Durable renal response after combination of bortezomib, corticosteroids, rituximab, and plasmapheresis for late antibody-mediated renal transplant rejection

Late occurrence of antibodymediated rejection (AMR), defined as occurring 6 months after transplantation, is associated with poor renal allograft survival, compared to early acute AMR and acute cellular rejection. The proteasome inhibitor bortezomib has multiple immunomodulatory effects on plasma cells, the source of donorspecific HLA antibodies which mediate AMR. Materials and methods: Consecutive patients who presented with biopsy-proven AMR and donor-specific anti-HLA antibodies (DSA) at a single institution between July 2011 and February 2015 were included. They received rituximab 375 mg/m2 on day 1, bortezomib 1.3 mg/m2 and methylprednisolone on days 1, 4, 8, 11, and plasmapheresis on days -1, 4, 8, 11, 14, 15, 17, with herpes zoster prophylaxis. The primary outcome was graft survival independent of dialysis. Patients were prospectively assessed with serial monitoring of renal function and proteinuria, and neuropathy symptoms. Toxicity determination was made by medical record review for hospitalizations within 3 months of therapy, or documentation of opportunistic infection. Results: Eleven patients were treated for late AMR (diagnosed at a median of 38 months post renal transplant) with this bortezomib-based protocol; 2 patients underwent the regimen twice. Of the 11 patients, 9 have functioning allografts (82% graft survival) with a median creatinine of 2.1 mg/ dL (range 1.1 - 3.4 mg/dL), at a median follow-up of 50 months after AMR therapy (range 24 - 63 months). One patient was retransplanted at 4 years post AMR treatment with no AMR recurrence to date at 2-years' follow-up, and a second patient re-initiated dialysis at 2 years post AMR treatment. Patient survival is 91% (10/11): 1 patient relocated out of state and was reported to have died from complications of hypertensive encephalopathy. The majority of patients (7/11) had several class I and class II DSA specificities; of these, 4 patients had negative class I DSA but persistent class II DSAs at 2 - 3 months post therapy. Only 1 patient who was positive for class II DSAs alone (DR53 and DQ2) converted to negative DSA, although DSA testing was delayed to 2 years' followup. Two patients were hospitalized within 1 month of the protocol, 1 for ileus and 1 for urinary tract infection and ruptured ovarian cyst. One other patient had herpes zoster. Conclusion: Renal allograft survival was 82% at 4 years after bortezomib-based therapy for late onset AMR; toxicity profile of this regimen was acceptable. Eradication of DSAs may not be necessary for meaningful and durable renal response.