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PubMed2006

Haplotype associations of 90 rare alleles from the National Marrow Donor Program.

The National Marrow Donor Program maintains an HLA database of over 4.1 million US adult volunteers, 43,000 cord blood units, and 111,000 patients from which we identified 1,999,424 samples having allele-level HLA-A, HLA-B, or HLA-DRB1 results. We analyzed 811 rare alleles reported at a frequency of less than 1 in 50,000 in this study pool and found strong predicted haplotype associations for 90 of them. The data set includes the number of times the allele was seen, the predicted haplotypes, and the racial or ethnic groups in which it was identified. This information can be helpful in designing search strategies for patients with rare alleles requiring hematopoietic stem cell therapy.

Alleles↗

PubMed1994

The U.S. National Marrow Donor Program.

PURPOSE: The National Marrow Donor Program (NMDP) of the United States has nearly 650,000 unrelated potential marrow donors in its registry and > 1,225 marrow transplants have been performed. PATIENT AND METHODS: In 1991, 43% of patients who requested a search found at least one HLA-A-, -B-, -DR-identical donor in the files. The chance of finding a donor match is much better within one's own ethnic group. The individuals enrolled in the donor file are 67.0% white, 3.8% black, 3.0% Asian, 3.9% Hispanic, and 0.8% Native American. Therefore, patients who belong to ethnic minorities are at an obvious disadvantage in obtaining marrow donors. Because of this deficiency, the program has embarked on an aggressive campaign of recruitment of minority donors. RESULTS: Reciprocal search agreements with other countries have made another 200,000 potential donors available, but it is not likely that black patients will find help by this route. CONCLUSIONS: Several efforts are being made to speed up the search process and to ensure more accurate definition of identities. These efforts include prospective HLA-DR typing of donors in the file, storage of a sample of frozen blood from each donor to permit class II typing (HLA-DR, -DQ) by DNA techniques, and eliminating the mixed lymphocyte culture test as a requirement for designating a given donor as HLA identical.

Bone Marrow Transplantation↗

PubMed2000

Maintaining updated DNA-based HLA assignments in the National Marrow Donor Program Bone Marrow Registry.

The National Marrow Donor Program (NMDP) has instituted an approach to address the impact of new alleles on the DNA-based HLA assignments obtained during volunteer donor typing. This approach was applied to the DRB typing results from 371,187 donors received from 14 laboratories in 1999. Samples were tested with a standardized set of sequence specific oligonucleotide reagents and the positive and negative hybridization results transmitted electronically to the NMDP. A software program interpreted the primary data into HLA assignments and rejected assignments which did not produce a result at the specified level of resolution. Comparison of the HLA assignments derived by the NMDP software to the assignments made by the laboratories using several local software prograins showed 90.5% of the assignments to be identical. Differences in assignments were explained by varying levels of typing resolution, variation in the inclusion of the second expressed DRB loci, disparity arising when alternative assignments were summarized, and failure to submit correct information. When the primary data collected in 1999 were interpreted into HLA assignments using the set of alleles defined in July 2000, 74% of the HLA-DRB assignments were altered by the description of new alleles, justifying the development of this software.

Base Sequence↗

PubMed1993

The National Marrow Donor Program.

As the number of successful marrow transplants has increased, the lack of HLA-identical sibling donors for 60 to 70 percent of transplant candidates has become a serious problem. Pilot studies established that marrow transplantation between phenotypically HLA-identical, unrelated individuals can be accomplished successfully. Therefore, the National Marrow Donor Program was established to develop a large file of volunteer marrow donors and to serve as a center for the coordination of the donor search and donor-recipient matching processes. By November 1991, 63 months after the program was established, 457,205 potential marrow donors typed for HLA-A and -B antigens had agreed to be listed in the marrow donor registry. A donor search had been initiated for 8481 patients. At least one potential donor matched for at least three of the four HLA-A and -B antigens was located for 99.8 percent of patients. Among the 3156 searches that were completed, 940 (29.8%) resulted in a transplant. The median time in which to locate a matched donor, complete all predonation evaluations, and obtain donor consent was 208 days. The most common diagnosis in patients who underwent transplantation was chronic myelogenous leukemia (42.0%). When this analysis was completed in November 1991, the National Marrow Donor Program was operating a national network of 99 donor centers and 53 transplant centers. The donor file was increasing rapidly, and a follow-up system was in place to determine the effects of donation on the donors and the outcome in the patients who underwent transplantation. This national network of donor and transplant centers exists and is now facilitating unrelated-donor marrow transplants. The National Marrow Donor Program made it possible to locate donors for many patients in need of a transplant and helped to determine the role of unrelated-donor marrow transplants in the treatment of many diseases.

