Impact of Human Leukocyte Antigen (HLA) Alleles on Outcomes of Allogeneic Transplantation (Allo-HCT) for B-Cell Non-Hodgkin Lymphomas (B-NHL); A CIBMTR Analysis

Even in the modern era of targeted therapies, allo-HCT remains a strategy that offers a chance of extended survival in B-NHL who relapsed after, or are deemed ineligible for, autologous transplantation (auto-HCT). Moreover, it was shown that efficacy of auto-HCT in extending survival in patients with diffuse large B-cell lymphoma is limited in the post-rituximab era. The use of allo-HCT for salvage of relapsed/refractory B-NHL is likely to increase with the wide adoption of reduced intensity conditioning (RIC) since transplant-related mortality (TRM) is lower while preserving the benefit of graft vs lymphoma (GVL) effect. Further understanding of the factors likely to predict a more robust GVL response, and potentially better clinical outcomes, would be very useful in selecting patients with B-NHL who are likely to benefit from allo-HCT. Multiple prior studies have shown that the presence of certain human leukocyte antigen (HLA) alleles may be instrumental in modulating the outcomes of B-NHL after immunochemotherapy and/or allo-HCT. We hypothesized that certain HLA alleles may have superior ability to present antigens to cytotoxic T-cells or possibly modulate natural killer (NK) cell activity.

We undertook a retrospective analysis of CIBMTR data to evaluate whether the presence of HLA-A2, HLA-C1C1, HLA-DRB1*01:01 or HLA-DRB1*13 alleles and HLA-A1+, HLA-A2- and HLA-B44- haplotypes were associated with outcomes of patients with relapsed/refractory B-NHL after transplantation from HLA-8/8 matched sibling (MRD) or unrelated (MUD) donors. The primary outcome was time to progression. Secondary outcomes included progression-free (PFS) and overall survival (OS), TRM, and incidence and severity of acute and chronic graft versus host disease (GVHD). Multivariate analyses were performed using Cox proportional hazards models adjusting for multiple disease and transplant related characteristics. HLA-A*02 was tested individually; HLA-DRB1*0101 and HLA-DRB1*13 were tested in 4 combinations; HLA-A1+/A2-, B44- vs. A2+ vs. neither. Because of multiple comparisons, p<0.01 is considered significant.

The final analysis population was restricted to 1314 patients who received the first allo-HCT during the years of 1995-2012 for indolent (N=506), aggressive (N=514), and mantle (N=294) B-NHLs from MRD (N=708) or MUD (N=606) utilizing myeloablative; MA (N=636), RIC (N=434), non-myeloablative; NMA (N=196) or other (n=48) conditioning. The different HLA allele analysis groups were well-balanced for all disease, patient, transplant and donor characteristics. In multi-variate analysis, we have observed no significant association between any of the HLA alleles or combinations we tested with any of the primary or the secondary end-points. A power calculation suggested very large numbers would be needed to reach statistical significant based on the data analyzed so far. The marked heterogeneity of different lymphoma subtypes, conditioning regimens, donor choices, GVHD prophylaxis, supportive regimens or other center-related characteristics likely limited the ability to detect effects of differences in individual recipient HLA alleles. In conclusion, this study represents the largest reported series of allo-HCT outcomes of B-cell NHL patients based on HLA type. Further study of other variables will be required to delineate the immunologic impact of donor-host interactions on outcomes of allo-HCT for B-cell NHL.