Epidemiology of Post-Transplant Lymphoproliferative Disorders in Children with Solid Organ Transplant over 34 Years of a Single Center Experience
Authors: Rojas Vasquez Marta , Peters Anthea , Lai Raymond , Mabilangan Curtis , Catherine Burton , Preiksaitis Jutta 
Published: November 2019

Background
Post-Transplant lymphoproliferative disorders (PTLD) are a heterogeneous group of lymphoid neoplasms following solid organ transplantation (SOT) caused by uncontrolled lymphoproliferation often induced by Epstein Barr Virus (EBV) due to the lack of cytotoxic T cell response resulting from immunosuppression. A pre-emptive intervention strategy for PTLD prevention was implemented in our center in 2002 for all EBV-mismatched SOT recipients consisting in close monitoring of the viral load and consideration for early intervention (Ex; reduction of immunosuppression) in addition to universal antiviral prophylaxis (implemented in 1990).
We aim to describe the incidence and risk factors for PTLD in children with SOT, including all transplant types, at a single center over 34 years. We also aim to analyze the impact of a pre-emptive PTLD prevention program.
Material and methods
All patients younger than 18 years of age who received SOT at the University of Alberta Hospital/Stollery Children's Hospital from January 1st, 1984 to December 31st, 2018 were included. Donor and recipient baseline data (age, sex, donor living status, date and type of transplant, EBV and cytomegalovirus serostatus) were extracted from a prospective database. Retrospective chart review was performed for PTLD cases along with expert pathology review (when tissue available). Local Ethics Board was obtained.
Statistical analyses were performed using SPSS software version 25 and R version 3.3.3.
Results
Characteristics of the study population, immunosuppression regimen used by transplant program and specific immunosuppression for PTLD cases are summarized in table 1, 2 and 3 respectively. PTLD characteristics were compared based on the time of presentation of PTLD ≤1 year, 1 to 5 years and &gt;5 years (table 4).
Most of the cases with PTLD presented with primary involvement in multiple sites followed by lymph nodes, gastro-intestinal tract, allograft, tonsils/adenoids and other sites. Advance staging (III-IV) was present in 71% of cases.
The incidence rate of PTLD for the whole group was 0.82/100 Person-year (Figure 1 A). The incidence rate peaked at 1-year post-transplant and had a decreasing trend in the following years post-transplant, with no cases beyond 12 years post-transplant (Figure 1 B). The cumulative incidence was the highest for the multi-visceral transplants followed by thoracic, liver and kidney transplants (Figure 1C).
Univariate analysis showed children younger than 5 years at transplant had 5-fold higher risk of PTLD compared to children ≥ 10 years of age at transplant. Donors ≤ 5 years of age at transplant, showed 3-fold higher risk PTLD comparing to older donors. Liver transplant had 2.8-fold and thoracic transplants had 5-fold higher risk of PTLD comparing to kidney transplants, no significant risk was associated with multi-visceral group (only 1 case in the cohort). EBV seronegative recipient was associated with 2.6-fold higher risk of PTLD comparing to EBV seropositive recipient. Era prior to implementation of pre-emptive intervention had 3-fold risk of PTLD comparing to era post implementation. Patients transplanted at 1.1 - 5 years of age was an independent risk factor associated with PTLD in multivariate analysis (table 3)
SOT recipients showed EBV seroconversion with age (Figure 3A). PTLD based on EBV Donor Recipient (DR) serostatus showed more cases D positive R negative (D+R-) in the first-year comparing to D negative Recipient negative (D-R-), D-R- cases increased between 1-5 years equivalent to D+R-, beyond 5 years D+R- decreased with no D-R- cases (Figure 3B). D-R- serostatus had the highest probability of PTLD followed by D+R- (Figure 3 C).
Eleven (24%) out of 45 patients with PTLD presented with PTLD relapse. Seven (5.6%) out of 125 deaths of SOT were secondary to PTLD. PTLD was the most common cause of death in the PTLD group (50%) followed by graft failure/rejection.
Conclusions
Incidence of PTLD peaked in the first-year post-transplant and decreased overtime with increase incidence in thoracic and multi-visceral transplants. Risk factors for PTLD included patients transplanted at younger age, younger donors, thoracic and liver transplants and EBV seronegativity in the recipient. A pre-emptive intervention strategy for PTLD prevention implemented in 2002 decreased the risk of PTLD.

Disclosures
No relevant conflicts of interest to declare.