Daratumumab as Salvage Therapy in Pediatric Thoracic Organ Transplantation: An Addition to the Antibody Mediated Rejection Toolbox?

Abstract

Purpose Antibody mediated rejection (AMR) is difficult to treat and often results in death or graft loss. Therapies targeted at antibodies or B cells are inadequate for decreasing donor specific antibodies (DSA), particularly to MHC class II. Bortezomib, a small molecule proteasome inhibitor targets plasma cells, but has many side effects and unsatisfactory results. Alternatively, we used Daratumumab (DAR), an anti-CD38 monoclonal antibody, in two pediatric transplant (Tx) recipients. Methods Chart review. Results An 18-year-old female with cystic fibrosis had a lung-liver Tx at 12-years-old. Twenty months post-Tx she developed severe AMR and Acute cellular rejection (ACR) treated with ATG, rituximab, TPE, photopheresis, and steroids. She ultimately required redo lung Tx. She did well for three years, but then developed AMR. She again received TPE, ATG, photopheresis, and rituximab. She was not considered a candidate for third lung Tx so all attempts were made to salvage her graft. She had no B cells, but continued to make DSA, so a plasma cell targeted therapy was desired. She received three doses of DAR 16 mg/kg on days 0, 7 and 21 with no infusion reactions. She developed neutropenia 2 months later which resolved with 3 weeks of GCSF. Both total PRA and DSA significantly decreased after DAR and have not returned 7 months later. PRA class I dropped from peak of 96% to 0, class II from peak 34% to 3%. She is maintained on subcutaneous IgG replacement for secondary hypogammaglobulinemia. Her graft function is poor, but has stabilized since DAR. She had one episode of presumed line associated sepsis and MSSA pneumonia without sequalae. A 3-year-old girl two years post heart Tx developed refractory AMR (by C4d and elevated DSA) despite ATG, TPE, IVIG, eculizumab, and ofatumumab. She then received two doses of DAR, 16 mg/kg each on days 0 and 14. She tolerated the infusions without any initial side effects. Not enough time has elapsed to follow up antibody levels or graft function. Conclusion Treatment for AMR remains challenging, especially when due to class II HLA antibodies. We safely administered DAR to two pediatric patients without infusion reactions or significant infectious complications to date. One patient had a decline in antibodies, while the other is too soon to determine. While more studies are needed, DAR may be a promising addition to the AMR toolbox.