Abstract
Identification of an HLA identical donor/recipient pair using high-resolution techniques at HLA A, B, C and DRB1 optimizes survival after adult unrelated hematopoetic stem cell transplant. It has been estimated that roughly 50% of African-Americans have suitable unrelated donors based on serologic typing, but there is little information on the likelihood of identifying an HLA-identical unrelated donor using molecular techniques. From 2/2002 to 5/2007, we performed 51 unrelated donor searches for African-American patients using the National Marrow Donor Program® and found HLA identical unrelated donors for only three. By contrast, 50 (98%) had at least one and often multiple appropriately matched cord blood units available. Very few African-American recipients have HLA-identical unrelated donors. In order to allow more African-American patients to proceed to transplant, innovative donor strategies, including adult cord blood transplantation, haplo-identical transplant or the identification of permissive mismatches should be investigated.
INTRODUCTION
For many hematologic disorders, allogeneic hematopoetic stem cell transplant represents the best chance for long-term survival. Only 25 to 30% of patients have HLA-identical sibling donors, (1) and the likelihood is even lower for patients of African-American descent.(2) Therefore, the majority of patients require an alternative donor source, usually from an unrelated adult or cord blood donor. For more than 20 years the National Marrow Donor Program® (NMDP) has been recruiting volunteer donors for patients without an HLA identical sibling.( 1;3) The identification of a donor matched at HLA-A, B, C, and DRB1 is important for the success of adult unrelated donor transplantation, since each HLA mismatch decreases overall survival by nearly 10% in patients with early stage disease.(4) Even after adjusting for HLA-mismatch at the major HLA loci, African-Americans have a 50% increased risk of death after hematopoetic stem cell transplantation.(4) This heightens the importance of finding a match at all 8 loci by high-resolution HLA typing.
There are approximately 510,000 registered African-American adult donors within the NMDP registry, compared to more than 5 million Caucasians.(3) African-Americans also have a high degree of polymorphism with respect to the major HLA loci compared to other populations.(5;6) Although it is thought that suitable donors can be identified for 50% of African-Americans, such estimates are based on serologic typing.(7) In this study, we sought to establish the likelihood of identifying an HLA-identical 8/8 unrelated donor, as well as alternative donor sources, including single antigen or allele mismatched unrelated donors and umbilical cord blood units in African-American patients treated at the University of Chicago.
MATERIALS and METHODS
From 2/2002 to 5/2007, the University of Chicago, an NMDP approved transplant center, performed 51 preliminary unrelated donor searches for African-American patients using the NMDP and its cooperative international registries. All preliminary searches were repeated between 5/2007 and 2/2008 in order to test the NMDP registry donor pool at its current level.
Umbilical cord blood unit preliminary searches only considered cord blood units available from the NMDP. Cord blood unit cell doses were calculated using the cord blood unit with the largest total nucleated cell count (TNC). Cord blood unit HLA match was determined by the current accepted cord blood criteria of low-resolution at HLA-A and B, and high resolution at HLA-DRB1.(8)
High resolution HLA typing of donor/recipient pairs at HLA-A, B, C and DRB1 was used to identify the most suitable donors. All formal unrelated donor searches were reviewed weekly by the transplant team, consisting of the transplant physicians, the transplant coordinator, and data management personnel. This retrospective analysis of unrelated donor and cord blood searches for African-Americans was approved by the University of Chicago institutional review board.
RESULTS
The median age of the 51 African-American patients was 38 years (range, 1–73), and diseases included AML (n=18), MDS (n=1), ALL (n=1), CLL (n=4), CML (n=4), Hodgkin lymphoma (n=4), NHL (n=4), MM (n=1), severe aplastic anemia (n=4), sickle cell anemia (n=6), and other (n=4). Thirteen (25%) patients had potential low resolution HLA-A, B, and DRB1 (6/6) unrelated donors, 37 (73%) patients had potential donors with a single allele or antigen mismatch at HLA-A, B, or DRB1 (5/6), and 1 patient had only potential 4/6 donors.
All unrelated donor searches are summarized in TABLE 1. In total, 275 donors were activated, and 133 were unavailable for confirmatory typing (48%). There were 13 patients with potential 6/6 donors from the preliminary search; 12 proceeded to a formal search for confirmatory high-resolution HLA typing. After a median formal search duration of five months (range 1–39), three patients were found to have an unrelated donor who was HLA identical by high resolution typing at all loci (i.e. 8/8 match), and two patients were found to have a donor with a single allele or antigen mismatch (i.e. 7/8 match). Since it can be assumed that only a 6/6 unrelated donor will yield an 8/8 donor, only 6% (3/51) of our African-American patients had an 8/8 unrelated donor (25% of formal searches with 6/6). Two of the three patients with an 8/8 HLA identical unrelated donor proceeded to transplant with that donor.
