Matched unrelated transplants

Matched Unrelated Transplants Kathleen Welte

N 1979, WHAT would you have done if your child needed a bone marrow transplant to survive and had no matched donor in your family? You would have watched your child die. The National Marrow Donor Program (NMDP) (formerly the National Bone Marrow Donor Registry) was established because several parents in the situation just described determined that there needed to be an alternative. They knew that only 25% to 30% of patients have a matched donor in their families. They began to confront their congressmen about the need for a centralized system to match patients with suitable unrelated donors. In 1986, Congress appropriated funds for the Office of Naval Research in the Department of the Navy to solicit proposals to establish a computerized registry of volunteer bone marrow donors for patients in need of a transplant. A consortium of the major blood-banking organizations in the United States, the American Association of Blood Banks, American Red Cross, and Council of Community Blood Centers, successfully responded to the request for proposal. Under the administration of the American Red Cross, the NMDP began operating in St. Paul, MN, in September 1987. Responsibility for the contract was transferred to the National Heart, Lung, and Blood Institute in February 1989. The original grant was modest and did not include funds to pay for HLA typing of willing volunteer donors. To establish a program, two things had to happen simultaneously. First, the NMDP had to identify a source of volunteer donors who were already HLA typed. Invitations to become NMDP donor centers were sent to those blood banks that maintained lists of HLA-typed platelet donors. Second, a notice went to transplant centers informing them that a central registry of volunteer

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From the National Marrow Donor Program, Minneapolis, MN. Kathleen Welte, BSN, MBA: Director, Recruitment Development, National Marrow Donor Program. Address reprint requests to Kathleen Welte, BSN, MBA, National Marrow Donor Program, 3433 Broadway St, NE, Suite 400, Minneapolis, MN 55413. Copyright 9 1994 by W.B. Saunders Company 0749-2081/94/1001-000455.0010

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donors would be available. It took donor centers approximately 2 years to recruit 40,000 volunteer donors who were willing to join the NMDP. To develop a coherent whole out of a fragmented system has meant developing a hub to coordinate donors centers that recruit and educate volunteer donors, transplant centers that care for patients who need transplants, and collection centers that are medical centers that collect marrow from donors, which is then taken directly to the patient who needs it. The point of intersection as shown in Figure 1 is the computerized registry of volunteer donors located at the NMDP Coordinating Center in Minneapolis. As of June 1993, there are more than 900,000 volunteer donors listed on the NMDP Registry. Over 100 donor centers coordinate recruitment and medical work-ups for volunteer donors who donate marrow. Marrow is collected from these volunteer donors in 70 medical centers that function as collection centers. More than 60 transplant centers in the United States and abroad perform marrow transplants from unrelated donors. Each month approximately 50 marrow transplants are facilitated by the NMDP. FINDING A MATCH

HLA Antigen Typing The HLA antigen system is a major determinant of transplant success. The experience gained with mismatched related transplants has helped define the degree of incompatibility between donor and recipient that can be tolerated. There are more than 90 separate HLA antigens that can form over 26 million possible combinations. This is a staggering number of possible combinations, but some tissue types are relatively common within the general population and others occur as rarely as once in a million individuals. Individuals inherit their HLA antigens (tissue type) in Mendelian fashion from their parents in the same way that eye and skin color is inherited. Some tissue types are found more often in certain racial and ethnic groups, and a matched donor is more likely to be found among a patient's own ethnic group. Preliminary research suggests heterogeneity of Seminars in Onco/ogy Nursing, Vol 10, No 1 (February), 1994: pp 20-27

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NMDP NETWORK

Fig 1. National Marrow Donor Program network.

