Epstein-Barr virus-associated post-transplant lymphoproliferative disorders in pediatric transplantation: A prospective multicenter study in the United States

Abstract

Background: Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disorders (PTLD) is the most common malignancy in children after transplant; however, difficulties for early detection may worsen the prognosis.

Methods: The prospective, multicenter, study enrolled 944 children (≤21 years of age). Of these, 872 received liver, heart, kidney, intestinal, or multivisceral transplants in seven US centers between 2014 and 2019 (NCT02182986). In total, 34 pediatric EBV+ PTLD (3.9%) were identified by biopsy. Variables included sex, age, race, ethnicity, transplanted organ, EBV viral load, pre-transplant EBV serology, immunosuppression, response to chemotherapy and rituximab, and histopathological diagnosis.

Results: The uni-/multivariable competing risk analyses revealed the combination of EBV-seropositive donor and EBV-naïve recipient (D+R-) was a significant risk factor for PTLD development (sub-hazard ratio: 2.79 [1.34-5.78], p = .006) and EBV DNAemia (2.65 [1.72-4.09], p < .001). Patients with D+R- were significantly more associated with monomorphic/polymorphic PTLD than those with the other combinations (p = .02). Patients with monomorphic/polymorphic PTLD (n = 21) had significantly more EBV DNAemia than non-PTLD patients (p < .001) and an earlier clinical presentation of PTLD than patients with hyperplasias (p < .001), within 6-month post-transplant. Among non-liver transplant recipients, monomorphic/polymorphic PTLD were significantly more frequent than hyperplasias in patients ≥5 years of age at transplant (p = .01).

Conclusions: D+R- is a risk factor for PTLD and EBV DNAemia and associated with the incidence of monomorphic/polymorphic PTLD. Intensive follow-up of EBV viral load within 6-month post-transplant, especially for patients with D+R- and/or non-liver transplant recipients ≥5 years of age at transplant, may help detect monomorphic/polymorphic PTLD early in pediatric transplant.

Keywords: Epstein–Barr virus; PTLD; pediatric transplantation.

Figure 1.. Cumulative incidence of PTLD, EBV DNAemia, and rejection according to the D/R combinations

A. Patients with D+R− developed significantly more PTLD than those with D+R+ (P =0.007). B. Patients with D+R− had significantly more incidence of PTLD than those with the other combinations (P =0.006). C. D+R− patients had significantly more EBV DNAemia than those with D+R+, D−R−, and D−R+ patients (P =0.002, =0.003, <0.001, respectively). D. Patients with D+R− developed significantly more EBV DNAemia than those with D+R+ and D− (P =0.002, <0.001, respectively). Patients with D+R+ had significantly more incidence of EBV DNAemia than recipients of EBV-naïve organs (P <0.001). E. There was no significant difference in the incidence of rejection between the 4 groups of D+R−, D+R+, D−R−, and D−R+. F. EBV-naïve recipients developed significantly more rejection than EBV-seropositive recipients (P =0.03). Abbreviations: D, donor; EBV, Epstein-Barr virus; PTLD, post-transplant lymphoproliferative disorders; R, recipient.

Figure 2.. Incidence of PTLD and patient survival after transplant and PTLD diagnosis

A. Of 21 patients with monomorphic/polymorphic PTLD, 13 patients (62%) developed PTLD within a year after transplant. The median time from transplant to PTLD diagnosis was 5.3 months (IQR: 3.8 – 23.5). B. Patients with monomorphic/polymorphic PTLD showed significantly worse prognosis than non-PTLD patients after transplant (P <0.001). The 1-year, 2-year, and 3-year survival rates of patients after PTLD diagnosis were 94%, 90%, and 90%, respectively. C. The prognosis of patients with monomorphic/polymorphic PTLD was likely to be worse than that of patients with hyperplasias after PTLD diagnosis (P =0.08). The 1-year, 2-year, and 3-year survival rates of patients with monomorphic/polymorphic PTLD after PTLD diagnosis were 90%, 83%, and 83%, respectively while those of patients with hyperplasias were 100%, 100%, and 100%, respectively. Abbreviations: PTLD, post-transplant lymphoproliferative disorders.

Figure 3.. EBV DNAemia and PTLD development within six months post-transplant

A. Patients with monomorphic/polymorphic PTLD showed significantly higher incidence of EBV DNAemia within six months post-transplant than non-PTLD patients (P <0.001). Patients with monomorphic/polymorphic PTLD tended to have more incidence of EBV DNAemia than patients with hyperplasias within six months post-transplant (P =0.09). B. Of 13 patients who had monomorphic/polymorphic PTLD within a year of transplant, 11 patients (85%) developed monomorphic/polymorphic PTLD within six months of transplant while no patient developed hyperplasias within six months post-transplant. C. Patients with monomorphic/polymorphic PTLD had an earlier clinical presentation of PTLD than patients with hyperplasias within six months of transplant (P =0.002). Abbreviations: EBV, Epstein-Barr virus; PTLD, post-transplant lymphoproliferative disorders.