High HLA Evolutionary Divergence in Donor HLA-B Locus Impacts Transplant Outcomes after Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide

The human leukocyte antigen (HLA) divergence allele advantage hypothesis states that an HLA genotype with two alleles that are more divergent results in more diverse presentation of immunopeptidomes. Higher divergence in the recipient after transplantation from a matched donor, will allow more tumor associated antigen s (TAA) and potentially lower risk of relapse. On the contrary, low HLA evolutionary divergence (HED) in HLA class I and HLA-DR were found to be strong predictors for worse overall survival after matched related donor transplantation. In the haploidentical transplantation (HIDT) setting with post-transplant cyclophosphamide (PTCY) , the level divergence in the donor can have an impact on the ability of donor cells to recognize recipient TAAs and potentially affect transplant outcomes. Additionally, Antigen presenting cells from donor have an impact on graft versus tumor effect post allogeneic transplantation (Jiang Ming Li, 2004). To study the effect of HED in donor HLA-B and its impact on transplant outcomes, we studied 322 consecutive recipient/donor pairs who received their transplant at our center with a median follow up of 69.2 months (range 30-208). HED was calculated as pairwise differences using Grantham distance metric by perl script (https:// sourceforge.net/projects/granthamdist/). We hypothesized that a higher HED score in donor HLA-B will improve survival post HIDT.

Data were collected from our database where it was prospectively entered. Patient diagnosis included AML (n=122), ALL (n=68), MDS (n=41), NHL (n=50), other (n=41). Baseline recipient characteristics included a median age of 50 years (19,80), 53% white, HCT-CI≥3 in 50%, Disease risk (intermediate 53%, high/very high 33%), PBSC graft 80% and myeloablative conditioning 49%. Donor characteristics were median age 37 years (13,73), CMV positive 61%, male 61% and female donor to male recipient 21%. Pairwise divergence of donor HLA -B showed the median HED score of 7.93 (0-14.33). On univariate analysis using median cutoffs, a high HED (>7.93) in donor HLA-B was associated with better OS ( HR 0.71, p=0.05), DFS ( HR 0.71, P=0.05), non-relapse mortality NRM (HR 0.51, p=0.03) and similar relapse ( HR 0.84, p=0.4) compared to lower HED scores. A multivariable analysis adjusting for factors such as disease risk, sex, comorbidity score and race, a high HED in donor HLA-B was significant for lower risk of non-relapse mortality (HR 0.509, p=0.04) compared to lower HED.

In conclusion, our data show that among HIDT recipients, a high HED in donor HLA-B has significant impact on transplant outcomes and survival by improving NRM. The benefit of higher HED in HLA-B among donors can be used to select the best donor to lower transplant mortality