tissue types within the African-American population and Asian/Pacific Islander populations within the United States (PG Beatty, personal communication, July 1993). Because the NMDP Registry file contains only about 15% of donors who are not Caucasian, major emphasis is placed on recruiting volunteer donors with diverse ethnic and racial backgrounds. HLA genes are found on the short arm of chromosome 6. Individuals inherit two sets of antigens, a paternal haplotype and a maternal haplotype. There are at least nine antigen groups: HLA-A, HLA-B, HLA-C, HLA-E, HLA-F, HLA-G, HLADR, HLA-DQ, and HLA-DP. 2 For marrow transplantation purposes, antigens are categorized into two classes. Class I comprises antigens (or loci) A and B. Class I antigens are found on the surface of most nucleated body cells and are readily detected on leukocytes. Class II comprises DR, DQ, and DP antigens. Class II antigens are less widely distributed in the body and are especially evident on B lymphocytes. The search for a matched donor involves comparing the HLA-A, B, and DR antigens, which are the most involved in developing a graft-versushost disease (GVHD) response. GVHD is the body's immune response whereby the newly transplanted marrow recognizes its host body as "foreign" or "not self" and attacks cells of the body.

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Serious GVHD in a marrow recipient can be a fatal disease. 1 Class I HLA-A and HLA-B antigens are numbered from 1 through 77. They are identified, or typed, serologically using a small blood sample. The type is determined using a typing tray containing known antisera.l'3 The newest typing used for class II HLA-DR antigens is not serological. It uses DNA technology to identify genes that specify antigens DR and DQ. Oligonucleotide probes are used to identify these genes. This is a very accurate typing method and, unlike serological typing that requires viable cells, can be performed from whole blood samples that have been frozen and stored. 4 The increased typing specificity obtained using DNA technology should allow identification of better matches between patients and available donors. The NMDP has begun a project to retype stored samples from past patient/recipient pairs using DNA technology. The degree of match will be correlated with the transplant results of those patients and analyzed.

Mixed Lymphocyte Culture (MLC) For a number of years the Mixed Lymphocyte Culture (MLC) test was considered important in determining class II antigen compatibility between the donor and recipient. The test involves mixing lymphocytes from the donor and recipient and culturing them together for 6 days. A strong reaction indicates differences in the HLA-D region antigens and clinically indicates higher risk for GVHD. The test has several weaknesses. It can be difficult to analyze or reproduce. It can also be impossible to interpret if the patient has an abnormal immune system, which may result from leukemia or its treatment.3 These weaknesses have caused many transplant centers to use additional compatibility tests to supplement serological HLA-A, HLA-B, and HLADR typing information. The NMDP no longer requires an MLC test but now requires confirmatory typing using DNA technology as an additional compatibility test between donor and recipient. ELIGIBILITY CRITERIA TO RECEIVE UNRELATED TRANSPLANT

The NMDP has established stringent eligibility criteria for the collection of marrow to ensure that

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a volunteer's marrow is put to the best possible use. The NMDP will not provide marrow from an unrelated donor who is less than a five out of six antigen match with the patient. NMDP standards are designed to protect a donor from risk when the possible benefit to the transplant recipient is remote. Each transplant center establishes its own criteria for the age and diagnosis of patients that will be transplanted and the degree of antigen match required between donor and patient. However, transplant centers that participate in the NMDP must meet certain requirements and qualifications. Centers must have performed at least 10 allogeneic transplants per year during the previous 24 months and at least 30 in the previous 5 years to be eligible for membership. Clinical criteria also are established for the transplant center medical director and transplant team; including a dedicated nursing unit for marrow transplantation. 5,6 PROCESS FOR A MATCHED UNRELATED DONOR BMT

The process of finding a compatible unrelated donor includes seven steps. The steps are designed to protect the health of both the volunteer donor and patient who will receive marrow. They are also designed to protect the confidentiality and interests of both individuals. Maintenance of strict confidentiality of donor and patient identity is required by the Transplant Amendments Act of 1990 and by NMDP Standards. 5 Thus, throughout the process, donors and patients are known to the NMDP only by identification number. The transplant center maintains the identity of the patient; the donor center maintains the identity of the volunteer donor. Because the process is so complex, the median length of time to find a donor through the NMDP is approximately 6 months. The following information describes each step in the process.

1. Preliminary Search Any physician can initiate a preliminary search of the NMDP Registry at no charge. The preliminary search of the computer registry results in a report that shows the number of donors on file in various match grade categories. The NMDP Registry computer algorithm ranks available donors against the patient's tissue type in order of best, or

most compatible, matches. The match grade report shows the number of volunteer donors who are defined by " 1 " or identical antigens to the patient, " 2 " or minor mismatches, " 3 " or major mismatches, and " 4 " or multiple mismatches.

