Proteasome Inhibitor Carfilzomib-Based Therapy for Antibody-Mediated Rejection of the Pulmonary Allograft: Use and Short-Term Findings

Abstract

We present this observational study of lung transplant recipients (LTR) treated with carfilzomib (CFZ)-based therapy for antibody-mediated rejection (AMR) of the lung. Patients were considered responders to CFZ if complement-1q (C1q)-fixing ability of their immunodominant (ID) donor-specific anti-human leukocyte antibody (DSA) was suppressed after treatment. Treatment consisted of CFZ plus plasma exchange and immunoglobulins. Fourteen LTRs underwent CFZ for 20 ID DSA AMR. Ten (71.4%) of LTRs responded to CFZ. DSA IgG mean fluorescence intensity (MFI) fell from 7664 (IQR 3230-11 874) to 1878 (653-7791) after therapy (p = 0.001) and to 1400 (850-8287) 2 weeks later (p = 0.001). DSA C1q MFI fell from 3596 (IQR 714-14 405) to <30 after therapy (p = 0.01) and <30 2 weeks later (p = 0.02). Forced expiratory volume in 1s ( FEV ) fell from mean 2.11 L pre-AMR to 1.92 L at AMR (p = 0.04). FEV was unchanged after CFZ (1.91 L) and subsequently rose to a maximum of 2.13 L (p = 0.01). Mean forced expiratory flow during mid forced vital capacity (25-75) (FEF ) fell from mean 2.5 L pre-AMR to 1.95 L at AMR (p = 0.01). FEF rose after CFZ to 2.54 L and reached a maximum of 2.91 L (p = 0.01). Responders had less chronic lung allograft dysfunction or progression versus nonresponders (25% vs. 83%, p = 0.04). No deaths occurred within 120 days and 7 patients died post CFZ therapy of allograft failure. Larger prospective interventional studies are needed to further describe the benefit of CFZ-based therapy for pulmonary AMR.

The role of C4d deposition in the diagnosis of antibody-mediated rejection after lung transplantation

“…However, it is noteworthy that only a minority of patients cleared all DSA despite aggressive antibody-depleting therapy. Furthermore, the prevalence of DSA to class II HLA, and to HLA-DQ, in particular, in our cohort is consistent with previous studies in pulmonary, renal, and cardiac AMR 2,3,5,[28][29][30][31][32][33]. Emerging data suggest that HLA-DQ may be uniquely immunogenic.…”

Pediatric lung transplantation and end of life care in cystic fibrosis: Barriers and successful strategies

“…[21][22][23] In a recent study using a proteasome inhibitor-based therapy with carfilzomib for AMR, responders of the treatment regimen had less chronic lung allograft dysfunction or progression. 24 Further study is required before their administration can be recommended in pediatric lung transplant recipients.…”

“…Bortezomib, an inhibitor of the 26S proteosome that depletes plasma cells, and eculizimab, a complement‐inhibitory monoclonal antibody that inhibits assembly of the membrane attack complex via C5, are newer therapies that are being introduced by clinicians . In a recent study using a proteasome inhibitor‐based therapy with carfilzomib for AMR, responders of the treatment regimen had less chronic lung allograft dysfunction or progression . Further study is required before their administration can be recommended in pediatric lung transplant recipients.…”

Heterogeneity of memory B cells

“…55,56 Thus, costimulation blockade with CTLA-4Ig was effective at preventing the development of a recall DSA response, a finding consistent with the clinical observations of significantly low rates of DSA development in transplant recipients receiving belatacept, despite high rates of acute rejection. 57 In contrast, reversing an established recall DSA response that is mediated predominantly by PC may be more amenable to drugs that deplete PC, such as bortezomib or carfilzomib, 58,59 whereas a recall response that is dependent on GC output may additionally be responsive to drugs that inhibit the GC response. In addition, the notion that memB cells have different longevity depending on the mutation load suggests that recently sensitized recipients may mount a recall DSA response that has a more rapid kinetics and higher affinity, whereas when the sensitizing event occurred many decades ago, a functional recall response may require reentry into a GC response and thus be more sensitive to immunosuppression that prevents the reactivation of Tfh and lower-affinity memB cells.…”