Contemporary approach to desensitization: Targeted therapies for HLA sensitized pediatric heart transplant candidates
Lakshmi R Gokanapudy Hahn1, Marlena Habal2, Adriana Zeevi3
1Washington University in St. Louis, School of Medicine, St. Louis, MO.
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.
Insights
This study evaluates Carfilzomib (CFZ) and Belatacept (BELA) for desensitizing pediatric heart transplant candidates with HLA antibodies. The goal is to improve donor availability and reduce waitlist mortality in highly sensitized patients.
Area of Science:
- Immunology
- Transplantation Medicine
- Pharmacology
Background:
- HLA sensitization is a major barrier in pediatric heart transplantation (HT), limiting donor options and increasing mortality.
- Current desensitization protocols for HLA-sensitized pediatric patients are often ineffective.
- Adult studies suggest a combination of Carfilzomib (CFZ) and Belatacept (BELA) can reduce HLA antibodies.
Purpose of the Study:
- To assess the clinical effectiveness of CFZ and BELA in reducing HLA antibody levels in pediatric and young adult heart transplant candidates.
- To evaluate the utility of this dual desensitization strategy in a highly sensitized pediatric population.
- To establish a standardized approach for desensitization and antibody evaluation in pediatric HT.
Main Methods:
- Prospective, observational study including approximately 30 highly sensitized patients (cPRA ≥ 50%) aged 10-24 years across 6 pediatric centers.
- Utilizes a central IRB and the Pediatric Heart Transplant Society (PHTS) registry for a harmonized, multicenter approach.
- Includes HLA and mechanistic core labs to measure antibody responses (MFIs, titers, cPRA) and investigate desensitization effects on antibody-producing cells.
Main Results:
- The study is designed to measure reductions in HLA antibody type and strength.
- Secondary endpoints focus on mechanistic insights into desensitization and its impact on post-transplant outcomes.
- Data will be collected through the PHTS registry and analyzed by HLA and mechanistic core labs.
Conclusions:
- This study aims to establish a transformative, standardized desensitization protocol for pediatric heart transplantation.
- The findings could significantly impact donor availability and outcomes for highly sensitized pediatric HT candidates.
- This research represents the first prospective, registry-based investigation of this desensitization strategy in pediatric HT.
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