Functional antigen matching in corneal transplantation (FANCY)
Final Report Abstract
Keratoplasty can restore vision in corneal blindness. However, immunological graft reactions may induce graft failure in a substantial percentage. Repeat keratoplasties in turn are associated with increased risk of graft failure and even possibly irreversible blindness. Immunosuppressants are administered for prophylaxis. However, adverse effects limit long-term usage. By contrast, matching for transplantation antigens might be effective without any adverse effects beside the additional time on the waiting list. FANCY is a prospective, controlled, randomised, double-blind, multi-centre clinical trial with two parallel arms. The primary objective is to evaluate superiority of the proposed HLA-matching strategy in comparison to random graft assignment with respect to the primary endpoint ‘time to first endothelial graft rejection’. Inclusion criteria are age over 18 years and awaiting penetrating or endothelial lamellar keratoplasty. Exclusion criteria are abuse of medication and/or drugs and a statistically anticipated waiting time for an HLA match longer than 6 months. After randomisation, patients either receive a HLA-matched graft (experimental intervention) or a random graft (control intervention). The allocation was conducted in a blinded fashion within the trial internet portal. The calculated sample size without the anticipated percentage of screen failures is 620 patients. The trial started in 2009 with a projected recruitment period of 24 months. We included a total of 721 patients. These had been recruited in 12 keratoplasty centres from Germany. 68 turned out screen failures due to rare HLA-phenotypes. 639 subjects were randomised. 165 did not obtain a FANCY allocation (5 violated inclusion criteria, 97 withdrew informed consent, 1 died, 62 other reasons). 474 patients underwent keratoplasty with a graft from a FANCY allocation, 1 was lost to follow-up, 473 were analysed. Surgical methods were 337 penetrating keratoplasties, 13 allogeneic limbo-keratoplasties and 123 lamellar endothelial keratoplasties. We observed 33 graft rejections in the matching arm (n = 224). The corresponding estimated cumulative incidence rate of immune reactions after two years is 15.7. We observed 40 rejections in the control arm (n = 249). This yields an estimated cumulative incidence rate of 17.0% after two years. We performed several sensitivity analyses on the basis of HLAMatchmaker. These reveal a beneficial tendency for matching at HLA-DR, especially in HLA-class I matched grafts. The minor antigens ACC-1, ACC-2, HA-3 and HA-8 all missed clinical relevance due to sparsity of the mismatched constellation and HLA-restrictions. The H-Y loci will be analyzed later when all donors have been gender typed. This analysis is ongoing at time of finalizing this report. Keywords: Keratoplasty, HLA matching, graft rejection
