseous. Most BMT centers administer anti-nausea medications to minimize discomfort.
THE TRANSPLANTA day or two following the chemotherapy and/or radiation treatment, the transplant will occur. The bone marrow is infused into the patient intravenously in much the same way that any blood product is given. The transplant is not a surgical procedure. It takes place in the patient's room, not an operating room.
Patients are checked frequently for signs of fever, chills, hives and chest pains while the bone marrow is being infused. When the transplant is completed, the days and weeks of waiting begin.
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The two to four weeks immediately following transplant are the most critical. The high-dose chemotherapy and/or radiation given to the patient during conditioning will have destroyed the patient's bone marrow, crippling the body's "immune" or defense system. As the patient waits for the transplanted bone marrow to migrate to the cavities of the large bones, set up housekeeping or "engraft," and begin producing normal blood cells, he or she will be very susceptible to infection and excessive bleeding. Multiple antibiotics and blood transfusions will be administered to the patient to help prevent and fight infection. Transfusions of platelets will be given to prevent bleeding. Allogeneic patients will receive additional medications to prevent and control graft-versus-host disease.
Extraordinary precautions will be taken to minimize the patient's exposure to viruses and bacteria. Visitors and hospital personnel will wash their hands with antiseptic soap and, in some cases, wear protective gowns, gloves and/or masks while in the patient's room. Fresh fruits, vegetables, plants and cut flowers will be prohibited in the patient's room since they often carry fungi and bacteria that pose a risk of infection. When leaving the room, the patient may wear a mask, gown and gloves as a barrier against bacteria and virus, and as a reminder to others that he or she is susceptible to infection. Blood samples will be taken daily to determine whether or not engraftment has occurred and to monitor organ function. When the transplanted bone marrow finally engrafts and begins producing normal blood cells, the patient will gradually be taken off the antibiotics, and blood and platelet transfusions will generally no longer be required. once the bone marrow is producing a sufficient number of healthy red blood cells, white blood cells and platelets, the patient will be discharged from the hospital, provided no other complications have developed. BMT patients typically spend four to eight weeks in the hospital.
A bone marrow transplant is a physically, emotionally, and psychologically taxing procedure for both the patient and family. A patient needs and should seek as much help as possible to cope with the experience. "Toughing it out" on your own is not the smartest way to cope with the transplant experience.
The bone marrow transplant is a debilitating experience. Imagine the symptoms of a severe case of the flu - nausea, vomiting, fever, diarrhea, extreme weakness. Now imagine what it's like to cope with the symptoms not just for several days, but for several weeks. That approximates what a BMT patient experiences during hospitalization.
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During this period the patient will feel very sick and weak. Walking, sitting up in bed for long periods of time, reading books, talking on the phone, visiting with friends or even watching TV may require more energy than the patient has to spare.
Complications can develop after a bone marrow transplant such as infection, bleeding, graft-versus-host disease, or liver disease, which can create additional discomfort. The pain, however, is usually controllable by medication. In addition, mouth sores can develop that make eating and swallowing uncomfortable. Temporary mental confusion sometimes occurs and can be quite frightening for the patient who may not realize it's only temporary. The medical staff will help the patient deal with these problems.
In addition to the physical discomfort associated with the transplant experiance there is emotional and psychological discomfort as well. Some patients find the emotional and psychological stress more problematic than the physical discomfort.
The psychological and emotional stress stems from several factors. First, patients undergoing transplants are already traumatized by the news that they have a life-threatening disease. While the transplant offers hope for their recovery, the prospect of undergoing a long, arduous medical procedure is still not pleasant and there's no guarantee of success.
Second, patients undergoing a transplant can feel quite isolated. The special precautions taken to guard against infection while the immune system is impaired can leave a patient feeling detached from the rest of the world and cut off from normal human contact. The patient is housed in a private room, sometimes with special air-filtering equipment to purify the air. The number of visitors is restricted and visitors are asked to wear gloves, masks and/or other protective clothing to inhibit the spread of bacteria and virus while visiting the patient. When the patient leaves the room, he or she may be required to wear a protective mask, gown and/or gloves as a barrier against infection. This feeling of isolation comes at the very time in a patient's life when familiar surroundings and close physical contact with family and friends are most needed.
'Helplessness" is also a common feeling among bone marrow transplant patients, which can breed further feelings of anger or resentment. For many, it's unnerveing to be totally dependent on strangers for survival, no matter how competent they may be. The fact that most patients are unfamiliar with the medical jargon used to describe the transplant procedure compounds the feeling of helplessness. Some also find it embarrassing to be dependent on strangers for help with basic daily functions such as using the washroom.
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The long weeks of waiting for the transplanted marrow to engraft, for blood counts to return to safe levels, and for side effects to disappear increase the emotional trauma. Recovery can be like a roller coaster ride: one day a patient may feel much better, only to awake the next day feeling as sick as ever.
After being discharged from the hospital, a patient continues recovery at home (or at lodging near the transplant center if the patient is from out of town) for two to four months. Patients usually cannot return to full-time work for up to six months after the transplant.
Though patients will be well enough to leave the hospital, their recovery will be far from over. For the first several weeks the patient may be too weak to do much more than sleep, sit up, and walk a bit around the house. Frequent visits to the hospital or associated clinic will be required to monitor the patient's progress, and to administer any medications and/or blood products needed. It can take six months or more from the day of transplant before a patient is ready to fully resume normal activities.
During this period, the patient's white blood cell counts are often too low to provide normal protection against the viruses and bacteria encountered in everyday life. Contact with the general public is therefore restricted. Crowded movie theaters, grocery stores, department stores, etc. are places recovering BMT patients avoid during their recuperation. Often patients will wear protective masks when venturing outside the home.
A patient will return to the hospital or clinic as an outpatient several times a week for monitoring, blood transfusions, and administration of other drugs as needed. Eventually, the patient becomes strong enough to resume a normal routine and to look forward to a productive, healthy life.
It can take as long as a year for the new bone marrow to function normally. Patients are closely monitored during this time to identify any infections or complications that may develop.
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Life after transplant can be both exhilarating and worrisome. On the one hand, it's exciting to be alive after being so close to death. Most patients find their quality of life improved after transplant.
Nonetheless, there is always the worry that relapse will occur. Furthermore, innocent statements or events can sometimes conjure up unpleasant memories of the transplant experience long after the patient has recovered. It can take a long time for the patient to come to grips with these difficulties.
Yes! For most patients contemplating a bone marrow transplant, the alternative is near-certain death. Despite the fact that the transplant can be a trying experience, most find that the pleasure that comes from being alive and healthy after the transplant is well worth the effort.
Blood is composed of many different kinds of cells, each with a specific function. Most blood cells are formed in the bone marrow and released into the bloodstream at various stages of maturity.
Red blood cells (erythrocytes) make up 45 percent of blood volume. Their primary function is to pick up oxygen in the lungs and transport it to tissues throughout the body. At the tissue site, red blood cells exchange oxygen for carbon dioxide and carry it back to the lungs to be exhaled.
White blood cells leukocytes) are only 1/1,000 as numerous as red blood cells in the bloodstream. There are five main types: neutrophils (also called granulocytes), eosinophils, basophils, monocytes, and Iymphocytes. Each plays a distinct and important role in helping the immune system fight infection.
Neutrophils contain granules of bacteria-killing enzymes in the cytoplasm - the substance surrounding the cell. Eosinophils attack protozoa that cause infection. Basophils are the least common type of white blood cell and their function is not completely understood. They play an important role in regulating allergic reactions such as asthma, hives, hay fever and reactions to drugs.
Monocytes are the largest white blood cells. They engulf and destroy invading bacteria and fungi and clean up debris once foreign organisms have been destroyed by other white blood cells. When monocytes leave the bloodstream and enter tissues or organs, they can evolve into larger cells called macrophages that have an increased capacity to destroy foreign organisms invading the body.
Lymphocytes are the smallest white blood cells and are the backbone of the immune system. Lymphocytes fight viral infections and assist in the destruction of other parasites, bacteria and fungi. One group of lymphocytes called T-cells regulates the immune system's response to invading organisms and is the body's main defense against viruses and protozoa. A second group called B-cells manufactures a kind of protein called an antibody or immunoglobulin. Antibodies attach to the surface of foreign organisms or the cells they have invaded and summon a group of proteins in the Woodstream called the complement system to surround the infected organism or cell and dissolve a hole in it.
