Younger Patients Are Impacted By Post-Transplant Lymphoproliferative Disorder: Findings from a Systematic Literature Review of Real-World Evidence
Authors: Watson Crystal , Xu Hairong , Forsythe Anna , Garib Shan Ashton , Barlev Arie 
Published: October 2019

Abstract
Introduction: Transplant recipients younger than 18 years old are believed to have a 2- to 4-fold higher risk of developing post-transplant lymphoproliferative disorder (PTLD) than adult transplant patients. Within the pediatric group, there is evidence to suggest an increased risk of PTLD in younger children. We conducted a systematic literature review (SLR) to estimate the weighted mean age (WMA) at PTLD diagnosis and describe patient demographics in the real-world setting.
Methods: An SLR was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines with the scope defined in terms of Population, Intervention Comparators, Outcomes, and Study design (PICOS) criteria. Studies were identified based on a systematic search using key biomedical literature databases: EMBASE, MEDLINE, and Cochrane. The literature search was conducted on July 19, 2018 and included studies published between database inception in January 1, 1959 and July 19, 2018. Relevant congress abstracts published between January 2015 and June 2018 were also identified. The PICOS-based inclusion and exclusion criteria were used to review identified citations. To ensure inclusion of all relevant evidence, no treatment limitations were imposed; however, the study designs were limited to prospective and retrospective observational studies. Case reports were included regardless of sample size. Two independent reviewers screened all citations and full-text articles; any discrepancies were resolved by a third independent reviewer. Data from included studies were extracted into a pre-defined template, and results were summarized using the PRISMA flow diagram. Using the sample size from the selected studies, the WMA for each relevant subgroup was determined and was compared to the average age at the time of diagnosis for other cancers reported in SEER Cancer Statistics (2011-2015; https://seer.cancer.gov/csr/).
Results: A total of 447 studies fulfilled the search criteria: 114 adult studies, 136 pediatric studies with varied definitions (< 16, < 18 or < 21 years old), and 197 that did not specify inclusion by age. Seventy studies enrolled only PTLD patients after allogeneic hematopoietic stem cell transplantation (HCT). Among these studies, 17 included pediatric patients with a WMA of 12.5 years, 10 included adult patients with a WMA of 40.2 years, and 41 had no age restriction with a WMA of 34.4 years. For pediatric patients, the risk of post-HCT PTLD was 1.3-23.5% and the time from transplant to PTLD was 0.9-6.0 months. There was only one pediatric HCT study (N=4; mean age, 9 years), which reported median survival of 27.6 months.
A total of 350 studies only enrolled PTLD patients after solid-organ transplant (SOT). Among these studies, 115 included pediatric patients with a WMA of 6.6 years, 98 included adult patients with a WMA of 46.9 years, and 136 had no age restriction with a WMA of 38.6 years. Among the pediatric SOT studies, the risk of PTLD was 0.3-25.0%, the time from transplant to PTLD was 1.4-92.8 months, and the reported survival was 0.9-37.2 months. The average age of lymphoma patients at cancer diagnosis according to the SEER Cancer Statistics database was 65 years.
Conclusions: This SLR of published real-world studies demonstrates that the WMA at PTLD diagnosis (for studies with no age restrictions: 34.4 years for HCT and 38.6 years for SOT) is substantially lower than the reported average age at diagnosis for lymphomas (65 years), irrespective of study design and inclusion criteria. PTLD greatly impacts the pediatric population, with a quarter of HCT studies and a third of SOT studies focusing on this population. Currently, there is no indicated treatment for this ultra-rare disease with poor prognosis, indicating a clear unmet need for patients with PTLD that disproportionately affects younger patients.

Disclosures
Watson: Atara Biotherapeutics, Inc: Employment, Equity Ownership. Xu:Atara Biotherapeutics, Inc: Employment, Equity Ownership. Forsythe:Novartis: Consultancy. Barlev:Atara Biotherapeutics, Inc: Employment, Equity Ownership.