Antigen Level Matching at HLA-C Improves Long-Term Outcomes after Double Umbilical Cord Blood Transplantation

Matching at HLA-C has been shown to influence outcomes and has been incorporated in selection of unrelated adult donors. In contrast, selection of UCB grafts has historically considered HLA-A and B at antigen and DRB1 at allele level resolution. Recent data in single, myeloablative pediatric UCB transplantation demonstrated that antigen level matching at HLA-C was associated with lower NRM and improved survival in patients receiving better HLA-matched units. Whether or not these same principles apply in the setting of double UCB (dUCB) transplantation has not been addressed. Thus, we retrospectively studied whether HLA-C matching would influence outcomes in 490 patients with hematological malignancies at two centers undergoing myeloablative and reduced intensity dUCB transplantation. We considered the worst HLA-matching of the 2 donor units with 316 (64%) patients receiving at least one 4/6 matched unit and 144 (29%) one or two 5/6 units, and 30 (6%) receiving two 6/6 HLA-matched units. Patients were scored considering the number of HLA-C antigen matches as 0-1 (23%), 2 (40%), 3 (18%), and 4 (19%), of 4 possible matches. The median age was 47 yrs. (range, 2-72), 59% were male, 285 (58%) had acute leukemia, 291 (59%) were CMV seropositive, 319 (66%) received RIC regimen, and 400 (82%) had CsA/MMF immunosuppression. In the overall study population, we observed no significant influence of HLA-C matching on the risk of death, treatment failure, non-relapse death, relapse, GVHD and hematopoietic recovery. However, we recognized an interaction between conventional HLA-matching at A, B, and DRB1 and number of matches at HLA-C in the survival endpoints. Thus, we analyzed two groups based on conventional HLA-matching at A, B and DRB1: those receiving at least one 4/6 HLA-matched unit (4/6 & 4-6/6; n=316) or those receiving ≥ 5-6/6 matched unit (5/6 & 5-6/6; n=174). In the ≥5/6 UCB transplants, there was no significant influence of HLA-C matching on the risk of death, treatment failure, non-relapse death, and relapse. However, in 4/6 & 4-6/6 transplants, better matching at HLA-C was associated with lower risk of death, treatment failure, and non-relapse death (Table), but there remained no association with risk of relapse. These data contrast with those reported with single UCB grafts and suggest that with 4/6 HLA-matched UCB units, additional matching at HLA-C reduces treatment failure and improves survival, and should be included in the match strategy.  In better matched (≥5/6) dUCB grafts further matching at HLA-C offers no additional benefit.

Table shows multivariate analysis results in 316 patient who received 4/6 & 4-6/6 dUCB grafts
Matching at HLA C	N	Overall mortality		Treatment failure		Non-relapse death		Relapse		Grade II-IV acute GVHD
		Relative Risk (95% CI)	P	Relative Risk (95% CI)	P	Relative Risk  (95% CI)	P	Relative Risk  (95% CI)	P	Relative Risk  (95% CI)	P
4/4	33	1.0		1.0		1.0		1.0		1.0
3/4	52	1.7	0.12	1.5	0.16	3.0	0.10	0.9	0.78	1.1	0.83
		(0.8-3.5)		(0.8-2.8)		(0.8-10.9)		(0.4-1.9)		(0.4-3.2)
2/4	136	2.3	0.01	1.7	0.06	5.4	<0.01	0.6	0.15	1.1	0.85
		(1.2-4.2)		(1.0-2.9)		(1.7-17.7)		(0.3-1.2)		(0.4-3.0)
0-1/4	95	2.3	0.01	1.8	0.03	4.4	0.02	0.9	0.71	1.1	0.86
		(1.3-4.4)		(1.1-3.2)		(1.3-14.4)		(0.5-1.7)		(0.4-3.0)