Matched HLA Haplotype Contributes to Reduce Sever Acute GVHD with Conserving GVL Effect in HLA-Mismatched Cord Blood Transplantation,

The cell dose of graft is the primary factor to select for cord blood (CB) unit and most of adult patients choose human leukocyte antigen (HLA)-mismatched CB graft. We have performed more than 7,500 CB transplantation (CBT) in Japan. Almost two-third of them has been using 2-loci HLA-mismatched CB unit. The degree of HLA disparity between patient and graft is known to be associated with risks of poor graft function and of graft-versus-host disease (GVHD) on allogeneic hematopoietic stem cell transplantation. On the other hand, those risks of transplant-related complications are not equivalent even among the donor-recipient pairs who have same number of mismatched HLA antigens. The mismatched HLA haplotype could be responsible for post-transplant adverse events because of incompatibility of non-HLA polymorphic genes. Recently, HLA haplotype matching effect on GVHD has been demonstrated in unrelated bone marrow transplantation (S Morishima, et al. Blood 2010). In this study, we have performed the single institutional analysis to determine the impact of HLA haplotype matching in HLA-mismatched CBT.

We studied the clinical outcomes of 170 consecutive adult patients who received unrelated CBT between August 1998 and January 2011 in the institute of medical Science, University of Tokyo. Patients received previous allogeneic transplants were excluded from this study. All patients received myeloablative regimens including 12 Gy of total body irradiation, cyclosporine plus short term methotraxate for GVHD prophylaxis and almost same supportive care by the institutional protocol. By low-resolution typing method for HLA-A, -B and -DR loci, 6 patients received matched grafts, 57 received 1 antigen-mismatched and 107 received 2 antigens-mismatched grafts in the graft-versus-host (GvH) direction. We have determined the HLA haplotype based on common haplotypes in Japanese population referred from the 11th International Histocompatibility Workshop and other previous reports. We evaluated the impact of haplotype matching on cumulative incidences of hematopoietic recovery, of GVHD, of relapse and of non-relapse mortality (NRM) using the Pepe and Mori's test. Estimates of overall and disease-free survivals were calculated using the Kaplan-Meier method and analyzed by the log-rank test.

Thirty-three among all 170 pairs were defined as the haplotype-matched pairs sharing same haplotypes in both grafts and recipients. The age, sex, cytomegalovirus serological status, diagnosis, risk of the disease at the transplant, numbers of total nucleated cells and CD34⁺ cells at the cryopreserved were not significantly different between both groups with and without matched haplotypes. Engraftment of platelet after CBT tended to be earlier in haplotype-matched group compared with control group among the 1 antigen-mismatched pairs in the host-versus-graft direction (median: 38 days versus 44 days) and among the 2 antigens-mismatched pairs (median: 38 days versus 42 days), but those were not significant. The cumulative incidences of grades III and IV acute GVHD in patients with haplotype-matched (7%) were significantly lower than non-matched group (9%) among 2 antigens-mismatched pairs in the GvH direction (P=0.033). Notably, cumulative incidences of relapse tended to be lower in haplotype-matched patients among this group (3 years cumulative incidences were 7% in haplotype-matched patients versus 21% in non-matched patients, P=0.086). The haplotype matching effects were not observed in survival rates, cumulative incidences of NRM among any HLA-mismatched pairs.

Those data suggest that untyped variation carried on the HLA haplotytpe might be better to be matched. The haplotype matching seemed to effect on lower risk of sever acute GVHD, on the other hand, graft-versus-leukemia effect was conserved in the setting of HLA-mismatched CBT.

No relevant conflicts of interest to declare.