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Thrombocytes (platelets) are the smallest cell elements in the bloodstream. Platelets are needed to control bleeding.
BLOOD CELL PRODUCTIONNew blood cells are constantly produced by the body. In healthy adults, an estimated 100 billion red cells and 400 million white cells are produced each hour. The life span of mature blood cells is short - only a few days or months.
Ninety-five percent of the body's blood cell production is believed to take place in the bone marrow. The remainder occurs in the spleen. While most blood cells produced in the bone marrow are discharged directly into the bloodstream, T-cells first travel to the thymus gland (thus, the name T cells) where they receive further education or programming before being released into the bloodstream.
All mature blood cells are believed to originate from very primitive cells in the bone marrow called "pluripotent stem cells." This cell is capable of producing other cells identical to itself. Pluripotent stem cells also produce other stem cells the lymphoid stem cell and the myeloid stem cell - from which the various types of mature blood cells evolve.
Like pluripotent stem cells, the myeloid and lymphoid stem cells can self-renew as well as produce colonies of offspring that eventually evolve into mature cells. However, their ability to self-renew is believed to be more limited than that of pluripotent stem cells and they are capable of producing fewer different types of offspring. Lymphoid stem cells only produce cells that evolve into lymphocytes (T-cells or B-cells). The offspring of myeloid stem cells can only evolve into either red blood cells, platelets, or white blood cells other than lymphocytes.
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The myeloid and Iymphoid stem cells produce colonies of "committed progenitor" cells. Unlike stem cells, committed progenitors are only capable of developing into one specific type of mature cell. Cells passing through the final stages of maturation are called precursor cells.
In healthy human beings, the number of each type of stem cell and their offspring is contained within very narrow limits. Certain proteins, such as interleukins and colony-stimulating factors, play a key role in determining whether a stem cell will replicate itself, produce offspring that evolve into mature Wood cells, do both or do neither at any given time. These proteins also regulate the maturation of precursor cells. If this regulatory mechanism breaks down, too many or too few stem cells will be present in the bone marrow and/or certain progenitor or precursor cells will proliferate and fail to properly mature.
In patients with leukemia, for example, one or more types of blood cells (usually white blood cells) fail to properly mature. They stall at one stage of development and self-replicate uncontrollably.
Bone marrow transplants enable physicians to destroy diseased bone marrow with high-dose chemotherapy and/or radiation, and replace it with healthy marrow that will produce normal blood cells. It also enables patients with other malignancies such as breast and ovarian cancer to receive higher than normal doses of chemotherapy to treat their disease. Although the higher doses of chemotherapy destroy bone marrow as well as the tumor, healthy bone marrow can be reinfused after treatment, enabling normal production of blood cells to resume.
When most people think about bone marrow transplants they envision two parties: the patient who is suffering from a bone marrow disorder such as leukemia, and a bone marrow donor whose healthy bone marrow is used to replace the patient's diseased marrow during transplant. This two-party transplant is called an allogeneic BMT, or syngeneic BMT if the donor is an identical twin.
However another type of BMT, called an autologous (pronounced au-tol'-o-gous) BMT is actually much more common. In an autologous BMT the patient is both the donor and the recipient of the bone marrow. Some 5,000 autologous BMTs are performed each year, outpacing allogeneic and syngeneic BMTs two to one.
Some complications associated with allogeneic BMTs such as graft-versus-host disease are avoided with autologous BMTs. The risk of infection is also somewhat less in autologous BMTs because the large doses of immunosuppressive medications given to patients in allogeneic BMTs to prevent GVHD are not needed.
Autologous BMTs (ABMTs) have expanded treatment options for thousands of patients diagnosed with life-threatening diseases such as Hodgkin's disease and non-Hodgkin's lymphoma, breast cancer, ovarian cancer, testicular cancer and pediatric solid tumors such as neuroblastoma. The autologous BMT has also given new hope to hundreds of patients suffering from leukemia who were previously denied a BMT because a suitable bone marrow donor could not be found.
Not all patients diagnosed with these diseases are candidates for an autologous BMT. The type of disease, the stage to which it has progressed, the responsiveness of the disease to prior treatment, and the patient's age and general physical condition are all factors that will determine whether a patient is considered a suitable candidate for an autologous BMT.
With the exception of leukemia, diseases treated by autologous BMTs are usually not disorders that start in or involve the bone marrow. Rather, they're "malignant" or cancerous tumors located elsewhere in the body that are responsive to treatment with high-dose chemotherapy and/or radiation. The high doses of chemotherapy and/or radiation, however, also destroy the patient's bone marrow. Without bone marrow, the body is unable to manufacture blood cells needed to defend against infection, carry oxygen and prevent bleeding. An autologous BMT enables physicians to "rescue" the patient from the effects of high-dose chemotherapy and/or radiation treatment by replacing the destroyed bone marrow.
For each disease discussed below, long-term survival rates following treatment with an autologous BMT are cited. Keep in mind that these numbers are only ballpark estimates which cover a wide range of circumstances. The projected survival rate of an individual patient will depend on his or her age and general physical condition, the specific characteristics of the disease, the stage to which the disease has progressed, and the responsiveness of the disease to prior treatment. The patient's own physician can provide the best assessment of a patient's chances for long-term survival following an autologous BMT.
Autologous BMTs are most frequently used to treat patients diag nosed with Hodgkin's disease and non-Hodgkin's lymphoma. In Hodgkin's disease, an abnormal cell called the Reed-Sternberg cell may be present in one or more Iymph nodes. Without treatment, this defective cell infiltrates neighboring organs and tissues, disrupting normal functions.
Similarly, in non-Hodgkin's lymphomas, defective Iymphocytes (a type of white blood cell) are produced in the lymph nodes, bone marrow, spleen and/or gastrointestinal tract. Left unchecked, they invade other tissues and organs, interfering with their normal functions.
Patients with Hodgkin's disease and non-Hodgkin's lymphoma can often be cured by radiation and/or chemotherapy. However, if patients have not achieved a remission with radiation /chemotherapy, have relapsed after chemotherapy, or have experienced progression of the disease while undergoing chemotherapy, an autologous BMT may be the best option to save their life. Patients with non-Hodgkin's lymphoma whose tumors are not responsive to chemotherapy (ie. the size of the tumor has not shrunk after chemotherapy) are less likely to achieve a long-term cure with an autologous BMT than those whose tumors are responsive to chemotherapy. This is not true for patients with Hodgkin's disease.
Patients with advanced Hodgkin's or non-Hodgkin's lymphoma who undergo an autologous BMT have a 25 to 50 percent chance of long term survival. Without a BMT, their chances for long term survival are 5 to 10 percent.
Treatment of leukemia with an autologous BMT is becoming more common. Patients with acute lymphocytic leukemia (ALL) or acute myelogenous leukemia (AML) (also called acute non-lymphocytic leukemia or ANLL) may be candidates for an autologous BMT if their disease is in complete remission. Since a complete remission is rarely achieved in patients with chronic myelogenous leukemia (CML), an autologous BMT is usually not a treatment option for these patients (although some very interesting studies are now underway using ABMTs to treat this disease).
Leukemia is a disease of the bone marrow, the organ that produces the body's blood cells. In patients with leukemia, a large number of abnormal white blood cells are produced in the bone marrow and interfere with the production of normal blood cells. Without normal blood cells, the body's ability to fight infection, carry oxygen to tissues, and prevent bleeding is impaired. Patients with acute leukemia will die within a matter of weeks or months without treatment.
Patients with acute myelogenous leukemia (AML or ANLL) who've achieved a first complete remission with standard chemotherapy may be able to increase their chances for long-term survival significantly with a BMT. Without a BMT, their expected long-term survival rate is 20 to 30 percent.
Researchers are currently studying whether autologous BMTs are more effective than standard chemotherapy in treating patients with AML in first remission. Preliminary results suggest that survival rates do improve with an autologous BMT, but further study is underway to determine whether these improved survival rates are the result of the autologous BMT or other factors such as the type of patients chosen to participate in the study or the sub-type of AML affecting the patient.
