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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.
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.
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.
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.
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.
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.)
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.
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.
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.
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
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
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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