A prospective, iterative, adaptive trial of carfilzomib-based desensitization

Abstract

Proteasome inhibitor–based strategies hold promise in transplant but have yielded varying results. Carfilzomib, a second‐generation proteasome inhibitor, may possess advantages over bortezomib, the first‐generation proteasome inhibitors. The purpose of this study was to evaluate the safety, toxicity, and preliminary efficacy of carfilzomib in highly HLA‐sensitized kidney transplant candidates. Renal transplant candidates received escalating doses of carfilzomib followed by plasmapheresis (group A) or an identical regimen with additional plasmapheresis once weekly before carfilzomib dosing. Thirteen participants received carfilzomib, which was well tolerated with most adverse events classified as low grade. The safety profile was similar to bortezomib desensitization; however, neurotoxicity was not observed with carfilzomib. Toxicity resulted in permanent dose reduction in 1 participant but caused no withdrawals or deaths. HLA antibodies were substantially reduced with carfilzomib alone, and median maximal immunodominant antibody reduction was 72.8% (69.8% for group A, P = .031, 80.1% for group B, P = .938). After depletion, rebound occurred rapidly and antibody levels returned to baseline between days 81 and 141. Bone marrow studies revealed that approximately 69.2% of plasma cells were depleted after carfilzomib monotherapy. Carfilzomib monotherapy–based desensitization provides an acceptable safety and toxicity profile while leading to significant bone marrow plasma cell depletion and anti‐HLA antibody reduction.

Safety, pharmacokinetics, and pharmacodynamic activity of obinutuzumab, a type 2 anti-CD20 monoclonal antibody for the desensitization of candidates for renal transplant

“…[4][5][6]19 With no approved pharmacological therapy to reduce the Potential mechanisms underlying these observations have been recently described in Rhesus macaques by Kwun et al 26 over bortezomib. 27,28 Alternatively, future therapeutic regimens could combine obinutuzumab with antibodies targeting plasma-cell survival factors like IL-6, B cell activating factor (BAFF), and/or a proliferation-inducing ligand (APRIL). 29 The benefit of suppressing anti-HLA alloantibodies via sustained plasma-cell depletion with combination therapy will need to be weighed against the safety risk of depleting protective humoral response and vaccinations.…”

Desensitizing highly sensitized heart transplant candidates with the combination of belatacept and proteasome inhibition

“…1,2 Contemporary desensitization strategies focus on eliminating antibodies (plasmapheresis and more recently Ides) and/or the precursor cells responsible for their production (proteasome inhibitors and anti-CD20 antibodies). [3][4][5][6] Although promising in select cases, their efficacy is variable and frequently complicated by rebound due to homeostatic proliferation (compensatory B cell proliferation in response to the depletion of antibody-producing cells). 7 These observations underscore the need for a more effective, durable "immune modulating" strategy that reliably and sustainably reduces HLA antibodies before and after transplant.…”

Plasma cell targeting to prevent antibody-mediated rejection

“…In a 50‐patient iterative desensitization trial, bortezomib demonstrated considerable ability to reduce HLA Ab levels, but was limited by dosing‐related toxicity 19 . Therefore, we next utilized carfilzomib for desensitization, finding that carfilzomib monotherapy, and carfilzomib in combination with plasmapheresis were more potent in terms of HLA Ab reduction with no apparent dose‐limiting toxicities at doses up to 36 mg/m 2 20,21 . In this experience after 6 weeks of carfilzomib therapy, patients with very high HLA Ab levels experienced near complete HLA Ab elimination for a broad array of HLA Abs.…”

“…In addition, pre‐bortezomib plasmapheresis was not given to sensitize PCs to terminal UPR induction via PIs by increasing Ig production and ER stress. The best evidence for this effect derives from comparison of Groups A and B in a recently published prospective trial of carfilzomib‐based desensitization 20 . In this trial, addition of a single plasmapheresis once weekly (Group B) demonstrated greater reduction in HLA Ab than carfilzomib alone.…”