BMTs are also performed on patients with acute lymphocytic leukemia. ALL typically strikes children. Because the cure rate with standard chemotherapy is quite high, only a few studies have been conducted to date on the use of BMTs in the treatment of ALL. While the studies have found that both autologous and allogeneic BMTs are an effective treatment option for ALL patients, some experts believe that too little data are currently available to reliably project long-term survival rates.
People are often surprised that an autologous BMT is a treatment option for patients with leukemia. Since it's known that malignant cells may remain in the bone marrow of patients with leukemia even after a complete remission has been achieved, they question why it makes sense to harvest imperfect marrow and re-infuse it back into the patient via an autologous BMT.
Researchers are not sure of the answer, but some theorize that the number of malignant cells re-introduced into the patient is so small that the body's normal defenses can destroy them before they proliferate. Many centers purge the harvested bone marrow to reduce the number of cancerous cells that remain in the sample. For more information on purging see page 30.
Breast cancer is the third most common cancer in women, resulting in thousands of deaths annually. In 1990, 150,000 new cases were diagnosed and 44,000 deaths from breast cancer were reported.
The initial treatment for breast cancer is surgery with or without radiation. In cases where the risk of relapse is high, chemotherapy has sometimes been administered after surgery. However, once breast cancer has spread or become metastatic (Stage IV) it is no longer curable with conventional treatment.
Over the past five years, researchers have been studying the possibility of treating advanced stage breast cancer with a combination of highdose chemotherapy and an autologous BMT. Since an autologous BMT enables a physician to replace the patient's bone marrow after the chemotherapy treatment, higher doses of chemotherapy can be used than previously possible.
The results of early clinical studies in which high-dose chemotherapy and an autologous BMT were administered to Stage IV breast cancer patients who had previously undergone intensive chemotherapy treatment were encouraging. A remission was achieved in 27 percent of the patients. That remission, however, was of short duration.
Subsequent studies conducted with patients who had just become Stage IV, had not previously undergone intensive chemotherapy treatment or were in their first relapse after remission, found that administering a cycle of chemotherapy before the high- dose chemotherapy and an autologous BMT produced remissions in 50 percent or more of the cases, with some remissions lasting three years or more.
Studies are now underway to determine whether chemotherapy followed by high-dose chemotherapy and an autologous BMT will improve the survival rates of some Stage II breast cancer patients (in whom the disease has spread to lymph nodes under the arm) and some Stage III patients who are in a first remission and have not yet relapsed, but are in a high risk category for relapse a.e. the disease has spread to 10 or more lymph nodes). Early results from the studies are encouraging.
Childhood neuroblastoma is a cancer affecting the nerves that run from the neck down the inside of the back to the pelvis. It occurs almost exclusivly in very young children. Radiation and surgery are used to treat the disease in early stages when it's localized, but chemotherapy has so far not cured more than a very small percentage of patients when the disease is widespread at diagnosis.
Researchers have attempted to increase the cure rate with high-dose chemotherapy and an autologous BMT. Studies have found that for patients in first remission whose tumor has become resistant to standard chemotherapy, 40 50 percent can achieve a remission lasting two years or more with high-dose chemotherapy and/or total body irradiation and an autologous BMT. Survival rates are not as favorable for patients undergoing an autologous BMT after a relapse. Long-term survival rates for patients treated with an autologous BMT are similar to results achieved with an allogeneic BMT.
Ovarian cancer, brain tumors, Ewing's Sarcoma, testicular cancer, and other solid tumor cancers may also be treated with autologous BMTs. Ask your doctor for information about the effectiveness of treating these diseases with an autologous BMT.
Purging is a technique used at some transplant centers to reduce the +number of cancerous cells that may be in bone marrow harvested from certain patients undergoing an autologous BMT. The theory behind purging is simple: by reducing the number of cancerous cells in the harvested bone marrow, the likelihood of relapse after an autologous BMT will be reduced.
Two different purging techniques are used. The first involves "monoclonal antibodies"-special proteins that distinguish malignant cells from normal cells and attach to the surface of the malignant cell. These "marked" malignant cells are then broken apart with additional proteins called "complement" or "immunotoxins". Alternatively, small magnetic beads or "microspheres" are coated with the monoclonal antibodies and mixed with the bone marrow. The marrow is then passedover electromagnets which remove the microspheres and malignant cells to which they've become attached.
A second technique is chemical or pharmacological purging. The bone marrow is incubated with chemicals more toxic to cancerous cells than normal cells. The marrow is then transplanted into the patient.
Most U.S. transplant centers now purge bone marrow harvested from patients with leukemia before an autologous transplant. Tests on animals have shown purging to be effective in removing leukemic cells that linger in the marrow. Recent European studies suggest a link between purging and improved long-term survival rates in this patient population.
Purging bone marrow harvested from patients with non- Hodgkin'slymphomas is more controversial. No studies to date have conclusively demonstrated that purging bone marrow improves the long-term survival for this group of patients.
Purging is generally not done on bone marrow harvested from patients with Hodgkin's disease. It's commonly done, however, on the bone marrow of patients with neuroblastoma.
Purging has its drawbacks. Pharmacological purging can damage normal as well as malignant cells, causing delayed engraftment of
platelets and granulocytes and extending the period in the hospital during which patients are susceptible to infection and bleeding. Problems associated with pharmacological purging are diminishing as researchers learn the optimal level of chemicals to use in the purging procedure.
The prognosis for long-term survival varies according to the disease being treated, the stage of the disease at which an autologous BMT was performed, the patient's age, prior treatment history, and any complications that may have developed during transplant. There is no guarantee that an autologous BMT (or any BMT for that matter) will cure the disease.
Nonetheless, the alternative is usually near-certain death. Each added day of life, therefore, is special. Most patients agree that the potential rewards of an autologous BMT are well worth the effort.
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This document was created by NYSERNet, Inc. through a grant funded by the New York State Science and Technology Foundation as part of the Breast Cancer Infomation Clearinghouse.
Between 1981 and 1990, the number of allogeneic BMTs performed annually worldwide grew six-fold, from 875 in 1981 to 5,529 in 1990. That number is expected to increase by at least 2,000 in 1992. Allogeneic BMTs are used most frequently to treat patients with leukemia, aplastic anemia and immune deficiency diseases. They different from autologous BMTs in that the bone marrow donor and patient are two different people.
Despite the increasing number of BMTs performed annually, 60 to 70 percent of patients who need an allogeneic BMT each year go without one because a suitable bone marrow donor can't be found. Although a sibling is usually the preferred bone marrow donor, not every patient has a brother or sister with "matching" bone marrow. Thus, transplants using unrelated donors and "mis-matched" donors are often tried.
In the United States, the National Marrow Donor Program (NMDP) is leading the effort to expand the international registry of volunteer bone marrow donors so that more patients in need of a BMT can access this treatment. As of June 1992, more than 600,000 volunteer donors were part of the NMDP registry and as many as 50 bone marrow transplants with unrelated donors were being facilitated each month. A smaller registry called the American Bone Marrow Donor Registry also maintains several thousand donor records that can be searched by patients needing a bone marrow donor.
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The difficulty in finding a suitable donor lies in the fact that the donor's and patient's "tissue type" must closely match in order for the transplant to be successful. Genetic markers on the surface of white blood cells called HLA-antigens define a person's tissue type. Since these genetic markers are inherited, siblings are much more likely to have similar HLA-antigens than unrelated persons.
There's a 30-35 percent chance that a patient's sibling will be a suitable donor. If a donor must be located in the general population, the chances of finding a match range from one in 1,000 to one in several million, depending on the frequency of the patient's tissue type in the general population.
Everyone has distinguishing physical characteristics inherited from their parents. Some, such as eye and hair color, are easily seen by the naked eye. Others, such as fingerprints and blood type, require more sophisticated technology to detect.
White blood cells carry a distinguishing "fingerprint" on their surface called the HLA system-the human leukocyte antigen system. (Leukocyte means white blood cell). These antigens are proteins that play a critical role in protecting the body against invading organisms such as bacteria, viruses and other foreign matter.
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At birth, certain white blood cells called T-cells are programmed by the thymus gland to identify all the antigens that belong in that person's body. When a foreign antigen is encountered, e.g. antigens on the cell
surface of invading bacteria or viruses, the T-cells summon the various components of the immune system to attack and destroy the invading organism.
