Donor-Recipient HLA-Matching of Unrelated Cord Blood Units At High-Resolution Reveals High Degrees of HLA-Mismatch and Alters Graft Selection
Authors: Dahi Parastoo B , Ponce Doris M , Evans Katherine L , Lubin Marissa N , Gonzales Anne Marie R , Byam Courtney , Ferrante Rosanna , Sideroff Melissa , Wells Deborah , Giralt Sergio A. , Kernan Nancy A. , Scaradavou Andromachi , Barker Juliet N 
Published: October 2019

Abstract
Abstract 957

Background:
Optimal criteria for cord blood (CB) unit selection are unknown. Traditionally, units are matched to the recipient only at human leukocyte antigen (HLA)-A, B antigens, and DRB1 alleles with up to 2 mismatches permitted. Recently, however, a significant association between intermediate resolution HLA-C matching and transplant-related mortality has been reported in single unit CB transplantation (CBT) (Eapen, M., Lancet Oncol, 2011). Moreover, we have recently demonstrated a decreased day 180 grade III-IV acute graft-versus-host disease incidence if the engrafting unit of a double-unit pair is ≥ 4/6 HLA-A, B, DRB1 allele matched to the recipient (Ponce, D., unpublished, 2012). This suggests that CB donor-recipient match criteria should be upgraded to 6 HLA-alleles or higher. However, how to clinically implement higher resolution HLA-matching and how it could affect CB unit selection are not known.

Methods:
To examine the extent of HLA-mismatch, we analyzed the HLA-match grade of 96 double-unit CB grafts (units 1a and 1b) and the 1–2 back-up units chosen for each transplant at various HLA-match grades. 362 CB units were selected for 95 patients (one patient was transplanted twice) who underwent CBT from 1/1/2009-6/30/2012 for hematologic malignancies. Units were selected based on cryopreserved total nucleated cell (TNC) dose (initially ≥ 1.5, later increased to ' 2.0 × 107/kg), donor-recipient 4–6/6 HLA-A, B antigen, DRB1 allele match, and CB bank. Unit-unit HLA-match was not considered. High-resolution typing for 10 alleles was obtained prospectively, although usually did not influence unit selection.

Results:
The median age was 41 years (range 1–69) and the median weight was 65 kilograms (range 10–125). The median cryopreserved TNC/kg × 107 of units 1a and 1b (n = 192) was 2.89 (range 1.53–17.78), and their median donor-recipient HLA-match was 4/6 (range 1–6/6), 5/8 (range 2–8/8), and 6/10 (range 2–9/10) at 6, 8 and 10 HLA-alleles, respectively. The median (range) of 6/6 HLA-A, B antigen, DRB1 allele matched units (n = 9) was 6/6 (3-6/6), 7/8 (5-8/8) and 9/10 (7-9/10) at 6, 8, and 10 allele resolution, respectively. However, 5/6 HLA-A, B antigen, DRB1 allele matched units (n = 90) were a median (range) of 5/6 (2-5/6), 6/8 (3-7/8) and 7/10 (3-9/10) at allele resolution. Moreover, 4/6 HLA-A, B antigen, DRB1 allele matched units (n = 93) were a median (range) of 3/6 (1-4/6), 4/8 (2-6/8) and 5/10 (2-8/10) at allele resolution. We then evaluated how often the use of higher resolution HLA-match criteria would change graft selection to substitute one or both back-up units over units 1a and/or 1b, and the effect on the graft TNC dose (Table). If a cryopreserved TNC/kg ≥ 2.0 × 107 and a better HLA-match were required for either units 1a or 1b to be substituted, the frequency that graft selection would change was up to 38/96 (40%) of transplants for 10 allele HLA-match. The effect on TNC was minimal (≤ 12% reduction in the total graft TNC dose).

Conclusions:
Recent data suggest the criteria for CB match should be re-evaluated. However, units currently chosen based on HLA-A, B antigen, DRB1 allele match have a very high degree of mismatch when typed at higher resolution (as low as 3/10 for 5/6 units, and 2/10 for 4/6 units). Adoption of higher match grade criteria will frequently change the selection of the “optimal” graft in both adult and pediatric patients. While both the new lower limit of acceptable HLA-match and how to “trade off” higher resolution HLA-match against TNC dose are unknown, our data suggest that higher resolution HLA-match is possible without significant compromise in graft dose. Ultimately, large studies will be required to understand the impact of higher resolution HLA-match on disease-free survival to further guide clinical practice.

Disclosures:
Giralt: Celgene: Honoraria, Research Funding.