Guilherme Costa, Ruy Cruz, Geoffrey Bond, Kyle Soltys, Kareem Abu-Elmagd

University of Pittsburgh Medical Center, Pittsburgh, PA, United States

Purpose: Donor specific antibodies (DSAs) have been proven to be detrimental to short-and long-term visceral allograft survival particularly of the liver-free allograft. It remains to be seen if bortezomib as a proteasome inhibitor will be an effective therapy to prevent or alter the natural history of acute and/or chronic allograft rejection.

Methods: Between March 10, 2010 and March 21, 2011, a total of 20 adult patients underwent intestinal and multivisceral transplantation. Of these, 4 (20%) were primary liver-free visceral allografts with positive virtual crossmatch and high titer DSA’s against multiple Class I and Class II HLA alleles. All patients were female with an age range from 28 to 45 years. All donors were ABO-identical with no antilymphocyte depletion. Bortezomib was given as part of the pretreatment protocol including an initial dose of 1.3 mg/m2 in addition to a single intravenous dose (30 mg) of alemtuzumab. IVIG was also given perioperatively at a dose of 2 g/kg body weight. Postoperative immunosuppression was with tacrolimus and steroid therapy. For most patients, the post-transplant prophylactic course of bortezomib was given weekly for a total of 4 doses. All patients were monitored with frequent endoscopic guided mucosal biopsies and serial measurement of the serum antibody titers. Both alemtuzumab and bortezomib were utilized for treatment of breakthrough moderate to severe rejection with diffuse positive C4d stains.

Results: All patients are currently alive with a follow-up ranging from 2 to 14 months. All grafts achieved full nutritional autonomy within the first 4 postoperative weeks. Vascular rejection with diffuse to focal C4d stains was observed in 3 (75%) allografts; moderate in 2 and mild in one. Despite successful reversal of the histological changes, the C4d stains continue to be focal in the intestinal mucosal biopsy with involvement of the capillary vessels. Only one patient experienced CMV viremia and pulmonary aspergillosis that was successfully treated with antiviral and antifungal therapy. There was no single example of graft versus host disease. It remains to be seen if any of these allografts escapes the potential risk of chronic rejection with long-term follow-up.

Conclusion: This preliminary study suggests that bortezomib may be an effective adjunctive induction and treatment therapy for visceral allograft recipients with preformed and/or de novo antibodies.