Similarly, when bone marrow is transplanted from a donor into a BMT patient, the patient's T-cells will examine the antigens on cells in the donated marrow, and will launch an immune system attack if they perceive the antigens to be "non-self". If the patient's immune system destroys the donated bone marrow, graft-rejection results and the BMT fails.
Alternatively (and more commonly) the T-cells in the donor's bone marrow overpower the patient's T-cells. They identify the patient's body as "non-self" and orchestrate an immune system attack on the patient's organs. This condition is called graft-versus- host disease (GVHD). (The graft is the donated bone marrow, the host is the patient). GVHD is usually not life-threatening. However, it can be a very uncomfortable side effect of an allogeneic BMT, and in severe cases can be lifethreatening. (See Chapter 9 for more information about GVHD.)
The HLA fingerprint on white blood cells is composed of a pair of antigens at several sites or "loci" on the white blood cell-one each inherited from the mother and the father. The antigens at three of these sites-the HLA-A, HLA-B, and HLA-DR loci are known to play an important role in determining whether graft-rejection will occur and the severity of GVHD. Pairs of antigens are also known to exist at other sites on white blood cells such as the HLA-C,-E,-DP and DQ-loci. However, their importance in bone marrow transplantation is not yet fully understood.
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To date, 24 different possible antigens have been identified at the HLA-A site, 52 at the HLA-B site, and 20 at the HLA-DR site. Since each person has two antigens at each site, more than 600 million combinations of HLA antigens are theoretically possible in the general population! Fortunately, the antigens at the HLA-A,-B and -DR loci are usually inherited as a set called a "haplotype" from one or both parents, and certain types tend to occur together, thus reducing the number of possible HLA combinations known to occur in the general population.
In the figure above, for example, one of the mother's haplotypes consists of the antigens A-1, B-8, and DR-3; the other consists of the antigens A-2, B-7 and DR-7. Children #1 and #4 have inherited the mother's first haplotype, while children #2 and #3 have inherited the second. Children #1, #2 and #4 have inherited the father's first haplotype, while child #3 inherited the father's second haplotype.
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To minimize the risk of graft rejection and graft-versus- host disease, a donor whose HLA type matches that of the patient is best. The optimal donor is often an identical twin. Not only will the twin have inherited from the father and mother the same antigens at the major loci (HLA-A,-B, and -DR) as the patient, but the antigens at tissue antigen sites other than HLA sites that are more difficult to detect or whose role in transplantation is unclear will also match. The risk of either graft-rejection or severe GVHD in BMTs using marrow from an identical twin is eliminated.
In other cases, the best bone marrow donor will be a sibling who is not an identical twin, but whose HLA-A, -B, and -DR antigens match those of the patient. In the figure on page 36, for example, Child #1 and Child #4 are a "perfect" HLA match, having each inherited one identical haplotype from their father and one identical haplotype from their mother. There may, however, be some mis-match at other less significant or well understood non-HLA loci which can cause mild to severe graft-versus-host disease post transplant. The risk of developing severe GVHD in a transplant using a matched sibling donor is approximately 20 percent, and the risk of graft rejection is usually less than 1 percent.
Child #2 and Child #3, on the other hand, each inherited an identical haplotype from their mother, but different haplotypes from their father. Were Child #2 or Child #3 to need a bone marrow transplant, either an unrelated bone marrow donor with matching antigens at the HLA-A, -B, and -DR loci would have to be found, or a transplant using "mismatched" bone marrow from their sibling would have tobe considered.
At least two tests are used to determine whether a patient's and donor's HLA-types match. The first is a blood test that can detect antigens at the HLA-A, -B and -DR loci. Secondary tests, such as the mixed lymphocyte culture (MLC) test, are used to assess whether or not the patient's and donor's bone marrow interact adversely.
Newer tests such as DNA typing will make HLA-typing more precise in the future. DNA testing has already revealed that antigens once thought to be identical may in fact have as many as 10 different variations or "microvariants". The significance of all these variations is not yet known, but they may explain the increased frequency and intensity of GVHD and occurrence of graft rejection in BMTs using mis-matched or unrelated donors.
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Between 1988 and 1990, approximately 12,000 allogeneic BMTS with matched related donors were performed worldwide, according to data compiled by the International Bone Marrow Transplant Registry. Forty-seven percent involved patients with acute leukemias, 27 percent were performed on patients with chronic leukemias, 10 percent on patients with lymphomas and other cancers, 9 percent on patients with aplastic anemia, and the remainder on patients with thalassemia, immune deficiency disorders and genetic or metabolic storage diseases.
Acute myelogenous leukemia (also called acute non-lymphocytic leukemia or ANLL) is a class of leukemias that includes acute myeloblastic leukemia (M1), acute myelocytic leukemia (M2, also called acute granulocytic leukemia), acute promyelocytic leukemia (M3), acute myelomonocytic leukemia (M4), acute monocytic leukemia (M5), acute erythroleukemia (M6), and acute megakaryocytic leukemia (M7). Most patients with AML who undergo an allogeneic BMT do so while in first remission.
When first diagnosed, patients with AML are given a cycle of chemotherapy called "induction chemotherapy" to achieve a remission (i.e., no leukemic cells can be seen when bone marrow is examined under a microscope). However, undetected leukemic cells usually persist following induction chemotherapy, and 80 percent of patients eventually relapse without further treatment
To improve the cure rate, induction chemotherapy is usually followed by another cycle of chemotherapy called consolidation chemotherapy, or by an allogeneic BMT. The cure rate with consolidation chemotherapy is 30 percent for adults, and 40 to 50 percent for children. The cure rate for those undergoing an allogeneic BMT in first remission is 50 percent for adults (some single institutions have reported cure rates as high as 65 percent), and 60 to 80 percent for children.
If a patient fails to achieve remission following induction chemotherapy, or if the patient relapses (the leukemia comes back) following consolidation chemotherapy, an allogeneic BMT may still be possible.
Under these circumstances, the chances for long-term survival are 10 to 30 percent. Without a BMT, the chances are 0 to 5 percent.
Some patients with AML who lack an HLA-matched donor, and thus are unable to have an allogeneic BMT, undergo an autologous BMT with purged marrow. (See Chapter 3 for more on autologous BMTs and marrow purging.)
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Acute lymphocytic leukemia (ALL) is the most common form of leukemia in children and is highly curable with conventional chemotherapy. Bone marrow transplantation is usually reserved for those who do not achieve a remission, or for those who relapse.
Approximately 30 to 40 percent of ALL patients who undergo an allogeneic BMT while in second remission are cured of their disease. Without a BMT, the chances for long-term survival among those who relapse or do not achieve a first remission are 0 to 5 percent.
Studies have been conducted to determine whether undergoing an allogeneic BMT while in first remission improves the cure rate for certain "high risk" ALL patients a.e., patients at high risk of relapse following standard chemotherapy because of age, high white blood cell count, etc.). Preliminary results suggest that cure rates as high as 50 to 70 percent may be achieved for this subset of patients, versus a 30 percent cure rate with standard chemotherapy. Further studies are underway to verify these promising results.
Chronic myelogenous leukemia (also called chronic granulocytic leukemia) is a form of leukemia that progresses more slowly than AML or ALL. It is often controllable for years with hydroxyurea or interferon. Eventually, however, CML reaches an acute stage in which the disease progresses rapidly, and death occurs without intensive therapy.
For patients who undergo an allogeneic BMT early in the course of their disease (during the first year of diagnosis appears to be optimal), the cure rate is 50 to 80 percent. Those who wait until the leukemia progresses to the acute stage have a cure rate of 10 to 30 percent.
Typically, patients with Hodgkin's disease and non- Hodgkin's lymphomas who cannot be cured with conventional chemotherapy undergo an autologous BMT rather than an allogeneic BMT (see Chapter 3). However, if the disease has spread to the bone marrow, an allogeneic BMT may be the best or only chance for a cure. For this subset of patients, the long-term survival rate following an allogeneic BMT is 20 percent, as compared to 0 to 5 percent with standard chemotherapy.
