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E. W. Petersdorf et al.
chronic graft-versus-host disease (GvHD) in cord blood transplantation compared to other allograft sources is related to the limited numbers of mature donor T cells in naïve cord blood grafts.6 Despite lower rates of GvHD, disease recurrence after cord blood transplantation is not
Table 1. Demographics of the study population. The effect of the HLA- B leader in clinical outcome was assessed among the base population of 4,822 single cord blood unit transplants, the subset of 2,178 trans- plants with one HLA-B mismatch, and the subset of 1,013 HLA-A and -DRB1-matched transplants with one HLA-B mismatch.
necessarily higher than that observed with other allograft
sources.12 The precise immunological pathways that lead
to these clinical outcomes remain to be elucidated; how-
ever, the innate immune system is an attractive mecha-
nism because natural killer (NK) cells are the earliest pop-
ulation of cells to reconstitute after cord blood transplan-
tation.13-16 Beneficial NK-associated responses have been
demonstrated in transplantation and the extent to which
they can be leveraged to lower posttransplant disease
recurrence remains an important area of clinical investiga- tion.8-10,17,18
A basic premise of transplantation is HLA compatibility between the graft and the patient. Recent evidence in unrelated donor transplantation implicates the HLA-B leader in graft-versus-host responses and demonstrates the importance of HLA that goes beyond the classic model based on matching under the framework of antigen pres- entation.19,20 As a peptide presented by classical class I molecules, the leader provides an antigenic stimulus to T cells. As a peptide that facilitates the cell-surface expres- sion of HLA-E, it also influences NK allorecognition. The HLA-B leader is distinguished from the leaders of other classical class I genes due to a dimorphism that leads to peptides with methionine (M) or threonine (T) at the sec- ond position of the leader peptide.21 Leader-associated dif- ferential expression of HLA-E influences inhibitory NKG2A- and to a lesser extent activating NKG2C-mediat- ed responses.22 In HIV-AIDs, the dimorphic HLA-B leader influences progression of the disease depending on the strength of HLA-E/NKG2 responses.23,24
Cord blood transplants are a unique population of pairs who may be mismatched concurrently at multiple HLA genetic loci and differ from unrelated donor transplants in whom the total number of HLA disparities must be limit- ed to prevent life-threatening complications.19 The contri- bution of an HLA mismatch to clinical outcomes after cord blood and unrelated donor transplantation may depend on the specific gene(s) that is mismatched and on additive effects of multi-locus mismatching across the HLA region.19,25-27 Furthermore, the effect of the HLA-B leader on specific outcomes may depend on the mis- matched HLA locus.19,20 The current study was designed to address an unmet need in cord blood transplantation for a better understanding of the clinical significance of the HLA barrier. We tested the hypothesis that the HLA-B leader informs outcome in a large, well-characterized cohort of single-unit cord blood transplants, beginning with an evaluation of all transplants and subsequently of transplants defined by matching at HLA-A, -B and -DRB1, the classic determinants of cord blood transplant out- comes. This hierarchy permitted the evaluation of the effect of the leader while minimizing contributions from other mismatched loci. The results may have important implications for future patients and advance understand- ing of the immunobiology of relapse.
Methods
Study population and design
The study population included 4,822 patients who received a single-unit unrelated cord blood transplant in an Eurocord/European Blood and Marrow Transplant (EBMT) cen- ter for the treatment of a blood disorder between 1990 and 2018 (Table 1; Online Supplementary Table S1). Data were collected by
Characteristics
Patient age, average yrs (range)
Patient sex, n (%) Female
Male
Missing or N/A
Disease type, n (%) Malignant Non-malignant
Single cord blood unit transplants
Base population n = 4,822
17.1 (0.1-70.7)
One HLA-A and HLA-B DRB1-
mismatch matched
986 (45%) 21 (0%) 3 (0%)
3,577 (74%) 1,769 (81%)
2,152 (45%)
2,649 (55%) 1,189 (55%)
n = 2,178
21.3 (0.1-70.7)
with one HLA-B mismatch n = 1,013
14.5 (0.1-69.0)
461 (46%) 551 (54%) 1 (0%)
766 (76%) 247 (24%)
258 (25%) 280 (28%) 165 (16%) 310 (31%)
381 (38%) 567 (56%) 65 (6%)
0 (0%)
1,013(47%) 1,013(100%)
1,245 (26%) Disease status at transplantation *, n (%)
409 (19%)
606 (28%) 600 (28%) 404 (19%) 568 (26%)
784 (36%) 1,258 (58%) 136 (6%)
low intermediate high
Missing or N/A
Patient CMV serology, n (%) negative
positive
Missing or N/A
HLA Matching, n (%) 6/6
5/6 4/6 Other
Year of transplantation, n (%) ≤2005
>2005
Transplant type, n (%) MAC
RIC
Missing or N/A
Total body irradiation, n (%) no
yes
Missing or N/A
Use of ATG, n (%) no
yes
Total nucleated cells infused, median (range)
1,189 (25%) 1,308 (27%) 735 (15%) 1,590 (33%)
1,900 (39%) 2,599 (54%) 323 (6%)
934 (19%) 2,233 (46%) 1,536 (32%) 119 (2%)
1269 (26%) 3,553 (74%)
3,558 (74%) 1,088 (23%) 176 (4%)
0 (0%)
1,110 (51%) 55 (3%)
595 (27%) 1,583 (73%)
1,578 (72%) 537 (25%) 63 (3%)
0 (0%) 0 (0%)
302 (30%) 711 (70%)
760 (75%) 222 (22%) 31 (3%)
599 (59%) 378 (37%) 36 (4%)
288 (28%) 725 (72%)
6.24 (0.38-81.4)
2,988 (62%) 1,230 (56%) 1,531 (32%) 812 (37%) 303 (6%) 136 (6%)
1,454 (30%) 645 (30%) 3,368 (70%) 1,533 (70%)
5.51 4.91 (0.20-94.9) (0.37-81.4)
*Disease status at transplantation: low risk (non-Hodgkin lymphoma [NHL] or Hodgkin disease [HD] in complete remission [CR] 1; acute leukemia in CR1; chronic myeloid leukemia [CML] in chronic phase; myelodysplastic syndrome [MDS]-refractory anemia [RA] with or without ring sideroblasts [RS]; refractory anemia with excess blasts [RAEB]- 1); intermediate risk (NHL or HD in ≥CR2; acute leukemia in ≥CR2; CML in accelerated phase; MDS-RAEB-2; RCMD; RCMD-RS; MDS associated with isolated del [5q], or unclassi- fiable MDS); high risk (NHL or HD untreated, refractory, partial remission or relapse; acute leukemia untreated, refractory or relapse; CML in blastic crisis; MDS transformed in acute leukemia; plasma cell disorders; chronic lymphocytic leukemia/lymphoma; secondary leukemia). N/A: not available.
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haematologica | 2021; 106(12)