Daratumumab for Antibody-mediated Rejection in Heart Transplant—A Novel Therapy: Successful Treatment of Antibody-mediated Rejection

Abstract

Daratumumab is a human IgG1κ monoclonal antibody directed against CD38, which is expressed on some subsets of lymphocytes and plasma cells. Mechanisms of action include complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and apoptotic signaling.1 Daratumumab is mainly used to treat multiple myeloma. Targeting CD38-positive plasma cells might decrease antibody production in antibody-mediated nonneoplastic diseases. Successful use of daratumumab to treat post-stem cell transplantation refractory autoimmune hemolytic anemia has been reported too. Its use has also been suggested in antibody-mediated rejection (AMR) in solid organ transplantation.2,3 We present the case of a 29-year-old male with a refractory AMR after a heart transplant (HTx) successfully treated with daratumumab. Our patient received a HTx at the age of 16. Follow-up was complicated by 2 episodes of acute cellular rejection 1 and 3 years after HTx. A previous AMR 7 years after HTx was successfully treated with intravenous immunoglobulin, plasmapheresis, rituximab, and cyclophosphamide. The patient remained stable in New York Heart Association class II with normal left ventricular ejection fraction (LVEF) for several years, although donor-specific anti-HLA antibodies (DSAs) values detected by the Luminex assay remained high during follow-up mean fluorescence intensity (MFI) 5000–8000 for DSA class I (A1, A2) and 8000–10 000 for DSA class II (DRB4 and DQA1*03). Thirteen years after HTx, the patient was admitted with a picture of congestive heart failure refractory to conventional therapy and renal failure. N-terminal pro-brain natriuretic peptide was 11 335 pg/mL (normal range, 10–125 pg/mL), LVEF was 30% with an interventricular septal wall thickness of 17 mm. Luminex assay showed an increase of the DSA titers (MFI of 14 000–18 000 for class I and 16 000–20 000 for class II). An endomyocardial biopsy showed endotheliitis, with diffuse deposits of C3d and isolated deposits of C4d on immunostaining, which was consistent with a pAMR1 (I+).4 He required admission to the intensive care unit. Treatment with methylprednisolone, immunoadsorption, and hemofiltration was initiated. A second HTx was ruled out because of the presence of anti-HLA antibodies. After careful reviewing of previous therapies, we decide to begin daratumumab on a compassionate basis after informed consent, because of the relative ineffectiveness of previously used treatments. We used the standard schedule, a weekly dose of 16 mg/kg of daratumumab for 8 weeks, then 8 fortnightly doses, and a monthly dose thereafter. Previous steroid therapy was tapered off. Therapy was well tolerated, with clinical, renal, and cardiac improvement in 4 weeks. After 12 months, he remains stable with New York Heart Association II class, N-terminal pro-brain natriuretic peptide of 2827 pg/mL, and normal LVEF, septal wall thickness, and renal function. DSA titers are only slightly reduced (MFI of 6000–12 000 for class I and 10 000–14 000 for class II). However, endomyocardial biopsy shows neither capillary injuries nor C3d, C4d, CD68, or CD20 deposits. To our knowledge, this is the first reported case of AMR in an HTx recipient treated with daratumumab, with clinical and histological improvement. Although we cannot exactly define the role of daratumumab added to high-doses of intravenous methylprednisolone and immunoadsorption; given the well-known difficulties of the treatment of AMR and its poor prognosis,5 a drug that specifically attacks antibody-producing cells with a favorable safety profile could represent a step forward in the field.

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