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In patients with aplastic anemia, the bone marrow malfunctions, resulting in low white blood cell, red blood cell and platelet counts. Therefore, patients with aplastic anemia are very susceptible to infection and bleeding.
An allogeneic BMT is the preferred treatment for younger patients with an HLA-matched donor. Fifty to 70 percent of patients achieve normal blood counts following an allogeneic BMT.
For older patients and those who lack a suitable bone marrow donor, antithymocyte globulin (ATG), used alone or in combination with steroids and cyclosporine, can successfully treat the disease in 50 percent of cases. ATG is used to destroy T-cells which may cause aplastic Eanemia in certain patients. If this treatment fails, an allogeneic BMT remains an option.
Since the chances of finding a donor among one's siblings are only 30 to 35 percent (given the current family size of 2.7 children) trials have been underway to determine whether partially matched or "mis-matched" related donors can be used effectively in BMTs. Results to date indicate that a sibling mis-matched for one antigen at either the HLA-A,-B or -DR site (a 5 out of 6 antigen match) can often be a suitable bone marrow donor.
In transplants using single antigen mis-matched related donors, the risk of developing severe graft-versus-host disease is approximately 30 percent (as compared to 20 percent in HLA- matched related transplants). The risk of graft-rejection is approximately 10 percent. Despite the higher risk of severe GVHD in one-antigen mis-matched related transplants, the long-term survival rate is approximately the same as that seen in BMTs using HLA- matched related donors.
When more than one antigen in the donated bone marrow is mismatched, the risk of developing severe graft-versus-host disease is 50 to 70 percent, and long-term survival rates decrease markedly for most types of patients.
Use of mis-matched related donors has been successful in BMTs for patients with immune deficiency diseases such as SCIDs (severe combined immune deficiency syndrome). A three-antigen mis- matched parent (or 3 out of 6 antigen match) can often serve as a donor for these patients. Since immune deficient patients have no functioning immune system, they are usually incapable of launching an immune system attack on the donated bone marrow and thus the incidence of graft-rejection is very low.
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New techniques to remove the T-cells from the donor's marrow (the cells believed responsible for causing graft-versus-disease) have reduced the incidence and severity of GVHD in this patient population.
Patients with severe aplastic anemia have responded least favorably to BMTs using mis-matched donors. Graft-rejection rates as high as 40-50 percent have been reported, but these numbers are less if the BMT preparative regimen includes total body irradiation. The high graft rejection rate may be partly due to the large number of transfusions many aplastic anemia patients receive prior to a BMT, which make the patient more sensitive to antigens on cells in the donor's bone marrow.
In patients with leukemia, transplants using single-antigen mis-matched related donors have produced long-term survival results similar to those obtained when marrow from an HLA-matched sibling is used, despite a higher incidence of GVHD and graft rejection. If more than one antigen is mis-matched however, the incidence of severe graft- versus-host disease increases significantly, and long-term survival rates fall. Although T-cell depletion techniques reduce the incidence of graft-versus-host disease, they also increase the rate of graft rejection in this patient population because T-cells are needed for engraftment. Thus, the overall survival rates have remained unchanged. Patients in an advanced stage of leukemia who must receive higher dosages of chemotherapy and/or radiation than others prior to their transplant have the greatest risk of developing life-threatening GVHD when mis-matched related bone marrow is used.
While BMTs using bone marrow from a single-antigen mis-matched related donor are often successful, this does not significantly expand the pool of potential donors for most patients. The chance of finding a family member mis-matched for one HLA-antigen is only 3 to 5 percent. Thus, efforts are underway to expand the international registry of unrelated bone marrow donors.
Bone marrow donor registries now exist in more than 30 countries, with over 750,000 potential bone marrow donors on file. Currently, 70 hospitals in the United States perform allogeneic BMTs with unrelated bone marrow donors.
The likelihood of finding a matched unrelated donor among the general population depends on a number of factors. The first is the patient's haplotypes-the two sets of HLA antigens inherited from his or her parents. If the haplotypes are fairly common, the chance of finding a matched donor in the current NMDP registry of 600,000 donors is quite good. Patients with very rare haplotypes, on the other hand, may have less than a 10 percent chance of finding a matched donor.
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The second factor is the patient's ethnic group. Some HLA-antigens are "pan-ethnic," i.e. they are found among members of nearly every ethnic group. Other HLA-antigens are found more frequently in members of a specific ethnic group. If a patient's antigens are more commonly found in one ethnic group than others, his or her ability to find a matched donor will be limited by the number of members of that ethnic group in the donor registry. For this reason, efforts are underway to expand the ethnic diversity of donors in the NMDP registry.
The third factor is the patient's diagnosis and stage of disease. Searching for an unrelated donor can take 3-10 months, sometimes years. Patients with a rapidly progressing disease are at a disadvantage when searching for an unrelated donor, because of the long turn-around time currently required to locate a matching donor. This is sometimes the reason that a mis-matched related donor is used.
Since the first BMT with an unrelated donor was attempted in 1973, several studies have shown that a BMT using an unrelated donor is an effective treatment for certain patients diagnosed with leukemia, aplastic anemia, and immune deficiency syndromes. More work needs to be done, however, to enable more precise matching of donors with patients, and to minimize the incidence and severity of graft-versus-host disease.
Research is underway at some BMT centers to determine the feasibility of using mis-matched unrelated donors in BMTs. Preliminary studies indicate that a BMT using a single antigen mis-matched (or a 5 out of 6 antigen match) unrelated donor can be successful, but the risk of severe GVHD is very high. The results tend to be better when the patient is a child, rather than an adult. If no donor is available, some patients may be candidates for an autologous BMT (See Chapter 3).
The National Marrow Donor Program (NMDP) maintains the largest database of donors in the United States. As of June 1992, more than 600,000 volunteer donor records could be accessed through the NMDP registry.
The NMDP conducts a donor search for individual patients only at the request of an authorized NMDP transplant center. Authorized centers are those that have performed 10 or more allogeneic transplants per
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year in the last two years and 30 in the last five years. Phone the NMDP at 800 654-1247 for a current list of NMDP authorized transplant centers and their criteria for accepting patients.
A smaller registry of bone marrow donors, the American Registry, reported 40,000 donors on file as of June 1992, with access to several hundred thousand international records as well. Most of the international records can also be accessed through the NMDP.
Any physician or transplant center can initiate a donor search of the American Registry. If the patient is over 50 years of age, the donor search must be requested by a transplant center willing to perform the transplant. For information on searching the American Registry's donor database call 800 726-2824.
Charges for searching the NMDP and American Registry databases vary, depending on the number of potential donors identified and fol low-up tests that must be performed. Fees for the donor search, donor blood tests, physical exam of the donor, and bone marrow harvest can be as much as $20,000. Not all insurance plans cover these donor-related costs.
If a person is called upon to serve as a bone marrow donor, the medical procedure he or she must undergo is called a bone marrow harvest. It is a surgical procedure that typically requires one overnight stay in the hospital. The procedure is generally performed under general anesthesia so the donor feels no discomfort while the bone marrow is being harvested. Afterwards, the donor may feel some soreness in the hip area where the bone marrow was withdrawn. This soreness can usually be relieved by taking oral medications like Tylenol. For a more detailed explanation of a bone marrow harvest, see page 13.
If you have volunteered to be a bone marrow donor through the National Marrow Donor Program or the American Registry, the costs associated with donating bone marrow are typically covered by the patient's family. Bone marrow donors can expect to spend approximately 40 hours (cumulatively, not consecutively) on the various blood tests, physical exams, counseling sessions and the bone marrow harvest itself.
If you are a related donor, you will probably also be asked to serve as the patient's platelet donor during the first few weeks following the BMT.
For most donors, the opportunity to give a person, especially a loved one, a second chance at life is very exciting. Keep in mind, however, that not all BMTs are successful. News of an unsuccessful transplant can be
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very hard on a donor who's made a substantial physical and emotional investment in saving another person's life. Donors can only be guaranteed that they'll give the patient "a future.n Whether that future is two months, two years or a lifetime cannot be predicted with certainty.
Forty-year-old Laura Wise of Glenview IL is a typical mother. At the first sign of illness, she hustles her three children and husband off to the doctor. But in the Spring of 1990, when flu-like symptoms started bothering her, she put off a call to the doctor for months. When she went for a check-up she was stunned by the news. She had chronic myelogenous leukemia. With conventional treatment, her doctor predicted she had 3-5 years to live.
