Carfilzomib‐based antibody mediated rejection therapy in pediatric kidney transplant recipients

Abstract

BackgroundTo date, the evidence for proteasome‐inhibitor (PI) based antibody mediated rejection (AMR) therapy has been with the first‐generation PI bortezomib. Results have demonstrated encouraging efficacy for early AMR with lesser efficacy for late AMR. Unfortunately, bortezomib is associated with dose‐limiting adverse effects in some patients. We report use of the second generation proteosome inhibitor carfilzomib for AMR treatment in two pediatric patients with a kidney transplant.MethodsThe clinical data on two patients who experienced dose limiting toxicities from bortezomib were collected along with their short‐ and long‐term outcomes.ResultsA two‐year‐old female with simultaneous AMR, multiple de novo DSAs (DR53 MFI 3900, DQ9 MFI 6600, DR15 2200, DR51 MFI 1900) and T‐cell mediated rejection (TCMR) completed three carfilzomib cycles and experienced stage 1 acute kidney injury after the first two cycles. At 1 year follow up, all DSAs resolved, and her kidney function returned to baseline without recurrence. A 17‐year‐old female also developed AMR with multiple de novo DSAs (DQ5 MFI 9900, DQ6 MFI 9800, DQA*01 MFI 9900). She completed two carfilzomib cycles, which were associated with acute kidney injury. She had resolution of rejection on biopsy and decreased but persistent DSAs on follow‐up.ConclusionsCarfilzomib treatment for bortezomib‐refractory rejection and/or bortezomib toxicity may provide DSA elimination or reduction, but also appears to be associated with nephrotoxicity. Clinical development of carfilzomib for AMR will require a better understanding of efficacy and development of approaches to mitigate nephrotoxicity.

Carfilzomib: Looking for ‘The Holy Grail’ to treat antibody‐mediated rejection

“…In this issue of Pediatric Transplantation, Cody and colleagues published a series of two pediatric KTR treated with carfilzomib, a second-generation irreversible epoxyketone PI, who had previous evidence of dose-limiting toxicities from bortezomib. 10 Carfilzomib has been used in desensitization for adult kidney transplant recipients 11 as well as AMR treatment for lung transplant recipients 12 with an improved safety profile compared to bortezomib.…”

“…The two pediatric KTR with renal allograft dysfunction and rejection were described in this article. 10 They presented with either overlapping or successively occurring phenotypes of AMR and TCMR.…”