*Purpose: Antibody-mediated rejection (AMR) after lung transplant (LT) is associated with early progressive chronic lung allograft dysfunction (CLAD) and death. Therapeutic regimens remain poorly evaluated. We present a case of successful CD38-antagonist augmentation of carfilzomib (CFZ)-based therapy for recalcitrant AMR after LT.

*Methods: CFZ, plasma exchange (PLEX), and IVIG, have been shown to result in donor-specific antibody (DSA) depletion and allograft recovery after AMR. Responsiveness to CFZ-based therapy declines after each recurrent AMR episode. CFZ-based therapy relies on buildup of ubiquinated proteins which results in plasma cell apoptosis. Plasma cells will survive if other proteasomes are able to degrade enough proteins. Plasma cell surface receptor CD38 antagonism represents an attractive therapeutic option for conventional complement-mediated cell wall disruption yielding plasma cell apoptosis. Augmentation of CFZ-based therapy with the CD38 antagonist daratumumab (DTM) has led to doubling in relapse free survival in patients with multiple myeloma prior to HSCT.

*Results: This is a 32-year-old black female with cystic fibrosis who presented 12 months after bilateral LT on TAC/MMF/Pred with significant drop in spirometry in the absence of cellular rejection. Strong Class II DSA DQ4 (DQA1*04:01/DQB1*04:02) was identified with MFI of 14801 in the neat serum and remained strong with MFI of 11861 at 1:8 dilution that was C1q positive. Transbronchial biopsy was diffusely positive for C4d deposition. She was treated for definite AMR with CFZ/PLEX/IVIG as previously reported by Ensor et al which resulted in DSA depletion to neat MFI of 4658 and 1:8 MFI of 0 and allograft function recovered. Response was not durable and definite AMR recurred 1 month later with allograft decline which was treated with CFZ-based therapy plus DTM 8 mg/kg (400 mg) on days 1,2,8,9,15,16 after CFZ. Neat MFI depleted from 10109 to 0 after DTM-augmented CFZ-based therapy and allograft function stabilized. Definite AMR again recurred 2 months later with neat MFI 8086 with further allograft decline which was treated with DTM-augmented CFZ-based therapy that resulted in durable elimination of detectable DSA (MFI 0) and third-party anti-HLA antibodies. Allograft function stabilized with FEV1 <1L and mixed restrictive/obstructive physiology. No grade 3 or higher adverse events were observed with DTM. Patient has been AMR free for 6 months and is listed for retransplantation.

*Conclusions: CD38-antagonist DTM augmented CFZ-based therapy resulted in resolution of AMR and elimination of DSA in this therapeutically recalcitrant case of recurrent definite AMR of the lung allograft. No additional toxicity above CFZ-based therapy was demonstrated due to DTM.

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