Blood Component Removal↗

PubMed1997

HLA gene and haplotype frequencies in the North American population: the National Marrow Donor Program Donor Registry.

BACKGROUND: As of May 1, 1995, the National Marrow Donor Program had a donor registry consisting of over 1.35 million HLA-typed volunteers recruited from most major cities and states in the United States. This registry represents the largest single HLA-typed pool of normal individuals in the world. METHODS: We analyzed the HLA-A, -B, -DR locus phenotypes of the National Marrow Donor Program donors in order to estimate gene and haplotype frequencies for major racial groups of the United States: Caucasian American, Asian American, African American, Latin American, and Native American. The large size of the database allowed us to calculate the frequencies of relatively rare antigens and haplotypes with more accuracy than previous studies. RESULTS: We observed 89,522 distinguishable HLA-A, -B phenotypes in 1,351,260 HLA-A, -B-typed donors and 302,867 distinguishable HLA-A, -B, -DR phenotypes in 406,503 HLA-A, -B, -DR-typed donors. Gene and haplotype frequencies differed remarkably among the five racial groups, with African Americans and Asian Americans having a large number of haplotypes that were specific to their racial groups, whereas Caucasian Americans, Latin Americans, and Native Americans shared a number of common haplotypes. CONCLUSIONS: These data represent an important resource for investigators in the fields of transplantation and population genetics. The gene and haplotype frequencies can be used to aid clinicians in advising patients about the probability of finding a match within a specific ethnic group, or to determine donor recruitment goals and strategies. The information is also a valuable resource for individuals who are interested in population genetics, selection and evolution of polymorphic human genes, and HLA-disease association.

Chi-Square Distribution↗

PubMed1999

The National Marrow Donor Program: improving access to hematopoietic stem cell transplantation.

The National Marrow Donor Program has established a large and ethnically diverse registry of volunteer, unrelated stem cell donors. More than 9,000 patients world-wide have received transplants from NMDP donors. In recent years, substantial resources have been invested to increase that portion of the NMDP donor file with complete HLA-A, -B and -DR typing. While this effort has improved the likelihood of patients identifying a suitable matched unrelated donor, it has also focussed more attention on issues surrounding donor availability. Several initiatives underway or planned are intended to improve donor availability and increase the overall success of the unrelated donor stem cell transplantation.

Bone Marrow Transplantation↗

PubMed1993

Experiences of the first 493 unrelated marrow donors in the National Marrow Donor Program.

More than 410,000 people participated in the National Marrow Donor Program (NMDP) as of October 1, 1991, and more than 850 volunteers had donated marrow. While the incidence of serious morbidity as a result of bone marrow donation is rare, the incidence of lesser complications and the long-term consequences of marrow donation are not known. To determine the incidence of donor complications and measure the recovery time of volunteer, unrelated marrow donors, we analyzed the results of surveys of the first 493 persons who donated marrow through the NMDP. The marrows were collected at 42 centers. The median age of the donors was 37.9 years (range 19.1 to 55.6 years). The median volume of marrow collected was 1,050 mL (range 180 to 2,983 mL). Autologous red blood cells were transfused to 89.8% (439) of donors but only 0.6% (3) of donors received allogeneic blood. Acute complications related to the collection procedure occurred in 5.9% of donors; but a serious complication, apnea during anesthesia, occurred in only one donor. When donors were questioned approximately 2 days following discharge from their hospitalization, most donors described symptoms related to the collection; 74.8% experienced tiredness, 67.8% experienced pain at the marrow collection site, and 51.6% of the donors experienced low back pain. Donors were surveyed repeatedly until they felt that they had recovered completely. Mean recovery time was 15.8 days; however, 42 (10%) donors felt that it took them > or = 30 days to recover fully. The duration of the marrow collection procedure and duration of anesthesia both positively correlated with donor pain and/or fatigue following the collection; but the duration of the collection procedure had the highest correlation with post-collection pain and fatigue. The volume of marrow collected per unit of donor weight was more weakly correlated with donor pain and/or fatigue than the anesthesia and collection times. When multivariate analysis was used to analyze the correlation between donor recovery time and these variables, only the duration of the collection was found to correlate significantly with donor recovery time (P = .001). This analysis demonstrates that marrow donation is well tolerated with few complications. To decrease further the incidence of donor discomfort and recovery time following donation, the duration of the collection procedure, and probably the duration of anesthesia, and the volume of marrow collected, should be kept to a minimum.

