R.J. Hartzman

HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry.

BACKGROUND Hematopoietic stem-cell transplantation (HSCT) is a potentially lifesaving therapy for several blood cancers and other diseases. For patients without a suitable related HLA-matched donor, unrelated-donor registries of adult volunteers and banked umbilical cord-blood units, such as the Be the Match Registry operated by the National Marrow Donor Program (NMDP), provide potential sources of donors. Our goal in the present study was to measure the likelihood of finding a suitable donor in the U.S. registry. METHODS Using human HLA data from the NMDP donor and cord-blood-unit registry, we built population-based genetic models for 21 U.S. racial and ethnic groups to predict the likelihood of identifying a suitable donor (either an adult donor or a cord-blood unit) for patients in each group. The models incorporated the degree of HLA matching, adult-donor availability (i.e., ability to donate), and cord-blood-unit cell dose. RESULTS Our models indicated that most candidates for HSCT will have a suitable (HLA-matched or minimally mismatched) adult donor. However, many patients will not have an optimal adult donor--that is, a donor who is matched at high resolution at HLA-A, HLA-B, HLA-C, and HLA-DRB1. The likelihood of finding an optimal donor varies among racial and ethnic groups, with the highest probability among whites of European descent, at 75%, and the lowest probability among blacks of South or Central American descent, at 16%. Likelihoods for other groups are intermediate. Few patients will have an optimal cord-blood unit--that is, one matched at the antigen level at HLA-A and HLA-B and matched at high resolution at HLA-DRB1. However, cord-blood units mismatched at one or two HLA loci are available for almost all patients younger than 20 years of age and for more than 80% of patients 20 years of age or older, regardless of racial and ethnic background. CONCLUSIONS Most patients likely to benefit from HSCT will have a donor. Public investment in donor recruitment and cord-blood banks has expanded access to HSCT. (Funded by the Office of Naval Research, Department of the Navy, and the Health Resources and Services Administration, Department of Health and Human Services.).

Assessment of optimal size and composition of the U.S. National Registry of hematopoietic stem cell donors.

Background. The National Marrow Donor Program (NMDP) receives federal funding to operate a registry of over 4 million volunteer donors for patients in need of a hematopoietic stem cell transplant. Because minority patients are less likely to find a suitably matched donor than whites, special efforts have been aimed toward recruitment of minorities. Significant financial resources are required to recruit and tissue type additional volunteer donors. Methods. Population genetics models have been constructed to project likelihoods of finding a human leukocyte antigen (HLA)-matched donor for patients of various racial/ethnic groups. These projections have been made under a variety of strategies for expansion of the NMDP Registry. Cost-effectiveness calculations incorporated donor unavailability and other barriers to transplantation. Results. At current recruitment rates, the probability of an available HLA-A,B,DRB1 matched donor is projected to increase from 27% to 34%; 45% to 54%; 75% to 79%; and 48% to 55%, for blacks, Asians/Pacific Islanders, whites and Hispanics, respectively, by the year 2007. Substantial increases in minority recruitment would have only modest impacts on these projections. These projections are heavily affected by donor availability rates, which are less than 50% for minority volunteers. Conclusions. Continued recruitment of additional volunteers can improve the likelihood of finding an HLA-matched donor, but will still leave significant numbers of patients of all racial/ethnic groups without a match. Efforts to improve donor availability (especially among minorities) and to increase the number of patients with access to the NMDP Registry may prove to be more cost-effective means of increasing transplants.

Frequencies of HLA-A2 alleles in five U.S. population groups: Predominance of A∗02011 and identification of HLA-A∗0231

Direct DNA sequencing was used to determine the frequency of alleles within the HLA-A2 family in five US population groups. The most frequently detected HLA-A2 allele in all groups was HLA-A*02011. Caucasian and Native American populations appear to be the most homogeneous exhibiting 95.7% and 94.3% A*02011, respectively. Hispanic and Asian/Pacific Islander populations were the most allelicly diverse populations with 9 and 7 different HLA-A2 alleles present, respectively, but the majority of the populations were HLA-A*02011. African-Americans were also diverse, not in the number of alleles seen, but in the percentage of non-A*02011 alleles in the population. HLA-A*0202 (25.8%) and A*0205 (12.9%) were present in a large percentage of African-Americans. Only 13 of the 31 known HLA-A2 alleles were observed in the study. The allelic distributions reflected statistically significant differences among population groups.