"It felt like a death sentence" Laura recalls "but fortunately my doctor gave me exactly what I needed right from the start: hope. He explained that a bone marrow transplant might possibly cure me and suggested we begin testing my two sisters and brother immediately to see if one of them could be a donor. Deciding to have the transplant was hard, but once I made the decision I never looked back."
Waiting for the HLA test results on her sisters and brother was even harder. "There was such a sense of urgency to proceed with the transplant, yet it seemed like an eternity before the test results were finally in. At first I didn't really understand what they meant. I'd look at them and think 'This is pretty good. They're only a couple of antigens off!' "
As is often the case, none of Laura's siblings was a perfect HLA-match. Her sister Mary was the closest a one-antigen mis-match-and her doctors decided she would be an acceptable donor.
In August, Laura, her husband Bob and Mary travelled to Seattle for the transplant. '1t was hard leaving our three children behind, but we wanted their life to be as normal as possible during the BMT. All three (ages 4-9) had a sense of what was happening and we phoned them every day."
Mary's "marvelous marrow" engrafted without problem and her "powerful platelets" sustained Laura until she was able to produce platelets on her own. She did, however, develop chronic GVHD after being discharged from the hospital.
"I've had a skin rash, mouth sores, dry itching eyes and elevated liver functions, and have been taking cydosporine
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to control it. At my one year check-up last August, I started tapering off the drugs. Six weeks later, the GVHD flared up and I had to go back on cydosporine. That was disappointing."
Since then, Laura's GVHD has subsided. "This July I'll have another check-up. Hopefully I can taper off the drugs and the GVHD will finally fizzle out."
"For me, the transplant was totally worth it. For the most part, I'm back to a normal routine."
Her suggestion for new BMT patients: "Always look on the hopeful side of things. That, and the wonderful support given to me by my husband and family made all the difference in the world in getting me through the experience."
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In 1991, an estimated 1,000 U.S. patients underwent a peripheral stem cell harvest tPSCH) and transplant. PSCHs have been used instead of or in addition to autologous bone marrow harvests when transplanting patients with acute myelogenous leukemia (AML, also called acute non-lymphocytic leukemia or ANLL), acute lymphocytic leukemia (ALL), Hodgkin's disease, non-Hodgkin's lymphoma, brain tumors, breast cancer, ovarian cancer, multiple myeloma, small cell lung cancer, testicular cancer and neuroblastoma.
More than 58 BMT centers in the U.S. now perform peripheral stem cell harvests and transplants and that number is growing. Peripheral stem cell transplants differ from autologous BMTs only in the method of collecting "stem cells," the cells that are reinfused into the patient during the transplant.
Mature blood cells evolve from "mother" cells called stem cells. The most primitive of these is the pluripotent stem cell that is believed to be the origin of all blood cells.
Pluripotent stem cells differ from other blood cells in that they are capable both of unlimited self-renewal and differentiation. Self-renewal means the cell is able to reproduce another cell identical to itself, thus maintaining a steady number of these types of cells in the body. Differentiation means the cell is capable of generating one or more subsets of more mature cells that eventually evolve into either erythrocytes, neu- trophils, eosinophils, basophils, lymphocytes, monocytes or platelets.
When physicians harvest bone marrow for use in a transplant, it is the stem cells they are seeking. Stem cells resemble medium sized white blood cells. It has been estimated that less than one in 100,000 cells in the bone marrow are stem cells.
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When stem cells are infused into a patient's bloodstream, they will migrate to the interior of certain bones, set up housekeeping or "colonize" and begin producing immature cells called "committed progenitors." These committed progenitors produce colonies of cells that eventually mature into red blood cells, white blood cells, or platelets.
Although the largest concentration of stem cells in the body is found in the bone marrow, stem cells also can be found in the bloodstream or l"peripheral blood." The concentration of stem cells in the bloodstream is normally 1/100 of that in bone marrow. Extracting stem cells from the peripheral blood is called a "peripheral stem cell harvest" or PSCH.
The process used to extract stem cells from the bloodstream is similar to the process used to collect platelets from platelet donors. Patients are connected to a cell separation machine or "apheresis" device. A needle is inserted in each arm and blood is withdrawn from one arm and circulated through the machine to extract the stem cells. The remaining cells are returned to the patient through a needle in the opposite arm. Alternatively, the blood may be withdrawn and returned to the patient through a catheter.
The PSCH is painless. Patients occasionally experience lightheadedness, coldness, numbness around the lips, or cramping in the hands during the harvest.
Typically, several two-to-six-hour sessions are required to collect sufficient stem cells from the bloodstream for transplantation. If drugs called "growth factors" or "colony-stimulating factors" (e.g., granulocyte-colony stimulating factor, G-CSF, or granulocyte- macrophage colony stimulating factor, GM-CSF) are given before and during the period of time when peripheral stem cells are being harvested, the number and duration of the sessions may be less. The procedure is usually performed on an outpatient basis over a one- to two-week period. After each session, the stem cells are frozen using a process called cryopreservation.
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REASONS FOR
PSCHSPhysicians may recommend a PSCH for a variety of reasons. Sometimes PSCHs are used to augment the stem cells collected from a bone marrow harvest. In other cases, a patient's bone marrow may be contaminated by cancerous cells and a PSCH may be used in lieu of a bone marrow harvest in the hope that the peripheral blood stem cells have not been similarlycontaminated. Prior radiation to the pelvic area or chemotherapy can also reduce the number of stem cells available via a bone marrow harvest, making a PSCH necessary.
A PSCH may provide patients whose bone marrow is unsuitable for harvesting their only opportunity to undergo an autologous transplant. PSCH also allows collection of stem cells without the use of general anesthesia, involves little or no discomfort and can be done on an outpatient basis. Collection of stem cells through a PSCH, however, requires many days or even weeks while bone marrow harvests can be completed in a single two-hour session in an operating room. The difference in time required to harvest stem cells from the peripheral blood vs. the bone marrow may be critical for patients whose disease is progressing rapidly.
PSCHs also require more laboratory processing time since each sample must be frozen separately. This may increase costs and/or strain laboratory resources at some centers. In a 1992 BMT Newsletter survey of 58 BMT centers performing PSCHs, 38 percent said PSCHs cost more than bone marrow harvests to obtain sufficient stem cells for transplantation. Thirty-one percent said the difference in cost was greater than 20 percent.
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Although stem cells derived from the bloodstream can be successfully used in an autologous transplant, they do not appear to be exactly the same as stem cells derived from bone marrow. Whether the stem cells used in a transplant are collected from the bone marrow or peripheral blood, however, does not appear to affect the incidence of full recovery or rate of long term survival. Ultimately, the success of an autologous BMT depends less on the source of stem cells used in the transplant than on the effectiveness of the chemotherapy and/or radiation administered to destroy the diseased cells before the transplant.
Forty-six-year-old Thelda DeLanghe of Bremen, Indiana has lots to be proud of. Less than a year after undergoing a peripheral stem cell harvest and transplant to treat her breast cancer, she's back to work full time, enjoying her first grandchild, Erin, and helping others who face the prospect of a bone marrow transplant.
For DeLanghe, the road to recovery wasn't easy. At first, Blue Cross/Blue Shield refused to pay for her treatment. "When the women at the school where I work heard about the denial they were very concerned," said DeLanghe. "They knew the same thing could happen to them." With the help of a letter writing campaign orchestrated by school employees and neighbors, the intervention of Indiana State Representative Kent Adams and former Governor Otis Bowen, and the work of an attorney, Blue Cross/Blue Shield finally relented and agreed to pay.
For eight consecutive days in April 1991, DeLanghe and her husband Larry drove the five-hour round trip to Chicago and back for the peripheral stem cell harvest. "The nurses were real angels of mercy," said DeLanghe. "One even fixed us home cooked meals and brought movies to keep us entertained during the harvest."