Adult↗

PubMed2001

The National Marrow Donor Program. Meeting the needs of the medically underserved.

BACKGROUND: The National Marrow Donor Program operates the world's largest registry of volunteer unrelated stem cell donors. In recent years, the program has focused on building a large and diverse donor file. After initial recruitment, however, months or years may elapse before a potential donor is contacted on behalf of a searching patient. Here, the author begins to explore factors that influence donor availability at the confirmatory typing stage of the search process. METHODS: Over a 1-year period from March 1, 1999 through February 29, 2000, the author evaluated donor unavailability rates at the confirmatory typing stage of the search process. Unavailability rates by donor racial/ethnic group and by donor center were evaluated. To determine the consistency within individual donor centers, the author compared donor unavailability during the first 6 months of the observation period with unavailability during the second 6 months. RESULTS: Donor unavailability at confirmatory typing was higher among donors registered with domestic (U.S.) donor centers. The self-identified racial or ethnic group of the donor also affected the likelihood the donor will be available when requested. Between individual donor centers, there were large differences in the overall donor unavailability. Rates of donor unavailability tended to remain consistent at individual centers over time. CONCLUSIONS: This study suggests that procedures used at individual donor centers may dramatically impact donor unavailability. Future initiatives should undertake to identify best practice models for donor recruitment, retention, and subsequent contacts.

Bone Marrow Transplantation↗

PubMedDate not supplied

Recruiting unrelated donors for the National Marrow Donor Program.

Medical advances have made bone marrow transplantation the treatment of choice for certain hematologic diseases. For those patients eligible for a marrow transplant only about 30 percent find an HLA-compatible match within their families. Studies indicate that unrelated volunteers are willing to donate their marrow. The National Marrow Donor Program was formed in 1986 as a result of a federal contract. This group is a network of donor centers, transplant centers, and collection centers. The Connecticut Red Cross Blood Services is one of approximately 70 donor centers. Recruitment methods vary with each donor center, depending on the resources available. The Connecticut Red Cross Blood Services has recruited more than 1,000 volunteers for entry into the National Marrow Donor Program.

Bone Marrow Transplantation↗

PubMed1997

Unrelated bone marrow transplantation from the National Marrow Donor Program.

Between November 1992 and December 1996, we carried out bone marrow transplantation through the National Marrow Donor Program (NMDP) for 11 patients who lacked an appropriate donor among their family members and the Japan Marrow Donor Program (JMDP). They accounted for 11% of 101 patients who had registrated to the NMDP Transplant Center Office in Japan. The median time required from the initiation of preliminary search to transplant for these 11 patients was 198 days. The 11 donors included four Caucasians, one Native American and the others were Asian/Pacific islanders. A median of 17 h was required to transport bone marrow from harvest institutes to our hospital and their viability determined in our laboratory had a median of 96%. Engraftment was observed in all recipients and the incidence of grade III-IV acute graft-versus host disease was 27%. Of four patients three (75%) with chronic myelogenous leukemia in chronic phase (standard-risk) and two (29%) of seven patients in progressive state of the disease (high-risk), are alive at present. Cooperation between the JMDP and the NMDP, which began in April 1997, could shorten the time for donor search and allow transplantation to more patients with more appropriate timing.

Adolescent↗

PubMed1993

Analysis of 462 transplantations from unrelated donors facilitated by the National Marrow Donor Program.