2. Formal Search The second stage of a search can only be initiated by an NMDP-participating transplant center. A formal search is initiated when a transplant center requests further contact and testing of particular volunteer donors to determine additional tissue typing information. A number of transplant centers require evidence of insurance coverage for costs of an unrelated transplant or a financial deposit before initiating a formal search for a patient.

3. Identifying Best Available HLA-A, HLA-B, and HLA-DR Matched Donors If there are potential HLA-A, HLA-B, or HLADR matches, the first activation request of the formal search would be to contact those donors for confirmatory typing and, although no longer required by the NMDP, perhaps MLC testing. However, because NMDP standards allow an individual to be recruited into the Registry with only HLA-A and HLA-B antigen test results, about 80% of donors on file have been tested for only these antigens. Thus, the first request from a transplant center for donor activation is often to call back donors who match the A and B antigens and test them for the HLA-DR antigens to see if they match the patient. Sometimes there may be only a few HLA-A and HLA-B matches with unknown DR types, other times there may be over 100 matches. The NMDP coordinating center instructs donor centers via a computerized worksheet to contact donors selected by the transplant center to be HLA-DR tested. Some volunteer donors are no longer medically qualified to be donors. Such medical changes may be permanent or temporary--perhaps due to pregnancy. Some donors are no longer interested in being a volunteer donor. It is sometimes difficult for patients to realize that volunteer donors on the Registry may have numerous legitimate personal reasons for not being immediately available for further testing. Patients searching for a donor may require a great deal of emotional support during this time. Regular communication between the transplant center and the patient and family on the

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status of the search for a marrow donor is very helpful and keeps the lines of communication open. Cost may be a factor in this phase of the process because NMDP charges the transplant center a fee for each completed HLA-DR test ordered. If the patient's insurance company does not cover this cost, some transplant centers choose to order a limited number of DR tests at one time and wait for results before ordering more. The NMDP has an Office of Patient Advocacy (OPA) to directly assist patients, their families, and physicians in the search for an unrelated donor. Among its services, the OPA helps patients resolve insurance problems, informs transplant centers of serious complaints of patients concerning the center, and assists with suggestions for finding funding for expenses related to the search process that are not covered by the insurance carder.

4. Confirmatory Typing and Health History Guidelines Confirmatory typing. Once donors who are the best HLA-A, HLA-B, and HLA-DR matches are identified, the process of selecting the most compatible donor begins. Potential donors are contacted for an additional blood sample for HLA testing using DNA technology. These tests are performed at the transplant center, which has the responsibility of ensuring that the original typing tests were accurate. Health history guidelines. At the time of initial recruitment into the Program, volunteer donors are asked a number of screening questions to determine their health status and whether they are at increased risk for infectious diseases, problems with anesthesia or surgery, or diseases that could be passed to the patient if the marrow were transplanted. Table 1 lists reasons for donor deferral at time of recruitment. Because an individual's health status may have changed since the time of recruitment, another health history is taken at the time of the confirmatory typing test. Tests are conducted for infectious diseases to be sure that the potential donor does not have any disease that puts either the donor or recipient at risk. NMDP standards require that a panel of tests be completed: serological test for syphilis, hepatitis B surface antigen (HBsAg), antibody to hepatitis B core antigen, alanine aminotransferase, antibodies to the human immunode-

23 Table 1. Medical Reasons to Defer an Individual at Time of Donor Recruitment Increased Risk of Anesthetic or Procedural Complications Addison's disease

Cardiac problems History of uncontrolled convulsions Uncontrolled hypertension Insulin-dependent diabetes Malignant hypothermia Narcolepsy Nephrectomy Polycystic kidney disease Tuberculosis Multiple sclerosis Severe obesity Recurrent back pain Risk of Transmissible Disease to the Recipient Tattoos within last 12 months Thalessemia major Sickle cell anemia Systemic lupus erythematosus HIV Idiopathic thrombocytopenic pupura Hepatitis non-A Blood transfusion within last 12 months (risk of hepatitis) Venereal diseases treated within last 12 months Rheumatoid arthritis Abbreviation: HIV, human immunodeficiency virus.

ficiency viruses (anti-HIV-1, anti-HIV-2), antibody to the cytomegalovirus, antibody to the human T-cell lymphotropic virus, type I, and antibody to the hepatitis C virus. 5 Positive test results for the HBsAg and for antiHIV-1 and anti-HIV-2 result in permanent deferral of the donor from the Registry. Whether to use a donor with positive results for the other infectious disease tests is the decision of the transplant center physician.