TABLE 1.
Unrelated Donor (URD) Searches for African-Americans with Hematologic Malignancies
| Potential URD HLA Match Level | Preliminary Search: Number of Patients with Potential URD | Number of Patients with Formal Search | Number of Patients with 8/8 URD | Number of Patients with 7/8 URD | Number of Patients with <7/8 URD | Patients Transplanted with the URD |
|---|---|---|---|---|---|---|
| 6/6 | 13 | 12 | 3 | 2 | 7 | 2 |
| 5/6 | 37 | 24 | 8 | 16 | 1 | |
| <5/6 | 1 | |||||
| Total | 51 | 36 | 3 | 10 | 23 | 3 |
Twenty-four of the 37 African-American patients with a potential 5/6 unrelated donor proceeded to formal unrelated donor search. The median formal search duration for this group was also five months (range 1–29). Eight patients were found to have a high resolution 7/8 unrelated donor (33% of formal searches with 5/6), but only 1 proceeded to hematopoetic stem cell transplant using this donor. Four did not proceed to transplant due to disease progression. The other three patients were offered a different therapy or donor strategy.
A retrospective preliminary search for unrelated cord blood units yielded at least one and often several (median 14, range 1 to 158) suitable potential 4/6 cord blood units for 50 of 51 (98%) patients. One patient had only potential 3/6 cord blood units. The median cell dose for patients with potential 4/6 cord blood units was 2.85 × 107/kg. Fifty-two percent (26/50) of the 4/6 cord blood units used to determine median cell dose had already been confirmatory HLA typed and were verified 4/6 cords by cord blood criteria. Twenty-nine (57%) patients had at least one (median 1, range1 to 10) potential 5/6 cord blood unit, and 3 had at least one potential 6/6 cord blood unit. The median cell dose for patients with potential 5/6 and 6/6 cord blood units was 1.88 × 107 /kg and 1.65 × 107/kg, respectively. Thirty-four percent (10/29) of the 5/6 cord blood units used to determine median cell dose were confirmatory HLA typed. No potential 6/6 cord blood units had been previously typed. Preliminary cord blood unit searches are summarized in Table 2.
TABLE 2.
Preliminary Cord Blood Unit Searches for African-Americans with Hematologic Malignancies
| Potential HLA Match Grade by Cord Blood Criteria | Number of Patients with Cord Blood Units (%) | Median Cell Dose | Percentage of Cord Blood Units used for Median Cell Dose with Confirmatory HLA |
|---|---|---|---|
| 6/6 | 3 (6) | 1.65 × 10(7)/kg | |
| 5/6 | 29 (57) | 1.88 × 10(7)/kg | 34 (10/29) |
| 4/6 | 50 (98) | 2.85 × 10(7)/kg | 52 (26/50) |
| <4/6 | 1 (2) |
DISCUSSION
Over the past decade it has been convincingly shown that the identification of an HLA identical donor/recipient pair using high-resolution techniques at A, B, C and DRB1 optimizes survival after adult unrelated hematopoetic stem cell transplant.(4;9) Our data illustrate the low likelihood of locating a matched unrelated donor for patients of African-American descent. Given the high frequency of rare and uncommon polymorphisms in the African-American population, increasing the donor pool seems unlikely to enhance the odds of finding a suitable adult unrelated donor.(5;6;9) Efforts that allow transplantation across HLA-barriers may be a better option to improve hematopoetic stem cell transplant accessibility. The wide availability and speedy acquisition of unrelated umbilical cord blood units creates an attractive resource for patients without an appropriate unrelated donor.(10–12) Our data show an abundance of unrelated cord blood units available for our African-American patients within the NMDP registry. It is likely that many additional suitable cords for African-American patients exist within other domestic and international cord blood registries. While the majority of identified units were only 4/6 matched, previous studies have shown promising results using such units, with cell doses comparable to our data, in adult and pediatric populations.(8;12;13) Whether or not umbilical cord blood transplantation will be equally permissive with respect to HLA disparity for African-American adults requires further study. Other strategies of interest include haplo-identical transplantation,(14;15) the combination of a haplo-identical donor and single cord blood unit,(16) as well as efforts to identify permissive HLA mismatches in recipients of unrelated donor transplantation.(17;18)
ACKNOWLEDGMENTS
Dr. van Besien is partially supported by NCI grant K24 CA116471-01.
Footnotes
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