Proteasome Inhibitor Carfilzomib-Based Therapy for Antibody-Mediated Rejection of the Pulmonary Allograft: Use and Short-Term Findings.
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 ( FEV1) fell from mean 2.11 L pre-AMR to 1.92 L at AMR (p = 0.04). FEV1was 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) (FEF25-75) fell from mean 2.5 L pre-AMR to 1.95 L at AMR (p = 0.01). FEF25-75rose 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.
School of Pharmacy, Department of Pharmacy and Therapeutics, University of Pittsburgh, Pittsburgh, PA.|School of Medicine, Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA.
C R
CR
Ensor
Department of Pathology, University of Pittsburgh, Pittsburgh, PA.
S A
SA
Yousem
Department of Pathology, University of Pittsburgh, Pittsburgh, PA.
M
M
Marrari
School of Medicine, Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA.
M R
MR
Morrell
Department of Pathology, University of Pittsburgh, Pittsburgh, PA.
M
M
Mangiola
School of Medicine, Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA.
J M
JM
Pilewski
Division of Cardiothoracic Surgery, Department of Surgery, University of Pittsburgh, Pittsburgh, PA.
J
J
D'Cunha
Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA.
S R
SR
Wisniewski
Department of Pathology, University of Pittsburgh, Pittsburgh, PA.|Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA.
R
R
Venkataramanan
Department of Pathology, University of Pittsburgh, Pittsburgh, PA.
A
A
Zeevi
School of Medicine, Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA.
J F
JF
McDyer
D000328:Adult; D000368:Aged; D064591:Allografts; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000188:drug therapy* / Q000209:etiology; D006085:Graft Survival / Q000187:drug effects*; D006801:Humans; D007518:Isoantibodies / Q000009:adverse effects*; D016040:Lung Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000627:therapeutic use*; D011183:Postoperative Complications; D011379:Prognosis; D061988:Proteasome Inhibitors / Q000627:therapeutic use*; D012307:Risk Factors
D007518:Isoantibodies; D009842:Oligopeptides; D061988:Proteasome Inhibitors; C524865:carfilzomib
alloantibody; clinical research/practice; lung (allograft) function/dysfunction; lung transplantation/pulmonology; plasma cells; plasmapheresis/plasma exchange; rejection: antibody-mediated (ABMR)