The National Marrow Donor Program 20 Years of Unrelated Donor Hematopoietic Cell Transplantation

In the 20 years since the National Marrow Donor Program (NMDP) facilitated the first unrelated donor transplant, the organization has grown to include almost 7 million donors, and has facilitated over 30,000 transplants on 6 continents. This remarkable accomplishment has been facilitated by the efforts of over 600 employees, and an extensive international network including 171 transplant centers, 73 donor centers, 24 cord blood banks, 97 bone marrow collection centers, 91 apheresis centers, 26 HLA typing laboratories, and 26 Cooperative Registries. In this article, we review the history of the NMDP, and cite the major trends in patient demographics, graft sources, and conditioning regimens over the last 20 years.

The effect of donor characteristics on survival after unrelated donor transplantation for hematologic malignancy

There are >24 million registered adult donors, and the numbers of unrelated donor transplantations are increasing. The optimal strategy for prioritizing among comparably HLA-matched potential donors has not been established. Therefore, the objective of the current analyses was to study the association between donor characteristics (age, sex, parity, cytomegalovirus serostatus, HLA match, and blood group ABO match) and survival after transplantation for hematologic malignancy. The association of donor characteristics with transplantation outcomes was examined using either logistic or Cox regression models, adjusting for patient disease and transplantation characteristics associated with outcomes in 2 independent datasets: 1988 to 2006 (N = 6349; training cohort) and 2007 to 2011 (N = 4690; validation cohort). All donor-recipient pairs had allele-level HLA typing at HLA-A, -B, -C, and -DRB1, which is the current standard for selecting donors. Adjusting for patient disease and transplantation characteristics, survival was better after transplantation of grafts from young donors (aged 18-32 years) who were HLA matched to recipients (P < .001). These findings were validated for transplantations that occurred between 2007 and 2011. For every 10-year increment in donor age, there is a 5.5% increase in the hazard ratio for overall mortality. Increasing HLA disparity was also associated with worsening survival. Donor age and donor-recipient HLA match are important when selecting adult unrelated donors. Other donor characteristics such as sex, parity, and cytomegalovirus serostatus were not associated with survival. The effect of ABO matching on survival is modest and must be studied further before definitive recommendations can be offered.

Relative HLA-DRB1∗13 allele frequencies and DRB3 associations of unrelated individuals from five US populations

The frequencies of 30 HLA-DRB1*13 alleles and 15 DRB3 alleles were determined for the 5 major U.S. ethnic populations: Caucasians, African Americans, Asian/Pacific Islanders, Hispanics, and Native Americans. A random sampling (163) of DRB1*13-positive individuals from each self-described ethnic group was selected out of a pool of 82,979 unrelated individuals, providing at least an 80% probability of detecting a rare allele that occurred at 1%. These 815 samples were subjected to allele-level SSOP typing and/or DNA sequencing which identified 11 different DRB1*13 alleles. DRB1*1301 and DRB1*1302 were the most common alleles seen in the five major ethnic groups while DRB1*1304 was not detected among Caucasians and DRB1*1305 was not detected among African Americans. DRB1*13 allele diversity was surprisingly more limited among African Americans compared to both Caucasians and Asian/Pacific Islanders. To determine the extent of DRB1*13-DRB3 associations, 504 of these samples expressing only one DRB3-associated DRB1 allele were subjected to PCR-SSOP typing and 14 DRB1*13-DRB3 haplotypes were detected. The distribution revealed that African Americans were significantly different from Caucasians, Asian/Pacific Islanders, and Hispanics. Allele frequency studies such as this further support previous findings that the distribution of HLA types can differ significantly among different ethnic populations.

Significant Improvement in Survival after Unrelated Donor Hematopoietic Cell Transplantation in the Recent Era