5. Donor Work-Up After the transplant center selects one individual as the best donor, the donor center begins a thorough process to ensure that the person is medically acceptable, fully informed of the risks of the collection process, and committed to being a marrow donor. The process begins with an information session where the potential donor and significant other(s) meet with the medical director and coordinator of the donor center who explain the process of marrow collection and attendant risks. The donor is asked to think about the information overnight and, if still willing to be a donor, to complete an Intent to Donate Form. The donor is

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told that although he or she can decide at any time not to continue, such a decision after the patient has begun preparatory chemotherapy and radiation means the patient will probably die. After the donor has signed the consent form, the next step is a thorough physical examination to ensure that the donor is in the lowest anesthesia risk (class I) category and that the marrow collection will be safe for the donor. As an additional precaution, the NMDP Program Standards state that the donor should not receive allogeneic blood. Therefore, several weeks before the marrow collection, the donor donates one or more units of autologous blood to be received after the marrow collection to replace the loss of peripheral blood that occurs during the marrow collection. 5

6. Marrow Collection After the transplant center and donor center agree on a date for the marrow collection, arrangements are made to admit the donor to an NMDP collection center. The transplant center writes a prescription for the volume of marrow to be collected. The prescription is written to ideally obtain 2 x 108 nucleated cells/kg of the recipient's body weight. If the marrow will be manipulated for T-cell depletion at the transplant center, slightly more cells will be required. NMDP recommends that no more than 1,500 mL of marrow should be aspirated from the donor. Marrow collected is neither frozen nor stored to avoid potential loss of cells. The donor may be admitted to the hospital the evening before the procedure or on the morning of the procedure. The selected collection center will generally be the closest one available to the donor. The procedure usually lasts 45 minutes to 11/2 hours and does not differ from the same procedure for a related donor marrow collection. The donor generally receives 1 to 2 units of autologous blood after the procedure. The volume of marrow withdrawn must not be so great as to require the donor to receive an allogeneic blood transfusion. Because donors are generally healthy people, many may have experienced limited or no previous hospitalization. Nurses caring for donors can provide emotional support by thorough explanations of all procedures and reinforcement of the altruistic decision made by the individual to donate marrow. A multiple-center study of the NMDP's first 493 marrow donors showed that acute complications

related to the collection occurred in 5.9% of donors, but only one had a serious complication. Two days after the procedure, most donors described symptoms related to the procedure such as fatigue, pain at the marrow collection site, and about half had low back pain. The mean time for donors to feel that they were completely recovered was just under 16 days, with 10% reporting that it took 30 days for full recovery. The duration of the collection procedure was the factor most directly related to the degree of donor pain and fatigue. 7

7. Transplantation Arrangements are made in advance for a courier to pick up the marrow immediately after collection and to fly with it to the waiting patient's transplant center. It is usually carded in a hard container at room temperature unless coming from abroad, in which case an ice pack (not dry ice) may be placed under the marrow. The actual transplantation procedure is the same as for marrow from a related donor. Any additional processing, such as removal of T cells (for GVHD prevention) or red blood cells (for blood group system [ABO] incompatibility), is completed at the transplant center. The NMDP pays for all medical and transportation costs of the donor's marrow collection. In turn, the NMDP bills the transplant center a fee for the marrow collected. Assurance that the patient's insurance company will pay the collection cost is usually obtained in advance by the transplant center. OUTCOME OF MATCHED UNRELATED TRANSPLANTS