BACKGROUND AND METHODS: Allogeneic bone marrow transplantation is curative in a substantial number of patients with hematologic cancers, marrow-failure disorders, immunodeficiency syndromes, and certain metabolic diseases. Unfortunately, only 25 to 30 percent of potential recipients have HLA-identical siblings who can act as donors. In 1986 the National Marrow Donor Program was created in the United States to facilitate the finding and procurement of suitable marrow from unrelated donors for patients lacking related donors. RESULTS: During the first four years of the program, 462 patients with acquired and congenital lymphohematopoietic disorders or metabolic diseases received marrow transplants from unrelated donors. The probability of engraftment by 100 days after transplantation was 94 percent, although 8 percent of patients later had secondary graft failure. The probability of grade II, III, or IV acute graft-versus-host disease was 64 percent, and the probability of chronic graft-versus-host disease at one year was 55 percent. The rate of disease-free survival at two years among patients with leukemia and good prognostic factors was 40 percent and among patients at higher risk, 19 percent. Twenty-nine percent of the patients with aplastic anemia were alive at two years, and the rate of two-year disease-free survival among patients with myelodysplasia was 18 percent. For patients with congenital immunologic or nonimmunologic disorders, the probability of survival was 52 percent. CONCLUSIONS: The National Marrow Donor Program has benefited a substantial number of patients in need of marrow transplants from closely HLA-matched unrelated donors and has facilitated the recruitment of unrelated donors into the donor pool and the access to suitable marrow.

Adolescent↗

PubMed1993

Psychosocial effects of unrelated bone marrow donation: experiences of the National Marrow Donor Program.

In this study, we investigated the psychosocial effects of unrelated marrow donation. Survey questionnaires were administered pre-donation, shortly post-donation, and 1 year post-donation to all donors through the National Marrow Donor Program over a 3-year period. Univariate, bivariate, and multivariate analyses were then performed. Donors were generally quite positive about the donation 1 year post-donation: 87% felt it was "very worthwhile" and 91% would be willing to donate again in the future. Marrow donors were more likely than kidney donors to feel better about themselves as a result of the donation (P < .001). Donors with longer collection times, in general, had less positive psychosocial outcomes from the donation. Donors who experienced lower back pain or difficulty walking as a result of the donation were more likely to experience the donation as more stressful and painful than expected, but no more likely to experience it as less positive emotionally than donors who did not experience these side effects.

Anesthesia↗

PubMed2000

Engraftment and survival after unrelated-donor bone marrow transplantation: a report from the national marrow donor program.

We analyzed engraftment of unrelated-donor (URD) bone marrow in 5246 patients who received transplants facilitated by the National Marrow Donor Program between August 1991 and June 1999. Among patients surviving at least 28 days, 4% had primary graft failure (failure to achieve an absolute neutrophil count > 5 x 10(8)/L before death or second stem-cell infusion). Multivariate logistic regression analysis showed that engraftment was associated with marrow matched at HLA-A, HLA-B, and DRB1; higher cell dose; younger recipient; male recipient; and recipient from a non-African American ethnic group. More rapid myeloid engraftment was associated with marrow serologically matched at HLA-A and HLA-B, DRB1 match, higher cell dose (in non-T-cell-depleted cases), younger recipient, recipient seronegativity for cytomegalovirus (CMV), male donor, no methotrexate for graft-versus-host disease prophylaxis, and transplantation done in more recent years. A platelet count higher than 50 x 10(9)/L was achieved by 47% of patients by day 100. Conditional on survival to day 100, survival at 3 years was 61% in those with platelet engraftment at day 30, 58% in those with engraftment between day 30 and day 100, and 33% in those without engraftment at day 100 (P <.0001). Factors favoring platelet engraftment were higher cell dose, DRB1 allele match, recipient seronegativity for CMV, HLA-A and HLA-B serologically matched donor, and male donor. Secondary graft failure occurred in 10% of patients achieving initial engraftment, and 18% of those patients are alive. These data demonstrate that quality of engraftment is an important predictor of survival after URD bone marrow transplantation.

Adolescent↗

PubMed1994

Unrelated-donor marrow transplants: the experience of the National Marrow Donor Program.

