Contemporary approach to desensitization: Targeted therapies for HLA sensitized pediatric heart transplant candidates – Study design and rationale

Purpose: HLA sensitization significantly limits donor availability and increases waitlist mortality in pediatric heart transplantation (HT). Current desensitization strategies are largely ineffective or equivocal. Recent adult studies show that a dual approach with Carfilzomib (CFZ), a proteasome inhibitor, and Belatacept (BELA), a costimulation blocker, reduces class I and II HLA antibodies (Abs). This study will evaluate the clinical utility of CFZ and BELA in reducing HLA antibody type and strength in pediatric and young adult patients. Methods: This prospective, observational study will include about 30 patients from 6 pediatric clinical sites, an HLA core and a mechanistic core lab. Patients aged 10-24 years, highly sensitized with class I and/or class II cPRA ≥ 50% (MFI > 4000), will be included. Exclusion criteria: EBV seronegative, HIV+, and a history of hematologic malignancy. Secondary endpoints include mechanistic studies on how desensitization affects cellular subsets producing HLA Abs, whether reductions in antibody strength persist until transplant, and post-transplant outcomes such as antibody mediated rejection and graft survival. Results: The study's unique design harmonizes the use of a novel protocol across sites using a central IRB and is the first prospective, registry-based investigation in pediatric HT using the Pediatric Heart Transplant Society (PHTS) registry. The HLA core will measure antibody response through MFIs, titers, and cPRA, while the mechanistic core will use advanced investigations to support the trial's clinical endpoints. Conclusion: This multicenter study aims to establish a transformative, standardized approach to desensitization and antibody evaluation.