Daratumumab for non-acute antibody-mediated rejection after pediatric heart transplantation: Treatment response in the presence and absence of circulating HLA donor-specific antibody.

Abstract

Background: Late graft survival after pediatric heart transplantation (HT) remains inadequate, with chronic rejection being a major contributor. Daratumumab has shown promise treating antibody-mediated rejection (ABMR) with limited published experience in HT.

Methods: We retrospectively analyzed all HT recipients at our center treated with daratumumab (16 mg/kg × 4 doses) for ABMR identified by elevated donor-derived cell-free DNA (dd-cfDNA) without graft dysfunction or hemodynamic compromise and confirmed by endomyocardial biopsy gene expression profiling (EMB-GEP). HLA-DSA and non-HLA antibodies, including angiotensin II type 1 receptor (AT1R) antibody, were assessed pre- and post-treatment.

Results: Ten recipients were identified and treated with daratumumab, including 4 without HLA-DSA at diagnosis. dd-cfDNA decreased (1.6% to 0.04%; p=0.002) post-treatment. Among 8 with post-treatment EMB, ABMR resolved (n=6) or showed only possible ABMR (n=2) after treatment. HLA-DSA total MFI (p=0.031), non-HLA antibody burden (p=0.004), and AT1R Ab concentration (p=0.004) declined post-treatment. Six patients experienced subsequent elevations of dd-cfDNA at a median of 246 days (IQR, 239-283) with ABMR recurrence on EMB and responded to retreatment. No T-cell mediated rejection occurred after treatment.

Conclusions: Daratumumab was associated with significant improvements in dd-cfDNA, EMB-GEP, and antibody burden in pediatric and young adult HT recipients with ABMR. Response among patients without circulating HLA-DSA or with reduced but persistent HLA-DSA after treatment implies effects beyond plasma cell depletion. Rebound ABMR was common but responded to retreatment, suggesting periodic maintenance dosing may be required. Prospective studies are needed to define optimal treatment strategies and long-term outcomes.