Exploratory Study of Predicted Indirectly ReCognizable HLA Epitopes in Mismatched Hematopoietic Cell Transplantations

Abstract

HLA-mismatches in hematopoietic stem-cell transplantation are associated with an impaired overall survival (OS). The aim of this study is to explore whether the Predicted Indirectly ReCognizable HLA-Epitopes (PIRCHE) algorithm can be used to identify HLA-mismatches that are related to an impaired transplant outcome. PIRCHE are computationally predicted peptides derived from the patient's mismatched-HLA molecules that can be presented by donor-patient shared HLA. We retrospectively scored PIRCHE numbers either presented on HLA class-I (PIRCHE-I) or class-II (PIRCHE-II) for a Dutch multicenter cohort of 103 patients who received a single HLA-mismatched (9/10) unrelated donor transplant in an early phase of their disease. These patients were divided into low and high PIRCHE-I and PIRCHE-II groups, based on their PIRCHE scores, and compared using multivariate statistical analysis methods. The high PIRCHE-II group had a significantly impaired OS compared to the low PIRCHE-II group and the 10/10 reference group (HR: 1.86, 95%-CI: 1.02-3.40; and HR: 2.65, 95%-CI: 1.53-4.60, respectively). Overall, PIRCHE-II seem to have a more prominent effect on OS than PIRCHE-I. This impaired OS is probably due to an increased risk for severe acute graft-vs.-host disease. These data suggest that high PIRCHE-II scores may be used to identify non-permissible HLA mismatches within single HLA-mismatched hematopoietic stem-cell transplantations.

Keywords: HLA; HLA mismatch; HSCT—hematopoietic stem cell transplant; Non-permissible mismatch; PIRCHE.

Figure 1

Early-stage disease patients transplanted with a high PIRCHE-II mismatch have an impaired 5-year OS compared to early-stage disease 10/10-matched transplantations (A) and a higher risk for severe aGVHD (B). (A) High PIRCHE-II had an impaired OS (36%) compared to the 10/10-MUD group (56%) and the low PIRCHE-II group (52%). (B) Patients with a high PIRCHE-II mismatch had a significantly increased risk of NRM and acute GVHD compared to 10/10-matched transplantations, whereas the risk for disease progression was not affected. Multivariate models included for NRM: Time to HSCT, KIR ligand status, patient CMV status, conditioning regimen intensity, patient age at transplantation, and donor age; for acute GVHD: donor age (for II-IV) and patient age (for III-IV); for chronic GVHD: aGVHD II-IV, conditioning regimen intensity, patient age at transplantation, stem cell source, and ATG; for DFS: patient age at transplantation; for progression: patient CMV status, conditioning regimen intensity, and ATG. 10/10-MUD: n = 212 patients; low PIRCHE-II group: n = 70 patients; high PIRCHE-II group: n = 33 patients. The number of outcome events in different groups: 10/10: n = 94; PIRCHE-II low: n = 34; PIRCHE-II high: n = 23. OS, overall survival; HR, hazard ratio; 95%-CI, 95%-confidence interval of hazard ratio. PIRCHE-II low, 0–13 PIRCHE-II; PIRCHE-II high, >13 PIRCHE-II; NRM, non-relapse, mortality; GVHD, graft-vs.-host-disease; DFS, disease-free survival.