Prospective iterative trial of proteasome inhibitor-based desensitization

Area of Science:

• Nephrology
• Immunology
• Transplantation

Background:

• High levels of Human Leukocyte Antigen (HLA) antibodies pose a significant barrier to kidney transplantation.
• Desensitization therapies are crucial for patients with positive HLA antibody screens.
• Proteasome inhibitors (PIs) have emerged as a potential therapeutic option.

Purpose of the Study:

• To evaluate the efficacy of a prospective, iterative proteasome inhibitor (PI)-based therapy for reducing HLA antibody levels.
• To assess the impact of varying bortezomib dosing and plasmapheresis timing on antibody reduction.
• To determine the safety and outcomes of PI-based desensitization in patients undergoing transplantation.

Main Methods:

• A five-phase prospective iterative trial involving 44 patients receiving 52 desensitization courses.
• Treatment included bortezomib cycles, rituximab, and plasmapheresis, with variations in PI dosing density and plasmapheresis timing.
• HLA antibody levels were measured using solid-phase assays and flow cytometry (FCM).

Main Results:

• 86% of patients (38/44) achieved significant and durable reductions in immunodominant HLA antibodies, persisting up to 10 months.
• Increased bortezomib dosing density correlated with greater antibody reductions across HLA Class I, II, and public antigens.
• Flow cytometry showed a mean decrease of 103 mean channel shifts (log scale) in 100% of assessed patients (11/11).

Conclusions:

• Proteasome inhibitor-based desensitization is a consistent and durable method for reducing HLA antibody levels.
• This therapy provides a viable alternative to intravenous immune globulin (IVIG)-based desensitization protocols.
• Successful transplantation was achieved in 43.2% of patients with low rates of acute rejection and de novo donor-specific antibody formation.