Total Lymphoid Irradiation in The Treatment and Prevention of Pediatric Cardiac Allograft Rejection — A 23-Year Experience

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Despite the development of increasingly efficacious immunosuppressive agents, allograft rejection is still a leading cause of morbidity and mortality in pediatric heart transplant patients. Total lymphoid irradiation (TLI) has emerged as a secondary treatment for recurrent cardiac allograft rejection refractory to medication in adults. However, there is limited evidence for long-term TLI efficacy and safety in the pediatric cohort. Our objectives were to evaluate 1) the long-term effects of TLI in treating recurrent pediatric cardiac allograft rejections at a single institution, and 2) the outcome of a unique prophylactic TLI protocol for re-transplant cardiac allograft in pediatric patients. This study included pediatric cardiac transplant patients who received TLI between 1996 and 2014, and who underwent regular right ventricular endomyocardial biopsies. TLI of 800 cGy in 10 fractions was delivered twice a week to the mantle and periaortic/splenic fields. Indication of TLI for treatment of allograft rejection included recurrent episodes (≥ 3) of rejection (defined as ISHLT Grade ≥ 1B/1R) or rejection episodes that failed to respond to medical therapy. Prophylactic TLI was indicated for patients who received a re-transplant cardiac allograft. Follow-up on these patients ended on January 23, 2020, comprising of 23 years of single institutional data. Comparisons in endpoints were performed using paired-sample, non-parametric tests. Eighteen patients underwent TLI for treatment of recurrent cardiac allograft rejection (n = 11, treatment cohort) and/or for rejection prevention in a re-transplant graft (n = 10, prophylactic cohort). Three patients completed 2 courses of TLI for both treatment and prevention of graft rejection. Median follow up was 10.1 years (range 0.5-23 years). In the treatment cohort, TLI demonstrated a trend to prolong the time to graft rejection, from a median of 62 days before TLI to 320 days after TLI (p = 0.054). In the prophylactic cohort, TLI increased ten-year graft survival from 11.1% to 44.4% (n = 9 due to a patient lost to follow-up; p = 0.38). Nine out of 10 patients underwent re-transplant due to graft coronary artery disease in the initial allograft – 1 patient developed coronary vessel narrowing in the re-transplant graft requiring a drug-eluting stent 17.1 years after prophylactic TLI, while the other 8 patients had no evidence of any narrowing, stenosis, or coronary allograft vasculopathy (CAV) in the re-transplant graft (mean CAV-free graft survival 9.4 years). During long-term follow-up, there was no incidence of hematological malignancies or blood dyscrasias. Our study showed that TLI was well tolerated and safe in long-term follow-up. It not only demonstrated a trend to prolong the time to graft rejection, but also showed promising results in preventing CAV and lengthening graft survival if given prophylactically. Further investigation into the role of treatment and prophylactic TLI is warranted.