*Purpose: Highly-HLA sensitized (HS) patients have an immunologic barrier to transplantation. ABMR promotes graft loss and poor patient survival. Methods to reduce anti-HLA antibodies are limited. We report use of daratumumab(anti-CD38), a monoclonal specific for plasma cells (PC) and plasmablasts (PB) for desensitization (DES) and ABMR treatment.

*Methods: Patient 1 was HS, awaiting heart transplantation, having failed multiple DES treatments. Patient 2 had severe, treatment-resistant ABMR. Both patients received daratumumab 16 mg/kg IV weekly x4. Prior to and after treatment, HLA antibodies and immune cell phenotyping were determined. Biopsy was performed pre and post-daratumumab (patient 2).

*Results: Infusions were well tolerated without significant AE/SAE. CD38+ PC, PB, B-memory and B-regs were eliminated and HLA antibodies significantly reduced post-daratumumab in both patients. Patient 1 had HLA class I & II antibodies reduced by 72% (Fig 1A). Flow cytometry (FC) analysis of peripheral B-cell & T-follicular (Tfh) subsets pre-and post-daratumumab vs normals showed more B-reg, PC, PB & Tfh cells prior to treatment. After treatment, B-regs, PC, PB were eliminated, Tfh cells reduced; coinciding with reduced antibodies. Unfortunately, patient died from heart failure before transplant. In patient 2, disparate results were seen for class I vs II antibodies. A significant, persistent reduction of class I antibodies was seen without rebound (55%, 69% post & 6M post). However, there was no impact on class II antibodies including a DSA to DQ5. Several antibodies rebounded and de novo class II DSAs appeared (Fig 1B). The original biopsy showed evidence of ABMR & CMR (Banff 1A) unresponsive to treatment with PLEX+IVIg+Rituximab+Eculizumab. The post-daratumumab biopsy showed ABMR resolution, however intense CMR was seen (Banff 1B). FC analysis of CD4+ T-cells pre- and post-therapy showed complete elimination of B-regs, PC, PB post-daratumumab. However, an increase in peripheral CD4+ T-cells was seen that coincides with worsening of CMR (Banff 1B) on biopsy. Daratumumab did not impact eGFR. Improvements in ABMR were seen despite a lack of impact on DSAs. This likely reflects NK cell depletion by daratumumab.

*Conclusions: Daratumumab effectively reduced HLA antibodies and improved ABMR. However, concerns for antibody rebound, B-reg depletion and CMR incitement may limit efficacy. NK cell depletion by daratumumab is likely responsible for improvements in ABMR where no impact on DSA was seen.

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