Meanwhile, friends and neighbors in Bremen held a dance and other fundraisers to help with expenses. Larry, a truck driver, had been laid off since Christmas and turned down the chance to return to work in the spring so he could be with Thelda during treatment. In June, 28 days after being admitted to the hospital for the transplant, Thelda arrived home. "The support I got from family, friends, and the community
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while I was hospitalized was unreal," said DeLanghe. "My 70 year-old parents, my son and his friends, and other family members all made the long drive to visit me. The school principal and teachers came to donate platelets. When my daugh ter, who was five months pregnant visited, I was really inspired to get well. I wanted to see my first grandchild." Thelda was back to work full time at the end of July. "The first week was hard-I barely had the energy to eat and go to bed when I got home. But it got better with each day that passed."
Before long, Thelda had a chance to repay the kindness she experienced during her treatment. "A 64 year-old man from a nearby community who buys cars in Bremen kept following my progress and asking about me," she said. "I finally found out he was going to have a peripheral stem cell transplant for lymphoma in Indianapolis, so I wrote to give him encouragement." They met for the first time a month ago and have been giving each other support ever since. "When you give a little of yourself, you get a lot back in return."
"Deciding to have a transplant is not easy," says Thelda. "At first you feel like you're on a roller coaster. Everything's out of control. Your life's in the hands of strangers and there's a tremendous fear of the unknown. Sometimes my mind was a blank and other times I wondered 'What am I doing?' But then I thought 'What's the alternative? If I'm going to die, I want to go down fighting.' I wasn't ready to give in to the disease. I feel special to be a survivor."
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A bone marrow transplant (BMT) provides hope for many patients diagnosed with leukemia, aplastic anemia, and other bone marrow disorders and cancers that were once thought incurable. This hope for a cure sustains patients and their families through the difficult period of treatment and recovery. Nonetheless, contemplating a bone marrow transplant, undergoing the procedure and coping with the recovery process is a trying experience for the patient, the patient's family and friends.
When a patient first faces the prospect of a bone marrow transplant, the news can be devastating. Many will not yet have come to grips with the fact that they're suffering from a life-threatening disease before being asked to decide whether or not to undergo a bone marrow transplant. Sometimes the decision must be made quickly to provide the greatest likelihood of success, adding more stress to an already difficult situation.
The sheer volume of information patients must absorb coupled with their unfamiliarity with the medical jargon used to describe the procedures can be mind-numbing. Some simply stop hearing new information as they struggle to deal with facts already provided and the prospect of their own mortality. Patients may ask the same question repeatedly, failing each time to comprehend the answer.
Little of the information BMT patients receive will sound like good news. What patients want to hear is that the bone marrow transplant will be a quick, painless, risk-free procedure. More importantly, they want assurance that it will cure their disease and provide them with many extra years of life. Unfortunately, no such assurance can be given. The patient can only be promised the "chance" of a future.
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Fear that more unsettling news is forthcoming precludes many patients from asking questions. As much as they may want answers, some opt to cope with uncertainty rather than open themselves up to more disturbing news.
In an effort to provide a complete and honest description of the BMT experience, doctors sometimes confuse and overwhelm patients. They may assume that patients are familiar with medical jargon like "catheters, IVs, aspirates, biopsies, etc." which is usually not the case. As one patient put it "doctors talk medical, patients talk human". Don't be embarrassed to ask your doctor to re-explain something or to translate it into words that you can understand. Keep asking ques tions until you're satisfied with the answer, regardless of how many repetitions it takes.
Ask your doctor to help you put the complications and side effects associated with a BMT into perspective. Don't assume that the likelihood of death or severe liver damage, for example, is as great as the likelihood of temporary hair loss or mouth sores. (It's not!) Ask what the probability is that various complications will occur. It can help ease your worries.
Doctors also sometimes forget to mention that pain relief will be provided during a BMT. Thus, when patients hear about the numerous complications that might occur, they presume they'll be in terrible pain while hospitalized. While pain can occur following a BMT, pain medications can be provided in most cases to alleviate the discomfort.
Family and friends can help patients sort through the deluge of information received from a doctor. A patient who's afraid or embarrassed to ask a physician the same question for the tenth time will appreciate a family member who asks the question on his or her behalf. Giving a patient the name of someone who has experienced a bone marrow transplant and is willing to talk about it can also be helpful. Before meeting your your transplant doctor, it helps to write down any questions you might have and bring them with you.
The time spent in the hospital before, during, and after a bone marrow transplant can seem never-ending. Patients seldom make daily progress by leaps and bounds. Each day will bring a small step forward, maybe a little backsliding, or no change at all. This slow pace of progress can depress patients (and their loved ones) who want desperately to get well and put this chapter of their life behind them.
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It helps to take one day at a time rather than worry about what will happen in five days, five weeks or five years. Physicians and health care workers can help by setting manageable goals for patients to achieve each day and by letting them know each and every time progress is made, no matter how small. What the medical staff may take for granted as the normal course of transplant recovery can be big, encouraging news for the patient. When the marrow engrafts, when test results are good, and when blood counts begin to rise, patients should be told and congratulated. Providing the patient with a chart that graphs his or her progress toward the blood count goals can help. Patients constantly feel overwhelmed by "bad" news. Any progress or positive news, no matter how small, can buoy a patient's spirits.
Similarly, encouraging comments from family members on days when a patient looks better can boost the patient's morale. On those inevitable days when backsliding occurs, it's best to discuss your disappointment with someone other than the patient.
A bone marrow transplant is a physically debilitating experience. Patients undergoing a transplant will be in a fragile state of health for several weeks and feel extremely weak and helpless. Walking without assistance, focusing on a book or television set, following the thread of a conversation, or even sitting up in bed may require more energy than the patient has to spare. Patients who are used to being in charge, taking care of themselves, or being the person upon whom others depend will find this physical debilitation very hard to cope with. This loss of control can both frighten and anger a patient.
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Two strategies can help to reduce the fear the patient feels during this period. First, patients should be assured that a loved one will be their advocate while they're too weak to fend for themselves. If a patient needs pain relief, has questions, or needs some other form of help, being able to rely on a loved one to track down the appropriate hospital personnel and get the problem solved can be an immense relief. Patients know that physicians and hospital staff have many patients' needs to juggle. Knowing that someone dose will be an advocate for the patient, and that patient only, can be very comforting.
Second, patients' fears can be needlessly heightened by a vacuum of information. Isolated in a private room, patients often wonder whether anyone is reviewing their case each day and following up on questions or complaints. Asking physicians, interns, and nurses to touch base frequently with the patient throughout the day, even if there is no new information to report, helps assure patients that they have not been forgotten.
Patients are frequently put in the hands of medical technicians, transport workers or other unfamiliar hospital staff for x-rays and other tests.
The fear engendered by their weakened condition is often heightened during these periods. X-ray technicians who handle patients clumsily or leave them stranded on tables for what seems like an eternity, transport workers who manipulate controls on IV lines during transport, etc. can frighten patients who lack the physical strength or medical knowledge to correct a problem if it arises. Similarly, tests that in some way physically restrain a patient, such as those requiring tight-fitting masks on a patient's face, or CAT scans that enclose the patient in a confining space can be frightening. Having a loved one or trusted nurse present during these procedures, or providing a mild sedative, can calm the patient and alleviate stress.
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Patients often react to the loss of control over their body with anger. This anger may be directed at physicians, other medical personnel or even at the patient's loved ones. There are several things caregivers can do to diffuse the patient's anger and frustration.
Most importantly, treat patients with respect. Even in a debilitated state, adult patients want and are entitled to be treated as adults. Their intelligence should be acknowledged, their modesty respected, and their need to assert some control over their own situation understood. Patients can react angrily to persons who try to "dictate" rather than tactfully encourage them to do things they'd rather not do. Giving the patient a chance to assert some control over these decisions can lessen their feeling of helplessness and anger.
Respecting a patient's modesty and privacy can also stem a source of anger. As sick and helpless as patients may be, there's no reason to require them to bare their bodies and souls to the world.
Patients often need time alone with physicians, psychologists, or social workers to discuss private concerns and feelings. Family members and friends should respect this need. Sitting in on discussions, especially between the patient and psychological or pastoral counselors, may prevent the patient from expressing feelings and concerns with which he or she needs help coping.
The special precautions taken to protect BMT patients against infection after the transplant while their immune system is suppressed make many patients feel lonely and isolated. Transplant patients crave a normal environment where they're not the center of attention, where they can interact freely with family and friends without special precautions or protective garb, and where they can think about something other than their disease and treatment.