As of December 1994, more than 3,000 marrow transplants had been accomplished using unrelated donors provided by the National Marrow Donor Program. With more than 1.5 million donors listed in the registry, over 60% of patients now find an HLA-A,B,DR phenotypic match at the initial search. The HLA types of these patients are biased toward the common Caucasian haplotypes, but the likelihood of identifying donors for non-Caucasian patients has improved with time. Analysis of the first 462 transplants showed disease-free survival (DFS) at 2 years to be approximately 40% in good-risk patients and 20% in poor-risk patients. Chronic myelogenous leukemia transplanted within the first year after diagnosis had 45% DFS. Some recent reports from individual transplant centers demonstrate results closer to those obtained with sibling donors, while a limited retrospective comparison suggests that unrelated-donor transplants are at least equivalent to and probably better than autologous transplants. A single HLA mismatch at A, B, or DR can be tolerated, but results are better with phenotypic identity. The most recent NMDP analysis has also identified younger donors and male donors as favorable variables in evaluating one-year survival of unrelated-marrow recipients.

Adolescent↗

PubMed1993

The MLC assay as a test for HLA-D region compatibility between patients and unrelated donors: results of a national marrow donor program involving multiple centers.

Mixed lymphocyte culture (MLC) assays from 763 patients and prospective unrelated marrow transplant donors identified through the National Marrow Donor Program (NMDP) were analyzed for their overall utility in measuring HLA-D region compatibility. The assays were performed at 31 different transplant centers (range, 1 to 197; median, 9 assays per center). A total of 325/763 (42.6%) of the tests were judged to be uninterpretable, either due to lack of sufficient control cells included in the assay (89 tests) or to insufficient reactivity by patient and/or donor cells (236 tests). Among the 438 tests that could be interpreted, HLA-Dw phenotyping with HLA-D homozygous cells was performed for a subset of 190. The relative response (RR) values from these 190 tests, however, were not clearly separable into distinct populations; i.e., RR values corresponding to Dw identity versus nonidentity between patient and donor could not be reliably discriminated. The predictive value of a nonreactive MLC for Dw identity was calculated to be 0.91 for RRs of < or = 20%, while the predictive value of a reactive MLC for Dw nonidentity was 0.35 for RRs of > 20%. These results, based on an analysis of data submitted from multiple transplant centers testing patients who had a variety of hematologic disorders, suggest that the MLC assay is a relatively imprecise method for determining HLA-D region compatibility between patient and prospective unrelated marrow donor.

Bone Marrow Transplantation↗

PubMed2002

Unrelated donor marrow transplantation for myelodysplastic syndromes: outcome analysis in 510 transplants facilitated by the National Marrow Donor Program.

Between April 1988 and July 1998, 510 patients with myelodysplastic syndromes (MDS) underwent unrelated donor bone marrow transplantation (BMT) facilitated by the National Marrow Donor Program. Median age was 38 years (range, <1-62 years). Several conditioning regimens and graft-versus-host disease (GVHD) prophylaxis methods were used, and T-cell depletion was used in 121 patients. Donors were serologically matched for HLA-A, -B, and -DRB1 antigens for 74% of patients. Of 437 patients evaluable for engraftment, 24 (5% cumulative incidence, with 95% confidence interval [CI] of 3%-7%) failed to engraft, and an additional 33 (8% cumulative incidence; 95% CI, 6%-10%) had late graft failure. Grades II to IV GVHD developed in 47% of patients (95% CI, 43%-49%), and limited and extensive chronic GVHD developed at 2 years in 27% (95% CI, 24%-30%). The incidence of relapse at 2 years was 14% (95% CI, 11%-17%). Greater relapse was independently associated with advanced MDS subtype and no acute GVHD. The estimated probability of disease-free survival (DFS) at 2 years was 29% (95% CI, 25%-33%). Improved DFS was independently associated with less advanced MDS subtype, higher cell dose, recipient cytomegalovirus (CMV) seronegativity, shorter interval from diagnosis to transplantation, and transplantation in recent years. Common causes of death were treatment-related complications accounting for 82% of fatalities. The 2-year cumulative incidence of treatment-related mortality (TRM) was 54% (95% CI, 53%-61%). Sixty-nine percent of TRM occurred within the first 100 days, and 93% occurred within the first year of transplantation. Higher TRM was independently associated with older recipient and donor age, HLA mismatch, and recipient CMV seropositivity. This study demonstrates that unrelated donor BMT cures a significant proportion of patients with MDS. TRM is the major problem limiting the success of unrelated donor BMT in MDS. The observations made in this study should facilitate the design of prospective trials aimed at improving the results of unrelated donor stem cell transplantation for MDS.

