Use of Bortezomib in the Treatment of Antibody Mediated Rejection (AMR) in Pediatric Heart Recipients

Abstract

Purpose No single agent has been found to adequately treat AMR after heart transplant (HTx). Bortezomib, which can reduce donor-specific antibody (DSA) production by elimination of plasma cells, has been used as adjunctive AMR treatment in adults, but its use in pediatric HTx recipients has not been well described. Methods Single center retrospective review of 27 consecutive patients (<21yo) diagnosed with AMR and treated with bortezomib from 1/2011-10/2017. Clinical and immunogenic data were reviewed. Results Median age at HTx was 36 months (IQR 9-108) and time from HTx to AMR was 308 days (35-2231). Majority of cases (81.5%) had an underlying diagnosis of CHD. Diagnosis was by biopsy in 23 patients (11 pAMR1, 11 pAMR2, and 1 pAMR3), while 4 were based on clinical evidence. Echocardiogram showed systolic dysfunction in 8 (29.6%). All 27 patients had circulating DSAs at diagnosis. Each received at least 1 course of bortezomib (1.3 mg/m2 x4 doses), while 10 had 2 courses, and 2 had 3 courses. Other intensive treatments for AMR were also administered. DSA production decreased in patients receiving bortezomib, more noticeably for HLA-I than HLA-II, with partial rebound noted after treatment.(Figure). Follow-up biopsy (median 68 days [41-122] after diagnosis) showed resolution of AMR in 21 (78%). At median follow-up of 603 days (79-1400), graft survival was 63%; 2 required retransplant (1 directly attributed to AMR) and 8 died (4 directly attributed to AMR). Adverse events leading to discontinuation or adjustment of dosing included headache (2), thrombocytopenia (2), elevated transaminases (3), neuropathy (2), and flash pulmonary edema leading to ARDS/death (1). Conclusion Bortezomib can reduce DSA production and may be a viable adjunctive therapeutic option for AMR in pediatric HTx recipients. However, risk of adverse effects requires close monitoring, with early intervention to adjust or discontinue dosing. Further study is needed to determine the precise role of bortezomib in pediatric AMR. No single agent has been found to adequately treat AMR after heart transplant (HTx). Bortezomib, which can reduce donor-specific antibody (DSA) production by elimination of plasma cells, has been used as adjunctive AMR treatment in adults, but its use in pediatric HTx recipients has not been well described. Single center retrospective review of 27 consecutive patients (<21yo) diagnosed with AMR and treated with bortezomib from 1/2011-10/2017. Clinical and immunogenic data were reviewed. Median age at HTx was 36 months (IQR 9-108) and time from HTx to AMR was 308 days (35-2231). Majority of cases (81.5%) had an underlying diagnosis of CHD. Diagnosis was by biopsy in 23 patients (11 pAMR1, 11 pAMR2, and 1 pAMR3), while 4 were based on clinical evidence. Echocardiogram showed systolic dysfunction in 8 (29.6%). All 27 patients had circulating DSAs at diagnosis. Each received at least 1 course of bortezomib (1.3 mg/m2 x4 doses), while 10 had 2 courses, and 2 had 3 courses. Other intensive treatments for AMR were also administered. DSA production decreased in patients receiving bortezomib, more noticeably for HLA-I than HLA-II, with partial rebound noted after treatment.(Figure). Follow-up biopsy (median 68 days [41-122] after diagnosis) showed resolution of AMR in 21 (78%). At median follow-up of 603 days (79-1400), graft survival was 63%; 2 required retransplant (1 directly attributed to AMR) and 8 died (4 directly attributed to AMR). Adverse events leading to discontinuation or adjustment of dosing included headache (2), thrombocytopenia (2), elevated transaminases (3), neuropathy (2), and flash pulmonary edema leading to ARDS/death (1). Bortezomib can reduce DSA production and may be a viable adjunctive therapeutic option for AMR in pediatric HTx recipients. However, risk of adverse effects requires close monitoring, with early intervention to adjust or discontinue dosing. Further study is needed to determine the precise role of bortezomib in pediatric AMR.