Short-term clinical outcomes and predicted cost savings of dd-cfDNA-led surveillance after pediatric heart transplantation.

BACKGROUND: Endomyocardial biopsy (EMB)-led surveillance is common after pediatric heart transplantation (HT), with some centers performing periodic surveillance EMBs indefinitely after HT. Donor derived cell-free DNA (dd-cfDNA)-led surveillance offers an alternative, but knowledge about its clinical and economic outcomes, both key drivers of potential utilization, are lacking. METHODS: Using single-center recipient and center-level data, we describe clinical outcomes prior to and since transition from EMB-led surveillance to dd-cfDNA-led surveillance of pediatric and young adult HT recipients. These data were then used to inform Markov models to compare costs between EMB-led and dd-cfDNA-led surveillance strategies. RESULTS: Over 34.5 months, dd-cfDNA-led surveillance decreased the number of EMBs by 81.8% (95% CI 76.3%-86.5%) among 120 HT recipients (median age 13.3 years). There were no differences in the incidences of graft loss or death among all recipients followed at our center prior to and following implementation of dd-cfDNA-led surveillance (graft loss: 2.9 vs. 1.5 per 100 patient-years; p = .17; mortality: 3.7 vs. 2.2 per 100 patient-years; p = .23). Over 20 years from HT, dd-cfDNA-led surveillance is projected to cost $8545 less than EMB-led surveillance. Model findings were robust in sensitivity and scenario analyses, with cost of EMB, cost of dd-cfDNA testing, and probability of elevated dd-cfDNA most influential on model findings. CONCLUSIONS: dd-cfDNA-led surveillance shows promise as a less invasive and cost saving alternative to EMB-led surveillance among pediatric and young adult HT recipients.

Early findings after integration of donor-derived cell-free DNA into clinical care following pediatric heart transplantation.

BACKGROUND: Endomyocardial biopsy (EMB) is costly and discomforting yet remains a key component of surveillance after pediatric heart transplantation (HT). Donor-derived cell-free DNA (dd-cfDNA) has been histologically validated with high negative predictive value, offering an alternative to surveillance EMB (sEMB). METHODS: We implemented an alternative surveillance protocol using commercially available dd-cfDNA assays in place of sEMB after pediatric HT. Recipients ≧7 months post-HT with reassuring clinical assessment were referred for dd-cfDNA. When not elevated above the manufacturers' threshold, sEMB was deferred. Subsequent clinical status and results of follow-up EMB were analyzed. RESULTS: Over 17 months, 58 recipients [34% female, median age at HT 3.1 years (IQR 0.6-10.6)] had dd-cfDNA assessed per protocol. Median age was 14.8 years (8.4-18.3) and time from HT 6.0 years (2.2-11.2). Forty-seven (81%) had non-elevated dd-cfDNA and 11 (19%) were elevated. During a median of 8.7 months (4.2-15), all are alive without allograft loss/new dysfunction. Among those with non-elevated dd-cfDNA, 24 (51%) had subsequent sEMB at 12.1 months (6.9-12.9) with 23 showing no acute rejection (AR): grade 0R/pAMR0 (n = 16); 1R(1A)/pAMR0 (n = 7). One had AR (grade 2R(3A)/pAMR0) on follow-up sEMB after decreased immunosuppression following a diagnosis of PTLD. All 11 with elevated dd-cfDNA had reflex EMB at 19 days (12-32) with AR in 4: grade 1R(1B-2)/pAMR0 (n = 3); 1R(1B)/pAMR2 (n = 1). CONCLUSIONS: dd-cfDNA assessment in place of selected, per-protocol EMB decreased surveillance EMB by 81% in our pediatric HT recipient cohort with no short-term adverse outcomes. Individual center approach to surveillance EMB will influence the utility of these findings.

Impact of routine surveillance biopsy intensity on the diagnosis of moderate to severe cellular rejection and survival after pediatric heart transplantation.

