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.

Keywords: alloantibody; clinical research/practice; clinical trial; desensitization; histocompatibility; immunosuppression/immune modulation; kidney transplantation/nephrology; panel reactive antibody (PRA); plasma cells; translational research/science.

FIGURE 1

Prospective, iterative trial of carfilzomib-based desensitization. A, Treatment regimen for group A. Carfilzomib was administered in a within-patient dose-escalation fashion (20 to 36 mg/m²). Bone marrow biopsies and aspirates were performed before treatment and after 1 cycle of carfilzomib therapy. B, Treatment regimen for group B. Treatment was identical to group A, but plasmapheresis was added once weekly prior to carfilzomib administration. Bone marrow biopsies and aspirates were optional in both groups

FIGURE 2

Study results. A, Patient disposition diagram. B, Reduction in iAb for groups A and B. Comparisons are for overall pairwise differences between days 1, 45, and 53

FIGURE 3

Carfilzomib reduces the breadth of HLA sensitization for both class I and class II antigens. A, Representative bar graph of reduction in a wide range of HLA class I antibodies before and after desensitization treatment. B, Representative bar graph of reduction in a wide range of HLA class II antibodies before and after desensitization treatment. C, Boxplot depicting reduction in overall class I HLA specificities for the entire study group. D, Boxplot depicting reduction in overall class II HLA specificities for the entire study group

FIGURE 4

Carfilzomib induces bone marrow (BM) CD138⁺ cell death. A, Reduction in live BM CD138⁺ cells as a function of total BM nucleated cells after 1 cycle of carfilzomib therapy. B, BM CD138⁺ cells, unexposed to proteasome inhibitors, were incubated with control media, bortezomib, and carfilzomib. After incubation, expression of annexin-V, a marker of apoptosis, was increased in cells incubated with proteasome inhibitors compared with control media