HLA-C Mismatch Is Associated with Inferior Outcome after Unrelated Donor Non-Myeloablative Hematopoietic Stem Cell Transplantation.

Donor-recipient disparity at HLA-C is an important determinant of clinical outcome after myeloablative unrelated donor (URD) hematopoietic stem cell transplantation, but its importance in URD non-myeloablative stem cell transplantation (NST) is less clear.

Methods: We performed a retrospective analysis of 111 patients who underwent unrelated donor NST for hematologic malignancies from 2000–2004. Of these, 78 were 10/10 matched at HLA-A, B, C, DRB1, DQB1, and 33 were mismatched at one or more HLA-C antigen/allele (21 single C, 3 double C, 9 single C + other HLA locus mismatch). A majority (78%) of the mismatches at HLA-C were detectable at the antigen level. Diseases included AML (24), ALL (3), MDS (17), CML (10), CLL (23), NHL (22), and HD (12). All patients received non-myeloablative conditioning with intravenous busulfan (0.8mg/kg/d x 4 days) and fludarabine (30mg/m²/d x 4 days). Graft-versus-host disease (GVHD) prophylaxis included cyclosporine plus prednisone or tacrolimus plus low-dose methotrexate based regimens. Stem cell source was primarily G-CSF mobilized PBSC.

Results: Median time to neutrophil engraftment (ANC > 500/ul) among patients who nadired was 12 days (range 8–21 days) in both groups. Median unfractionated marrow donor chimerism were ≥ 90% donor at day+30 and day +100 in both groups. There was one late graft failure in the C-mismatched cohort, and one early graft rejection in the 10/10 matched cohort. HLA-C disparity was associated with an increased risk for grade III-IV acute GVHD (33% vs. 12%, p = 0.01) in univariate and multivariate logistic regression analyses (odds ratio 3.6, p = 0.03). This finding remained significant even when baseline differences in GVHD prophylaxis between the 2 cohorts were taken into consideration. Cumulative relapse incidence was not statistically different: 35% in the C-mismatched group, versus 55% in the 10/10 matched cohort, p = 0.09. There was a higher incidence of treatment related mortality in the C-mismatched group: 48% versus 16% (p = 0.001). Overall survival at 2 years was 27% in C-mismatched, vs. 47% in 10/10 matched patients (p = 0.009). In Cox regression model, HLA-C disparity was an independent factor for poor survival (hazard ratio 1.85, p = 0.04).

Conclusions: Donor recipient disparity at HLA-C does not influence engraftment or donor chimerism after URD NST, but is associated with increased acute GVHD and inferior survival. HLA-C is an important transplantation antigen and should be considered in the selection of unrelated donors for NST.