Significant Reduction of Donor Specific Antibodies in Heart Transplant Recipients Treated with Proteasome Inhibitors for Antibody Mediated Rejection

Abstract

<h3>Purpose</h3> Antibody-mediated rejection (AMR) results in deleterious outcomes, including coronary artery vasculopathy (CAV), graft failure, and death. Proteasome inhibitors (PI) were used in pre-transplant desensitization to reduce antibodies to Human Leucocytes Antigen (HLA). We report our experience treating heart transplant recipients with AMR using PI, plasmapheresis (PLEX), and intravenous immunoglobulin (IVIG). <h3>Methods</h3> We retrospectively analyzed all patients treated with PI, either bortezomib (BTZ) or carfilzomib (CFZ), for AMR at our institution from 2018-present. CFZ (20mg/m2) or BTZ (1.3mg/m2) was given in combination with PLEX on days 1,2, 8, 9, 15 and 16, followed with IVIG 2g/kg. Mean fluorescence intensity (MFI) for donor-specific antibody (DSA) was evaluated by Luminex single antigen beads (One Lambda). Graft dysfunction (GD) was defined by left ventricular ejection fraction (LVEF) < 40%. <h3>Results</h3> Eleven patients were treated with PI for AMR (10 with CFZ, 1 with BTZ). Patients received 1-3 cycles of PI (1 cycle n=4; 2 cycles n=4; 3 cycles n=3), based upon the response in DSA. Before treatment, all patients except one had one or more strong DSAs (MFI> 8000) at neat serum. Most of the 22 strong DSAs observed were specific for HLA class II (DQ, n=14, 64%; DR, n=5, 23%). The treatment reduced MFI by 47+/- 46% at neat serum and by 70+/- 31% at 1:16 dilution (Figure 1). Four DSAs from 3 patients did not respond to treatment at 1:16 dilutions: one patient had high-titer DSA before treatment (MFI=14027 at 1:1024 dilution), another had rebound DSA from pre-transplantation. 5/11 patients presented with GD at onset (median EF reduction by 67%); 3/5 recovered LVEF to >40% after treatment. 9/11 (81.8%) patients survived to 1 year after AMR diagnosis. <h3>Conclusion</h3> Using PI in AMR treatment resulted in significant DSA reduction in 8/11 patients. Large studies are needed to further evaluate PI in AMR treatment.