Patients and physicians may defer unrelated donor hematopoietic cell transplantation (HCT) as curative therapy because of the mortality risk associated with the procedure. Therefore, it is important for physicians to know the current outcomes data when counseling potential candidates. To provide this information, we evaluated 15,059 unrelated donor hematopoietic cell transplant recipients between 2000 and 2009. We compared outcomes before and after 2005 for 4 cohorts: age <18 years with malignant diseases (n = 1920), ages 18 to 59 years with malignant diseases (n = 9575), ages ≥ 60 years with malignant diseases (n = 2194), and nonmalignant diseases (n = 1370). Three-year overall survival in 2005 to 2009 was significantly better in all 4 cohorts (<18 years: 55% versus 45%, 18 to 59 years: 42% versus 35%, ≥ 60 years: 35% versus 25%, nonmalignant diseases: 69% versus 60%; P < .001 for all comparisons). Multivariate analyses in leukemia patients receiving HLA 7/8 to 8/8-matched transplants showed significant reduction in overall and nonrelapse mortality in the first year after HCT among patients who underwent transplantation in 2005 to 2009; however, risks for relapse did not change over time. Significant survival improvements after unrelated donor HCT have occurred over the recent decade and can be partly explained by better patient selection (eg, HCT earlier in the disease course and lower disease risk), improved donor selection (eg, more precise allele-level matched unrelated donors) and changes in transplantation practices.

DRB1*14 diversity and DRB3 associations in four major population groups in the United States

At least 59 DRB1*14 positive individuals from each of four U.S. population groups, Caucasoids, African Americans, Asians/Pacific Islanders, and Hispanics, were randomly selected from a database of 82,979 individuals. DRB1*14 alleles were identified by DNA sequence analysis using intron-specific primers to obtain complete exon 2 sequences. Only 23% of the known DRB1*14 alleles were detected. DRB1*14011 was the predominant DRB1*14 allele in three populations while Hispanics carried DRB1*1402 and DRB1*1406 more frequently. Asians/Pacific Islanders were the most diversified carrying seven alleles. DRB3*0101, DRB3*02021 and DRB3*0210 were detected in a subset of individuals typed for this locus and 15 DRB1-DRB3 haplotypes were defined. This study completes the exon 2 sequences of previously identified alleles, DRB1*1405-*1408, including the identification of two silent codon 90 variants of DRB1*1407. In addition, two new DRB1*14 alleles, DRB1*1441 and DRB1*1442, are described.

DRB1*03 diversity and DRB3 associations in five major population groups in the United States.

One hundred sixty-one DRB1*03 positive individuals from each of five U.S. population groups (Caucasoids, African Americans, Asians/Pacific Islanders, Hispanics, and Native Americans) were randomly selected from a database of 82,979 individuals. DRB1*03 alleles were identified by polymerase chain reaction-sequence-specific oligonucleotide probe typing. A total of six DRB1*03 alleles out of 21 known alleles were detected. DRB1*03011 was the predominant DRB1*03 allele in all populations. Caucasoids were found to be the least diversified; only DRB1*03011 was observed. African Americans carried DRB1*03021 at a high frequency. This allele was observed in three other populations. DRB1*0304 was found in Asians/Pacific Islanders and DRB1*0305, DRB1*0307 and a new allele, DRB1*0316, was found in Hispanics. A subset of individuals was also typed for DRB3 alleles. DRB3*0101, DRB3*0202, and DRB3*0301 were detected and seven DRB1-DRB3 haplotypes were defined. Testing of other individuals not included in the DRB1*03 frequency study identified a variation of a common extended haplotype, A1, B8, DR3, which carries DRB1*0304 and two previously unreported DRB1*03 alleles, DRB1*0311 and *0320, are also described.

Donation Activities and Product Integrity in Unrelated Donor Allogeneic Hematopoietic Transplantation: Experience of the National Marrow Donor Program

Despite many clinical advances in allogeneic hematopoietic cell transplantation (HCT), the one factor that is consistently required to apply HCT to a wide variety of diseases is the successful donation and the safe transport and administration of viable donor cells to the HCT recipient. Since 1987, the National Marrow Donor Program (NMDP) has maintained a registry of volunteer HCT donors for those patients who lack a suitable related donor, facilitated the donor search, and managed the collection and transportation of donor cells to transplant centers for use in increasingly complex therapies. The NMDP has collected data on marrow and peripheral blood stem cell (PBSC) donations as well as additional donations of lymphocytes, whole blood, or platelets. These additional donations are provided for a variety of reasons, including treating post-transplant complications such as graft failure or relapsed disease, supporting immune reconstitution or providing transfusion support. For donor safety, rates of placement of central venous catheters for collecting PBSC are monitored. Data have also been collected on rare events that may affect the integrity of the HCT product (e.g., graft clotting or leaks from the transport bag). Quality assurance and review of these donation processes is an essential component of the transplantation approach. Data from the broad NMDP experience further illuminate factors surrounding the donation process and product integrity.