The controversial role of Bortezomib in the treatment of AMR

The controversial role of Bortezomib in the treatment of AMR
E.Theodoropoulou1, H.Gakiopoulou2, G.Vlachopanos1, A.Iniotaki1, E.Patsouris2,
J.Boletis1, G.Zavvos1
Transplantation Unit, Laiko Hospital, Athens, Greece
First Department of Pathology, School of Medicine, University of Athens, Greece
Objectives To date, no effective immunosuppressive standard protocol has been
established for the prevention or treatment of alloantibody production in antibody
mediated rejection (AMR) of renal transplants. Bortezomib (BZ), a proteasome
inhibitor inducing plasma cell apoptosis, has been considered to represent a promising
drug with anti-humoral activity in the situation of an already established humoral
alloimmune response after renal transplantation. We present two patients with AMR
who were treated with BZ.
Methods The two patients underwent a renal biopsy, 2 and 3 years after
transplantation, respectively. Both presented with a slight deterioration of renal
function while the second one also showed proteinuria. Both patients had circulating
DSAs (Donor Specific Antibodies) and both had been switched to everolimus, the
first because of an increased chronicity index in zero hour biopsy and the second
because of a history of renal cell carcinoma. Interestingly, the first patient developed
DSAs after switching to everolimus. A diagnosis of AMR (Banff 1997/2009 updates)
was made based on the renal biopsy findings [morphologic evidence and diffuse C4d
staining (C4d3)] together with the presence of DSAs. Following the biopsy results,
both patients were re-switched to CNIs (tacrolimus) and were treated with BZ (1.3
mg/m2 in days 1, 4, 8, 11 every 21 days X 4 cycles). In the second patient, BZ
treatment was supplemented with rituximab, immunoadsorptions (IA) and iv
immunoglobulin. PRAs (Panel Reactive Antibodies) were measured before and after
every treatment. Patients’ follow up is 10 months and 17 months, respectively.
Results After treatment, renal function of both patients returned near the pre-biopsy
levels and the proteinuria of the second patient decreased significantly. The first
patient who was treated with BZ alone showed no decrease of the titers of DSAs and
interestingly, a second and later a third DSA appeared while under treatment, with no
clinical deterioration. The second patient showed a transient decrease of DSA titers
after treatment with BZ (4 cycles), rituximab(1 dose of 375mg/m2), 9 sessions of IA,
iv immunoglobulin and switch to CNI. However, the titers subsequently increased
with a concurrent increase in proteinuria and stable renal function. A second renal
transplant biopsy was then performed which demonstrated morphologic evidence of
acute and chronic tissue injury with diffuse C4d staining. A 15% increase of
interstitial fibrosis and tubular atrophy was also noted. The patient underwent 9
sessions of IA with concurrent administration of iv immunoglobulin. The patient
responded to treatment with reduction of proteinuria and DSA titers. In the last follow
up, a new rise of DSA titers was noted, reaching the pretreatment levels. Notably, the
patient developed severe peripheral neuropathy after the fourth cycle of BZ.
Conclusions Although BZ seems a promising tool in the treatment of AMR, our
preliminary cases failed to demonstrate any effect on anti-HLA antibodies in more
than one year renal transplant recipients which is in keeping with the results of
Sberro-Soussan et al who used BZ as a solo therapy in 4 patients with AMR and at
least 1 year out from transplantation. The efficacy of BZ in the management of AMR
does not seem to overcome the known therapeutic limitations regarding long-lived
antibody levels (further than one year post-transplant). However, BZ’s role may be
better elucidated as more clinical data and well-designed clinical trials become