Converting a hospital room into the patient's room can make the patient feel less detached from normal life. Having pictures of family members on hand, displaying cards and well wishes, substituting pictures of the patient's choosing for the "art" that normally adorns hospital room walls helps. Bringing in the patient's own bed clothes, a tape deck with favorite music, books, a VCR, etc. can also make the hospital room seem homier. When family and friends visit, they should talk about the world outside. Positive, upbeat anecdotes about family members and friends, descriptions of stores or museums visited, plays or movies that have been seen, the latest gossip from work or school - anything that brings the outside world to patients - will make them feel less isolated and cut off from normal life.
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Some side effects of the high-dose chemotherapy and/or radiation patients undergo prior to transplant as well as post-transplant medications and complications can be stressful for patients.
Temporary hair loss can change one's self image, making some patients self-conscious or embarrassed to be seen by family and friends. During the hospital stay, wearing a head scarf, turban, or hat may make a patient feel less conspicuous and can be more comfortable than a wig. Meals, too, can be a stressful time. Hospital food, even on the best days, can be a pretty miserable bill of fare. Mouth sores, a common side effect of the treatment, can make eating uncomfortable. Some of the drugs administered to patients during treatment may radically alter the taste of foods, making them unpalatable. Patients often appreciate having family members bring in "comfort foods" that are more appealing to the patient (provided they've been approved by the doctor).
The large quantity of medications patients will need to take orally each day can be daunting, and some may have difficulty as they try to force the pills down. The battery of tests administered to monitor the patient's overall physical condition, while not painful, can leave patients feeling like their bodies are under constant assault. Though little can be done to curtail these necessary medications and tests, sympathy from all caregivers can help patients cope with the stress they produce.
In some cases, it is possible to reduce the physical discomfort associated with a test and thus reduce stress. Pre-medication with demerol or morphine prior to a bone marrow aspirate, for example, can calm a patient and make the procedure more comfortable. Patients should not be reticent about asking for pre-medication or other pain relief if they're worried about discomfort. Don't be intimidated if the medical staff seems resistant to your request. There's no reason to endure more pain than necessary.
Families of BMT patients should take an active, aggressive role in advising physicians and hospital staff of a patient's discomfort and needs. Family members know the patient's personality best and will know the extent to which a patient will be stoic about pain and discomfort before asking for help. The hospital staff needs to know if the patient will request relief as soon as pain begins or only after the discomfort is really intense. The speed with which they respond to the patient's call for help is often influenced by this important information.
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Anxiety and stress are a normal and expected part of the BMT experience. Patients who become very anxious or agitated are not "weaklings" or losing their minds. They're reacting in a very normal way to a very stressful experience.
Most BMT patients benefit from the services of a psychiatrist or psychologist during the BMT process and patients should be encouraged to take advantage of their professional help. If your physician does not volunteer these helpful services to you, ask for them.
Some patients will be shocked or embarrassed at the notion that they may be incapable of coping with the stress of a BMT on their own. This is particularly true of persons who've never before required the help of a psychologist or psychiatrist. Needing and seeking psychological or psychiatric help during a BMT is normal. It does not mean the patient is falling apart, or that he or she will require ongoing psychiatric help after the BMT.
Psychiatrists often help patients manage stress with sedatives and anti-depressant medications. Most BMT patients never before will have needed or used these medications. Short-term use of these drugs during the hospitalization is common, and does not mean the patient will develop a long-term drug dependency.
Sedatives and sleeping pills are particularly helpful in managing a very common problem experienced by BMT patients-insomnia. Deprived of sleep, a patient can quickly become exhausted, unfocused and extremely irritable, making it even harder to cope with daytime stresses. Medications are available to counteract insomnia; there's no need to put up with sleepless nights and the stress they produce.
It's extremely important that family members be involved on a day- to-day basis with the patient's care. Often, the best thing that family members or friends can do for the patient is to just " be there." Just having a loved one or friend close at hand can be very comforting. Don't feel you need to keep up a non-stop conversation during your visit. Read, chat with the patient periodically, watch television, share time as you would at home. It's your presence that counts most.
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Throughout much of the hospitalization, the patient may be much too weak to visit with guests or even accept phone calls. Nonetheless, it's important for patients to know that family members, friends, and co-workers are concerned about their progress and rooting for their recovery. It can be very depressing for a patient to feel that he or she has been forgotten by someone. Cards, handwritten notes, and words of encouragement passed along through family members or friends can mean a lot to a patient who feels isolated in a hospital room. Installing an answering machine on the patients phone is one way to let family and friends communicate their well-wishes without requiring the patient to engage in exhausting phone conversations.
Sometimes friends and acquaintances are afraid to "intrude" and therefore do not call or write. If you're concerned, check first with a family member; but more often than not your expression of concern will boost the patient's spirits and help the recovery process. Other gestures like donating platelets for the patient, helping with family household chores, caring for the patient's children, providing an evening off for the patient's support person, or filling in for the patient until she returns to work will also be greatly appreciated.
Nights are an especially stressful time when patients feel most isolated and lonely. There are fewer distractions and fewer familiar faces upon whom to rely for help. Alone in the dark, fears that normally grip the patient during the day are intensified.
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Many transplant facilities allow a support person to spend nights in the patient's room on a cot or daybed. Having a loved one present in the room at night greatly relieves patients' stress. If your transplant center does not routinely provide overnight accommodations for support persons,they may be willing to make special arrangements.
The day of hospital discharge can be both exciting and frightening. On the one hand, patients are glad to leave the isolation of the hospital room behind them. On the other hand, losing the "safety net" of hospital personnel who've been available to support the patient's every medical need can be frightening.
The sights, sounds and smells of the world outside the hospital will assault the patient's senses. It's a very moving and exhausting experience when patients take the first step out of the hospital and start back on the road to a normal life.
During this period of recovery, patients desperately want to feel normal and be treated as such. They don't want pity. They want to be able to take care of themselves to the extent possible, and don't want to be singled out for special treatment unless absolutely necessary.
Family members, friends and co-workers sometimes have difficulty re-establishing their relationship with patients. Patients will look different. They may have lost weight, will have temporary hair loss, be wearing a face mask to protect against infection, or look physically drained. Because the patient will have been "out of circulation" for several weeks or months, he or she will not have shared as many experiences with family members or friends as usual. Vlsitors can feel awkward as they grope for an appropriate topic of conversation, and this awkwardness can discourage some people from calling or visiting.
In some cases, particularly with children, ignorance may make a person fearful of associating with the patient. One high school adolescent reported that, upon her return to school the school corridors would literally dear out each time she appeared. The other children were afraid they might "catch it" and were uncomfortable interacting with a classmate they believed was about to die.
Friends and family members of patients can overcome some of this post-transplant awkwardness by not losing touch with patients while they're undergoing treatment Sharing normal life experiences with the patient either during a visit, by a note, or with a phone call can help make the re-establishment of relationships post-transplant easier.
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Children of adult transplant patients, as well as friends and class mates of children undergoing a transplant, should be prepared for the return of the patient, with the myths of "catching it" or the inevitability of the patient's death dispelled well in advance. This will not only ease the patient's stress, but relieve unspoken fears the children may have about their parent or friend.
Oftentimes friends will be unsure about how and when to re-establish a normal relationship with the patient, and will look for a cue from the patient before making a move. Some patients have found that asking friends to help with a small task such as picking up a prescription at the drug store, taking the patient/s child to a school event, or returning a purchased item to a department store will "break the ice" and let friends know that the patient is ready for their companionship.
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Friends of transplant patients may help ease the transition back to normal life by inviting patients to accompany them to places or events that do not pose undue health risks. Despite the fact that the patients may need to wear a face mask when going on these excursions (which will make the experience less than perfect), their desire to get back into the normal flow of life may overcome their aversion to being conspicuous, and the invitation will be much appreciated.
During the recovery period, graft-versus-host disease (GVHD), a post-transplant side effect that affects many patients who undergo allogeneic transplants, can also be very stressful. GVHD is discussed at length in Chapter 9.
A BMT is difficult, not only for the patient, but for support persons as well. This is especially true if the support person has ongoing family and/or job responsibilities. Here are a few tips that may help.