By February 1, 1993, over 1,600 unrelated transplants had occurred with unrelated donors from the NMDP. 1 Assessment of the outcome of unrelated transplants requires sufficient time between the transplant and analysis of outcome data. A multiple transplant center study of 462 patients transplanted in the first 4 years of NMDP's existence (December 1987 to November 1990) provides the best summary of results. 8 The 462 patients in this study had a variety of diagnoses (see Table 2) and received transplants at 28 marrow transplant centers in the United States. They received a variety of preparative regimens including total body irradiation and/or chemotherapy as de-

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Table 2. Patient Diagnoses and Percentages Receiving Marrow From the National Marrow Donor Program

Patient diagnosis I. Malignant diseases Chronic myelogenous leukemia Acute lymphoblastic leukemia Acute nonlymphocytic leukemia Biphenotypic leukemia Myelodysplastic syndrome Other malignancy II. Nonmalignant diseases Anemia Congenital disorders

(% Total) (84%) (42%) (18%) (15%) (1%) (7%) (1%) (16%) (9%) (7%)

Adapted with permission from The New England Journal of Medicine. s

termined by their disease. Of the 462 patients, 66% received marrow from a donor that was serologically matched for six HLA-A, HLA-B, and HLA-DR antigens. The marrow received by the patients was manipulated for various reasons in slightly over half of the cases. The most common reasons for marrow manipulation were for volume reduction, red cell depletion (for ABO incompatibility), and T-cell depletion (for GVHD prevention).

Engraftment of Marrow The probability of new marrow engraftment by 100 days after transplant was 94%. The median time to engraftment was 22 days with a range of 6 to 84 days. Although most patients achieved marrow engraftment, 8% had subsequent graft failure between days 25 and 263 after transplant. Use of T-cell depleted marrow was associated with a faster engraftment.

Survival Survival rates vary depending on the original disease and stage of the disease that necessitated the transplant. Forty percent of the patients with good-risk leukemia had a probability of diseasefree survival at 2 years. Good-risk leukemia is defined as acute leukemia in first or second complete remission or chronic myelogenous leukemia in first chronic phase. The 2-year disease-free survival for patients with poor-risk leukemia (acute leukemia in greater than second remission, relapse, or chronic myelogenous leukemia in accelerated or blastic phase) was approximately 19%. Receipt of T-cell depleted marrow was associated with a reduction in mortality rate of 60% during the first 50 days post-

transplant, but no difference in survival thereafter. Because only a small number of centers used T-cell depleted marrow and it may be associated with different transplant regimens, further study is needed in this area. Patients with myelodysplasia or aplastic anemia showed a poorer rate of survival. The probability of 2-year survival for patients with aplastic anemia or paroxysmal nocturnal hemoglobinuria was 29%. However, 4 of 10 patients with aplasia who survived 1 year after transplant continued to require transfusion support. For patients with congenital immunodeficiency or hematologic or metabolic disorders, the probability of survival at 2 years posttransplant was 52%. Because of the nature of these diseases, it was impossible to determine their disease-free status at the time of the study. COMPLICATIONS AND CAUSES OF DEATH

The complications and causes of death after unrelated marrow transplantation are the same as for related marrow transplantation. A brief summary of the most common complications and causes of death is presented next.

Graft Failure Although the vast majority of patients who received unrelated marrow transplants undergo engraftment, lack of engraftment or graft failure is usually a fatal complication. Therefore, second bone marrow transplants have been tried for a small number of patients. Of the seven patients who received a second marrow transplant from a NMDP donor, only one survived. This patient received an autologous transplant after the failure of two unrelated transplants. ~

GVHD GVHD is a major complication among patients who receive related and unrelated transplant. However, it is more frequent and severe among patients who receive transplants from unrelated donors. Even in six of six antigen matches, there will be minor histocompatibility differences between donor and recipient who are not related that will cause an increased rate of GVHD. The possibility of developing grade II to IV acute GVHD by day 100 posttransplant was 64%. Many of these patients developed severe grade HI/

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KATHLEEN WELTE

IV acute GVHD. Acute GVHD development was associated with receiving T-cell replete marrow and with increasing patient age. It was not associated with the level of HLA disparity between donor and recipient. Development of limited or extensive chronic GVHD 1 year after transplant showed a probability of 55% - 0.7%. Development of extensive chronic GVHD was associated with receiving T-cell replete marrow and diagnosis of chronic myelogenous leukemia (CML).

