Proteasome Inhibitor Therapy for Antibody-Mediated Lung Transplant Rejection

Abstract

Purpose Antibody mediated rejection (AMR) is a significant challenge after lung transplantation and no consensus exists on the optimal therapeutic approach. Bortezomib may serve as a treatment option by eradicating the antibody-producing plasma cells. We report clinical experience with bortezomib for AMR after lung transplantation. Methods and Materials Five lung transplant recipients with clinical AMR and donor-specific antibodies (DSA) (defined as MFI > 2000) were treated with bortezomib (1.3 mg/m 2 ). Serial measurements of DSA were conducted by single antigen bead on Luminex, OneLambda. The immunodominant DSA (iDSA) was assigned to the DSA with the highest MFI value at the time of diagnosis. Results In this cohort, AMR developed a median of 10.5 months after transplant; bortezomib treatment resulted in elimination of iDSA in 2 patients (1, 2), and a 50% reduction without clearance in another (3). The remaining two patients (4, 5) had persistent DSA without decline in MFI. Despite iDSA reduction in patients 1, 2, and 3, this did not translate to a meaningful clinical benefit (absence of resolution of acute AMR in patient 1). During therapy, one patient experienced grade IV thrombocytopenia; otherwise, side effects were mild and transient. Prior to AMR, all patients had normal graft function; however, all 3 patients surviving to hospital discharge developed chronic, severe graft dysfunction. Two of the 5 patients are still alive 132 (2) and 230 (5) days after treatment for AMR. Conclusions Although these preliminary results do not support a strong clinical or immunological response to bortezomib, we cannot exclude a prescribing bias for use in more severe cases of AMR. Bortezomib treatment for AMR warrants further investigation to fully elucidate its potential benefit. iDSAMFI at DiagnosisMFI at last follow-upResolution of acute AMRPatient 1DQ64516