Clinical outcomes of the use of subcutaneous daratumumab for donor-derived cell-free DNA guided treatment of antibody mediated rejection in asian kidney transplant recipients at the Singapore General Hospital

Introduction: Long-term kidney transplant (KTX) survival following treatment of antibody mediated rejection (ABMR) with standard of care therapies like plasmaphresis, intravenous immunoglobulin and rituximab remains poor. This may be because critical effectors of ABMR such as antibody-secreting CD38+ plasma cells and natural killer cells are not targeted with these therapies. In recent years, anti-CD38+ therapies have gained interest especially following a randomized controlled trial showing that Felzartamab resolved ABMR in 80% of cases. We report our own experience of the use of another anti-CD38 agent, Daratumumab (DARA) in the treatment of ABMR.
Methods: This was a retrospective cohort study of 10 kidney transplant recipients who received variable doses of subcutaneously administered DARA (1800 mg dose each) following light microscopic and molecular diagnosis of ABMR. Donor-derived cell-free DNA (dd-cfDNA) was also measured for all patients during treatment.
Results: The study population comprised of 10 KTX recipients (5 living, 5 deceased kidney donors) who were diagnosed with ABMR at a median time of 44.1 (range 6.1-206.3) months. Light microscopic diagnosis was active ABMR in 9 and chronic active ABMR in 1. Except for 1 patient who was referred from another hospital, all also had tissue send for transcriptomic analysis using MMDx and confirmed the presence of ABMR (4 early, 5 fully developed molecular ABMR). Median percent and copies/mL of dd-cfDNA before the first dose of DARA was 0.53% (range 0.37-4.36) and 27.5 (range 8-293) copies/mL. DARA was used as first line treatment for 6, 3 for persistent ABMR and 1 who could not undergo plasmaphresis due to a recent stroke. The number of doses of DARA was determined by the trend of dd-cfDNA with 5 patients receiving 4 doses, 1 receiving 3 doses, 3 receiving 2 doses and 1 receiving only 1 dose. Following the last dose of DARA, the median percent and copies/mL of dd-cfDNA fell in all to 0.08 (range 0.08-0.45) and 11 (range 5 to 12) respectively at last median follow-up time of 247.5 (range 42-297) days. Only 2 patients had repeat biopsies following completion of DARA treatment - 1 had histological resolution of ABMR while the other had improvement in microvascular inflammation from 4 to 2. There was 100% graft survival but only 4 patients had improvement in percent change in estimated glomerular filtration rate (eGFR) between first dose of DARA and last follow-up at +36.2% (range 2.2-141.7) while the others experienced a decline in eGFR at -14.7% (range -1.3 to -36.7). No factor (baseline eGFR, dd-cfDNA level, histological and most molecular scores) was found to be significantly associated with improvement in eGFR except for molecular atrophy-fibrosis score (p=0.014).
Conclusion: Our preliminary experience with DARA treatment for ABMR is positive since all experienced a decline in dd-cfDNA but is limited by the lack of follow-up biopsies in most patients.