Relapse

Table 3. Primary and Secondary Causes of Death After Matched Unrelated Bone Marrow Transplantation in 307 Patients Percentof Deaths Infection Acute or chronic GVHD Interstitial pneumonia Chemoradiotherapy toxicity Recurrence of disease Hemorrhagic complication Graft failure Secondary malignancy Other

37% 33% 21% 14% 14% 15% 11% 1% 19%

Reprinted with permission from the New England Journal of Medicine, 1993.e

For all patients with leukemia, the probability of relapse was 0.19% --- 0.06%. The following factors increase the risk of relapse: (1) recipient more than 18 years of age; (2) acute leukemia; (3) donorrecipient HLA mismatch; (4) recipient who is positive for the cytomegalovirus antibody; and (5) use of T-cell replete marrow. Receiving T-cell depleted marrow appeared to delay the relapse rather than reduce the relapse rate overall. The low probability of relapse in these patients suggests that receiving an unrelated marrow transplant includes a significant graft-versus-leukemia effect. 8 Further study in this area is needed.

Causes of Death Recipients of unrelated transplants experienced an increased risk of infections and lymphoproliferative disorders similar to that of recipients of mismatched marrow from related donors. Infection or interstitial pneumonia contributed to 60% of patient deaths. The most common causes of death are listed in Table 3. CONCLUSIONS

For the 70% of patients who could benefit from a marrow transplant but do not have a suitable related donor, the donors available through the

NMDP offer an option. More research is needed to evaluate the differences in survival and to better anticipate and manage the complications inherent in unrelated transplantation. As more is learned about effective immunosuppression, transplants may be performed more frequently with five of six antigen matches, which means that many more patients would find a donor through the NMDP Registry. For marrow donors, the act of donation is described very positively. Based on the donors' knowledge after the procedure, 98% said that they would make the same decision to donate. Also, many donors report an increased sense of selfesteem after donation. 9 Gradually more will be learned about histocompatibility factors that are most important in successful matches between unrelated individuals. The NMDP is beginning work in this area using new laboratory technology. Much of the work of the NMDP today is designed to speed the relatively long time from initiation of a formal search for a donor to the transplant date. Shortening the time span to transplantation will increase the number of patients with acute diseases who can receive a transplant through the NMDP.

REFERENCES 1. Weinberg P: The human leukocyte antigen system (HLA), the search for a matching donor, National Marrow Donor Program development and marrow donor issues, in Whedon M (ed): Bone Marrow Transplant: Principles, Practice and Nursing Insights. Boston, MA, Jones & Bartlett, 1991, lap 105131 2. Sullivan KA, Amos DB: The HLA system and its detec-

tion, in Rose NR, Freedman H, Fahey JL (eds): Manual of Clinical Laboratory Immunology. Washington, DC, American Society of Microbiology, 1986, pp 835-846 3. Beatty PG, Mickelson EM, Petersdoff EW, et al: Histocompatibility 1991. Transfusion 11:1-10, 1991 4. Franklin-Barbajosa C: DNA profiling: The new science of identity. Natl Geograph 181:112-124, 1992

MATCHED UNRELATED TRANSPLANTS 5. NMDP: National Marrow Donor Program Standards (ed. 8). Minneapolis, MN, National Marrow Donor Program, 1993 6. Executive Committee of the World Marrow Donor Association: Special report: Bone marrow transplants using volunteer donors-recommendations and requirements for a standardized practice throughout the world. Bone Marrow Transplant 10:287-291, 1992 7. Stroncek DF, Holland PV, Bartsch G: Experiences of the

27 first 493 unrelated marrow donors in the national donor program. Blood 81:1940-1946, 1993 8. Keman NA, Bartsch G, Ash RC, et al: Analysis of 462 unrelated marrow transplants facilitated by The National Marrow Donor Program, N Engl J Med 328:593-602, 1993 9. Butterworth VA, Simmons RG, Bartsch G: Psychosocial effects of unrelated bone marrow donation: Experiences of the National Marrow Donor Program. Blood 81:1947-1959, 1993