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Purpose Reduction in circulating alloantibodies is a common goal in treating antibody mediated rejection (AMR) and in desensitization of highly sensitized transplant recipients. There are limited data about safety and efficacy of these treatments in children. We report our experience using combined therapy with rituximab, plasmapheresis (PP), and bortezomib to reduce anti-HLA antibodies (Abs) in AMR and desensitization in pediatric heart transplantation (HT). Methods There were 16 treatment courses for desensitization or AMR at our institution from 5/2012-3/2018: 4 for desensitization and 12 for AMR. A typical cycle consists of PP followed by rituximab (375mg/m2) with 4 subsequent PP cycles, each followed by bortezomib (1.3mg/m2), over 21 days. Cycles may be repeated based on response. AlloAb burden was quantified using the OPTN cPRA calculator for Abs ≥4000 MFI to capture clinically relevant Abs. cPRA prior to treatment and at 3 and 12 months after therapy completion were analyzed. Results Median patient age was 12.6 (2.9-20.4) years. All 4 desensitized candidates achieved HT (3 with negative cytotoxicity crossmatch), with median wait time of 166 (68-412) days from therapy initiation. All are alive and free from >pAMR1 at 341.5 (119-904) days from HT. Of the 12 treated for AMR, 10 are alive and 4 had coronary allograft vasculopathy during median follow-up of 948.5 (40-1483) days from AMR diagnosis. Mean class I and II cPRAs were 28.5% and 51.4%, decreasing to 16.4% (p=0.29) and 20.1% (p<0.01) at 3 months and 9.7% (p=0.11) and 11.4% (p<0.01) at 1 year, respectively, after treatment (Figure). Complications included 3 patients with bacteremia, 2 with peripheral neuropathy, and one with stroke. Conclusion Combined therapy with rituximab, PP, and bortezomib reduced circulating Abs, both in desensitization and treatment of AMR, in our small pediatric HT series. Survival to HT (for desensitization) and after HT (for AMR) also appear reassuring, with some risk of complications. More detailed and regimented multicenter studies are warranted. [ABSTRACT FROM AUTHOR]

Purpose Recent reports indicate that >50% of pediatric heart transplant (HT) candidates are HLA-sensitized at time of HT. Clinicians have a difficult choice: wait for an ideal organ offer without HLA antibody (Ab) or take the first acceptable offer. Desensitization can be useful to facilitate HT by decreasing or abrogating HLA Ab. We have evolved to use desensitization to evaluate which HLA Ab may be safely crossed and which to avoid. To illustrate our approach, we present: a non-responder, a partial-responder, and a total-responder. Methods HLA Ab analysis was done by Luminex® single antigen bead assay (SAB), with serial dilutions and C1q-fixing assay. Ab ≥2000 MFI by IgG-SAB and ≥500 MFI by C1q-SAB were used to determine the calculated PRA (cPRA). One desensitization cycle consisted of rituximab (x1), bortezomib (BTZ) (x4), and plasmapheresis (x5). Cycles are repeated leaving 2 weeks between last and first doses of each cycle. Results Non-responder (Fig 1A): Bw4/Aw4 sensitized patient did not respond to desensitization. Ab reassessment showed rebound, and after the 3rdcycle the titer increased and Ab was C1q+. The patient received HT with a Bw6/Bw6 donor without Aw4 antigens; no donor specific Ab (DSA) is detected 1 year post-HT. Partial-responder (Fig 1B): selective response for 1 HLA Ab group. Both anti-DR53 and DQ7/DQ8/DQ9 Abs were C1q+. However, DQ7/DQ8/DQ9 Ab had lower baseline titer. After 2 cycles, DR53 Ab did not change while DQ7/DQ8/DQ9 Ab was reduced in titer and became C1q-. HT proceeded with a DQ7+ donor and DSA remains negative 2.5 years post-HT. Total responder (Fig 1C): Ab to all but self HLA. A complete response was seen; by the end of 3rdcycle, most Ab was reduced to low titer and C1q-. HT was done crossing 2 C1q- Abs. No DSA detected 118 days post-HT. Conclusion Multi-dimensional testing of HLA Ab titer and C1q binding and serial monitoring pre- and post-desensitization helps to determine if more treatment is needed and allows for safe HT risk assessment when crossing HLA Abs. [ABSTRACT FROM AUTHOR]