Data are lacking on RSB intensity and outcomes after pediatric heart transplantation. PHTS centers received a survey on RSB practices from 2005 to present. PHTS data were obtained for 2010-2013 and integrated with center-matched survey responses for analysis. Survey response rate was 82.6% (38/46). Centers were classified as low-, moderate-, and high-intensity programs based on RSB frequency (0-more than 8 RSB/y). RSB intensity decreased with increasing time from HT. Age at HT impacted RSB intensity mostly in year 1, with little to no impact in later years. Most centers have not replaced RSB with non-invasive methods, but many added ECHO and biomarker monitoring. Higher RSB intensity was not associated with decreased 4-year mortality (P=.63) or earlier detection of moderate to severe (ISHLT grade 2R/3R) cellular rejection (RSBMSR) in the first year (P=.87). First-year RSBMSR incidence did not differ with intensity or age at HT. Significant variability exists in RSB intensity, but with no impact on timing and incidence of RSBMSR or 4-year mortality. Reduction in RSB frequency may be safe in certain patients after pediatric HT.

Impact of age on incidence and prevalence of moderate-to-severe cellular rejection detected by routine surveillance biopsy in pediatric heart transplantation.

BACKGROUND: The effect of age at transplant on rejection detected by routine surveillance biopsy (RSB) in pediatric heart transplant (HT) recipients is unknown. We hypothesized there would be low diagnostic yield and decreased prevalence of rejection detected on RSB in infants (age <1 year) when compared with children (age 1 to 9 years) and adolescents (age 10 to 18 years). METHODS: We utilized Pediatric Heart Transplant Study (PHTS) data from 2010 to 2013 to analyze moderate-to-severe (ISHLT Grade 2R/3R) cellular rejection (MSR) detected only on RSB (RSBMSR). RESULTS: RSB detected 280 of 343 (81.6%) episodes of MSR. RSBMSR was detected in all age groups even >5 years after HT. Infant RSBMSR had a greater proportion (p = 0.0025) occurring >5 years after HT (39.2 vs 18.4 vs 10.8%) and a lower proportion (p = 0.0009) occurring in the first year after HT (25.5 vs 60.6 vs 51.7%) compared with children and adolescents, respectively. Freedom from RSBMSR was 87 ± 7% in infants, 76 ± 6% in children and 73 ± 7% in adolescents 4 years after HT. In 1-year survivors who had RSBMSR in the first year after HT, the risk of RSBMSR occurring in Years 2 to 4 was significantly (p < 0.0001) greater than patients without RSBMSR in the first year (hazard ratio 21.28, 95% confidence interval 10.87 to 41.66), regardless of recipient age. CONCLUSIONS: RSBMSR exists in all age groups after pediatric HT with long-term follow-up. The prevalence in infant recipients is highest >5 years after HT. Those with RSBMSR in the first year after HT are at a high risk for recurrent rejection regardless of age at HT.

Bortezomib use in a pediatric cardiac transplant center.

Data are limited on the efficacy and safety of bortezomib for the treatment of AMR following OHT for pediatric acquired or CHD. Retrospective chart review identified patients who received bortezomib for acute (n = 3, within two wk of diagnosis) and chronic (n = 1, three months after diagnosis) AMR or as part of a desensitization regimen (n = 1). Bortezomib was associated with a 3-66% reduction in class I DSA and a 7-82% reduction in class II DSA. Two of the three acute AMR cases resolved by the first follow-up biopsy. Two patients with AMR resolution are currently well. One patient developed a second episode of AMR, which was unresponsive to bortezomib therapy and required retransplantation for progressive coronary allograft vasculopathy. One patient died shortly after the third cycle from multi-organ failure. The desensitization patient showed transient HLA reduction with two cycles, but died five months after transplant from sepsis. Complications included infection (3/5), peripheral neuropathy (2/5), AKI (2/5), and thrombocytopenia (3/5). Adverse events appear more common in critically ill patients. Bortezomib therapy resulted in variable DSA reduction and AMR resolution in AMR in OHT secondary to pediatric acquired or CHD.