Adolescent↗

PubMed1993

Unrelated donor marrow transplantation therapy for chronic myelogenous leukemia: initial experience of the National Marrow Donor Program.

In the interval from December 1987 to November 1990, 196 consecutive patients with chronic myelogenous leukemia (CML) received unrelated donor marrow transplantation using marrow procured by the National Marrow Donor Program (NMDP) at 21 NMDP-affiliated marrow transplant centers. Baseline donor and recipient data as well as follow-up data were obtained systematically in all cases by the NMDP. The median interval from the initiation of a search for an unrelated donor to bone marrow transplantation was 8.4 months (range, 1.7 to 34.6 months). Median age of the recipients was 33.3 years (4.5 to 54.5 years). Seventy-five recipients were female and 121 were male. At time of transplant, 115 patients were in chronic phase, 51 in accelerated phase, 14 in blast crisis, and 16 in a second or subsequent chronic phase. In 133 cases, donors and recipients were identical at the HLA A, B, and DR loci using standard serologic typing, and in 63 cases, there was nonidentity at one HLA locus. Patients were prepared for transplantation with a combination of high-dose chemotherapy and total body irradiation (N = 169) or with high-dose chemotherapy only (N = 27). Thirty-five patients received marrow depleted ex vivo of T lymphocytes, whereas 161 patients received non-T-depleted marrow. One hundred seventy-four of 196 patients engrafted (absolute neutrophil count > or = 500/mm3 for 3 consecutive days). The median time to engraftment was 22 days (6 to 69 days). Twenty-two patients failed to engraft, and an additional 10 patients experienced late graft failure. The incidence of grades III or IV acute graft-versus-host disease (GVHD) was 0.54 +/- 0.10, and that of extensive chronic GVHD was 0.52 +/- 0.12. A lower incidence of both grades III and IV acute GVHD (P = .0003) and of extensive chronic GVHD (P = .01) were independently associated with use of T-depleted marrow. The actuarial incidence of hematologic relapse at 2 years is 0.11 +/- 0.06. The 2-year actuarial incidence of disease-free survival for patients transplanted in first chronic phase within 1 year of diagnosis is 0.45 +/- 0.21, in chronic phase more than 1 year from diagnosis is 0.36 +/- 0.11, in accelerated phase is 0.27 +/- 0.12, in second or subsequent chronic phase is 0.22 +/- 0.21, and in blast crisis is 0. Fifteen of 55 patients transplanted at 40 to 50 years of age survive.(ABSTRACT TRUNCATED AT 400 WORDS)

Acute Disease↗

PubMed2000

Unrelated donor marrow transplantation for chronic myelogenous leukemia: 9 years' experience of the national marrow donor program.

Over a period of 8.5 years (February 1988 to October 1996), 1423 patients with chronic myelogenous leukemia (CML) underwent unrelated donor (URD) bone marrow transplants (BMTs) facilitated by the National Marrow Donor Program (NMDP) at 85 transplant centers. One hundred thirty-seven evaluable (9.9%) patients failed to engraft, and an additional 83 (6.6%) evaluable patients experienced late graft failure. Grade III/IV acute graft-versus-host disease (GVHD) developed in 33% of patients (95% confidence interval [CI], 30%-36%). The incidence of extensive chronic GVHD was 60% (95% CI, 56%-63%) at 2 years. Only 5.7% of patients (95% CI, 3.6%-7.8%) transplanted in chronic phase developed hematologic relapse at 3 years. Several factors were independently associated with improved disease-free survival (DFS), including transplant in chronic phase, transplant within 1 year of diagnosis, younger recipient age, a cytomegalovirus seronegative recipient, and development of no or mild acute GVHD. The combined effect of these factors on outcome is manifest in a subset (n = 157) of young (less than 35 years), chronic phase patients transplanted within 1 year of diagnosis using HLA-matched donors who had 63% (95% CI, 53%-73%) DFS at 3 years. URD BMT therapy for CML is both feasible and effective with more frequent and more rapid identification of suitable donors. Early URD transplant during chronic phase yields good results and should be considered in CML patients otherwise eligible for transplant but without a suitable related donor.

Age Factors↗