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HLA-B leader and cord-blood transplantation
Table 3. Impact of leader match status and leader of the shared allotype on clinical outcome in 1,013 single HLA-B-mismatched cord blood trans- plantations (matched at HLA-A and -DRB1). A total of 814 patients are evaluable for relapse and non-relapse mortality.
Clinical Endpoint
Grades II-IV acute GvHD
Relapse
Mortality
Non-relapse mortality
Leader Match Status/ Leader of Shared Antigen*
Leader-matched/T (169/464=36%) Leader-matched/M (51/140=36%) Leader-mismatched/T (100/299=33%) Leader-mismatched/M (38/85=45%)
Leader-matched/T (98/386=25%) Leader-matched/M (34/112=30%) Leader-mismatched/T (70/248=28%) Leader-mismatched/M (22/68=32%)
Leader-matched/T (248/479=52%) Leader-matched/M (84/141=60%) Leader-mismatched/T (146/306=48%) Leader-mismatched/M (36/87=41%)
Leader-matched /T (127/386=33%) Leader-matched/M (41/112=37%) Leader-mismatched/T (68/248=27%) Leader-mismatched/M (11/68=16%)
Odds Ratio or Hazard Ratio
1 1.05 0.90 1.42
1 1.14 1.03 1.08
1 1.15 0.94 0.71
1 1.18 0.84 0.44
95% Confidence Interval
-
0.70-1.57 0.66-1.23 0.87-2.29
-
0.76-1.74 0.75-1.43 0.66-1.77
-
0.90-1.48 0.76-1.15 0.50-1.01
-
0.82-1.69 0.62-1.13 0.23-0.81
P (Global P)
(global P 0.37) 0.83
0.49
0.16
(global P 0.94) 0.54
0.84
0.77
(global P 0.10) 0.26
0.52
0.06
(global P 0.02) 0.37
0.25 0.009
*The numbers refer to the number of patients who developed the clinical endpoint out of the total number of evaluable patients (for whom data for the clinical endpoint was available). GvHD: graft-versus-host disease.
Relative to leader-matched transplants, leader-mismatched trans- plants had lower non-relapse mortality (HR 0.72, 95% CI: 0.55- 0.94; P=0.02) (Table 2); overall mortality was lower but not statis- tically significantly so.
When the leader of the shared HLA-B allele is considered along- side the leader match status, there was a statistically significant dif- ference in the risk of non-relapse mortality across the resultant four groups (Table 3, global P=0.02). This result was largely driven by transplantation from leader-mismatched units that share an M leader allele with the patient compared to transplantation from leader-matched units that share a T leader allele (Table 3; HR 0.44, 95% CI: 0.23-0.81; P=0.009). Not surprisingly, the comparison of overall mortality for these same groups showed a difference in the same direction as that for non-relapse mortality; however, the magnitude of the difference was smaller and was not statistically significant) (Table 3). Other pairwise comparisons of non-relapse mortality that may be of particular interest include leader-mis- matched units that share a T leader allele with the patient com- pared to transplantation from leader-mismatched units that share an M leader allele (HR 1.92, 95% CI: 1.01-3.65; P=0.05) and leader- matched units that share an M leader allele with the patient com- pared to transplantation from leader-mismatched units that share an M leader allele (HR 2.70, 95% CI: 1.38-5.29; P=0.004).
In summary, the HLA-B leader genotype of the cord blood unit may inform outcome after transplantation from HLA-B-mis- matched units. Among patients transplanted from HLA-A and
DRB1-matched units with one HLA-B mismatch, leader mis- matching and presence of a matched M-leader allele may be asso- ciated with lower non-relapse mortality. Units with MT and MM leader genotypes may be associated with a higher risk of relapse; however, the higher relapse risk conferred by the genotype together with lower non-relapse mortality associated with leader mismatching appeared to have no demonstrable impact on overall survival.
Discussion
An unmet need of CBT is a better understanding of the factors that influence outcome. The current study was designed to test a series of novel hypotheses regarding the significance of the dimorphic HLA-B leader in CBT. Interest in the HLA-B leader is founded on its pivotal role in both adaptive and innate immune pathways. A role for the HLA-B leader in HLA-B-mismatched unrelated donor transplantation in GvHD provides an approach for under- standing the immunogenicity of M and T leader alleles in a way that may bridge T- with NK-cell biology.
The effects of HLA mismatching are well-tolerated in CBT, permitting a higher overall degree of disparity between the patient and cord blood unit. The majority of CBT are mismatched at HLA-B. With over 7,000 known
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