Case report: Daratumumab for treatment of refractory late or chronic active antibody-mediated rejection in renal allograft recipients with high levels of de novo donor-specific antibodies

Abstract

Background: Late or chronic active antibody-mediated rejection (AMR) associated with de novo donor-specific antibodies (dnDSA) after renal transplantation is a great clinical challenge because it is often resistant to conventional therapies. Daratumumab, an anti-CD38 monoclonal antibody that can deplete plasma cells, may be effective for the treatment of late or chronic active AMR.

Methods: We designed a novel regimen that included early intensive therapy with daratumumab plus plasmapheresis (PP)/intravenous immunoglobulins (IVIG) and later maintenance therapy with daratumumab alone, and used this regimen to treat late or chronic active AMR in two kidney transplant recipients with extremely high levels of anti-DQ7 dnDSA.

Results: Both patients had a limited clinical response to the early treatment with rituximab and PP/IVIG (with or without splenic irradiation); however, they had a remarkable decrease in anti-DQ7 DSA (MFI value from ~20,000 to ~5,000) after 2-3 months of intensive therapy with daratumumab plus PP/IVIG. Over 20 months of follow-up, patient 1 maintained a low DSA (as low as 1,572) and normal renal function on daratumumab maintenance therapy. Patient 2 retained a low DSA and improved renal function and pathological lesions within one year after treatment but then deteriorated because of acute T cell-mediated rejection.

Conclusions: Our daratumumab-based regimen has shown promising results in the treatment of refractory late active or chronic active AMR in renal transplant recipients with high-level dnDSA. This may provide a reference for better use of daratumumab in the treatment of late or chronic active AMR.

Keywords: HLA-DQ; case report; chronic active antibody-mediated rejection; daratumumab; donor specific antibodies; kidney transplantation.

Figure 1

Histological features of subclinical chronic active AMR in Patient 1 before treatment and changes in DSA throughout treatment. (A) HLA phenotype results for the recipient and his donor. (B) Typical histological findings of chronic active AMR and their Banff 2017 Scores. (C) Changes in MFI values of the anti-DQ7 DSA (1:3 or 1:12-diluted serum) during the first round of treatment containing rituximab, PP/IVIG, and carfilzomib. (D) Changes in MFI values of the anti-DQ7 DSA (1:4/1:32/1:64-diluted serum and positive control serum) after the treatment with daratumumab-based therapy.

Figure 2

Course of Patient 2’s DSA and renal function after the diagnosis of late active AMR. (A) HLA phenotype results for the recipient and his donor. (B) Changes in MFI values of the anti-DQ7 DSA (1:4 or 1:64-diluted serum and positive control serum) during the treatment. (C) Changes in serum creatinine and eGFR levels after the diagnosis and treatment of late active AMR.

Figure 3

Histological features of late active AMR in Patient 2 before and after treatment. (A) Typical histological findings of active AMR in Patient 2 before the treatment and their Banff 2019 Scores. (B) The pathology results of a second renal biopsy performed on day 137 after the initiation of treatment and their Banff 2019 Scores. (C) The pathology results of a third renal biopsy performed on day 350 after the initiation of treatment (when acute rejection was clinically suspected) and their Banff 2019 Scores. (D) The pathology results of a fourth renal biopsy performed on day 422 after the initiation of treatment (when poor response was observed to daratumumab intensive therapy) and their Banff 2019 Scores.