title: Prospective iterative trial of proteasome inhibitor-based desensitization.
abstract: A prospective iterative trial of proteasome inhibitor (PI)-based therapy for reducing HLA antibody (Ab) levels was conducted in five phases differing in bortezomib dosing density and plasmapheresis timing. Phases included 1 or 2 bortezomib cycles (1.3 mg/m(2) × 6-8 doses), one rituximab dose and plasmapheresis. HLA Abs were measured by solid phase and flow cytometry (FCM) assays. Immunodominant Ab (iAb) was defined as highest HLA Ab level. Forty-four patients received 52 desensitization courses (7 patients enrolled in multiple phases): Phase 1 (n = 20), Phase 2 (n = 12), Phase 3 (n = 10), Phase 4 (n = 5), Phase 5 (n = 5). iAb reductions were observed in 38 of 44 (86%) patients and persisted up to 10 months. In Phase 1, a 51.5% iAb reduction was observed at 28 days with bortezomib alone. iAb reductions increased with higher bortezomib dosing densities and included class I, II, and public antigens (HLA DRβ3, HLA DRβ4 and HLA DRβ5). FCM median channel shifts decreased in 11/11 (100%) patients by a mean of 103 ± 54 mean channel shifts (log scale). Nineteen out of 44 patients (43.2%) were transplanted with low acute rejection rates (18.8%) and de novo DSA formation (12.5%). In conclusion, PI-based desensitization consistently and durably reduces HLA Ab levels providing an alternative to intravenous immune globulin-based desensitization.
authors.affiliation: Department of Surgery, Division of Transplantation, University of Cincinnati College of Medicine, Cincinnati, OH.
authors.forename: E S
authors.initials: ES
authors.lastname: Woodle
authors.forename: A R
authors.initials: AR
authors.lastname: Shields
authors.forename: N S
authors.initials: NS
authors.lastname: Ejaz
authors.forename: B
authors.initials: B
authors.lastname: Sadaka
authors.forename: A
authors.initials: A
authors.lastname: Girnita
authors.forename: R C
authors.initials: RC
authors.lastname: Walsh
authors.forename: R R
authors.initials: RR
authors.lastname: Alloway
authors.forename: P
authors.initials: P
authors.lastname: Brailey
authors.forename: M A
authors.initials: MA
authors.lastname: Cardi
authors.forename: B G
authors.initials: BG
authors.lastname: Abu Jawdeh
authors.forename: P
authors.initials: P
authors.lastname: Roy-Chaudhury
authors.forename: A
authors.initials: A
authors.lastname: Govil
authors.forename: G
authors.initials: G
authors.lastname: Mogilishetty
mesh_terms: D000293:Adolescent; D000328:Adult; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D003888:Desensitization, Immunologic; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000188:drug therapy / Q000276:immunology*; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D006680:HLA Antigens / Q000276:immunology*; D006650:Histocompatibility Testing; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000008:administration & dosage; D007674:Kidney Diseases / Q000276:immunology* / Q000601:surgery; D007677:Kidney Function Tests; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D010956:Plasmapheresis; D011379:Prognosis; D011446:Prospective Studies; D061988:Proteasome Inhibitors / Q000627:therapeutic use*; D011719:Pyrazines / Q000627:therapeutic use*; D012307:Risk Factors; D000069283:Rituximab; D055815:Young Adult
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D001897:Boronic Acids; D006680:HLA Antigens; D016756:Immunoglobulins, Intravenous; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069283:Rituximab; D000069286:Bortezomib
keywords: alloantibody; desensitization; kidney transplantation/nephrology; plasma cells; translational research/science