A Systematic Literature Review Of Real-World Evidence In Post-Transplant Lymphoproliferative Disorder

Introduction: Recipients of solid-organ transplant (SOT) or allogeneic hematopoietic stem cell transplantation (HCT) have an increased risk of cancers from Epstein-Barr virus (EBV), specifically lymphomas due to immunosuppression. Post-transplant lymphoproliferative disorder (PTLD) is a disease with a range of clinical presentations, including that of an aggressive lymphoma, that occurs after transplantation. PTLD occurs rarely after transplantation and is associated with poor survival outcomes. Publications on the clinical evidence for PTLD are scarce; therefore, a systematic literature review (SLR) was conducted to better understand the real-world evidence in PTLD. 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. Results: A total of 447 articles were identified that met the SLR criteria: 350 SOT, 70 HCT, and 27 that included both SOT and HCT. Among 97 studies of PTLD post HCT, 81 involved allogeneic HCT, 2 involved autologous HCT, and 14 did not report the type of HCT. Of the 376 identified studies with PTLD post-SOT, the most prevalent SOTs involved were: kidney (193 studies), heart (126 studies), liver (91 studies), lung (84 studies), pancreas (43 studies), and intestine (25 studies). Data on the risk of PTLD, treatment patterns for PTLD, and utilization and survival outcomes following PTLD were reported in 334, 331, and 210 studies, respectively. There was notable clinical and methodological heterogeneity among studies. For example, there was variability in the study populations: 114 were adult populations, 136 were pediatric populations, and 197 did not specify age. Most of the studies were retrospective (419 studies) versus prospective (28 studies), and most were single-center studies (340 studies) versus multicenter studies/registries (98 studies), limiting the generalizability of the results. In addition, the sample sizes were small among most PTLD studies, with fewer than 50 patients in 376 studies, 50-100 patients in 9 studies, and more than 100 patients in 46 studies. The clinical and methodological heterogeneity noted above may explain the large variations in reported risk of PTLD in both HCT and SOT. Among adult SOT patients, the risk of developing PTLD was 0.2% to 11.5%, while among pediatric SOT patients, the risk was 0.3% to 25.0%. Among adults with HCT, the risk of developing PTLD was 1.0 to 20.0%, while among pediatric patients with HCT, the risk was 1.3% to 23.5%. Conclusions: To the best of our knowledge, this is the first comprehensive SLR to examine the published real-world evidence in patients with PTLD. Our SLR reveals important differences with respect to methodology and reporting of real-world published studies assessing the current landscape in PTLD. Additional large, high-quality studies employing more rigorous study methodology are required to understand the current landscape of PTLD in the real-world setting. Disclosures Xu: Atara Biotherapeutics, Inc: Employment, Equity Ownership. Forsythe: Novartis: Consultancy. Barlev: Atara Biotherapeutics, Inc: Employment, Equity Ownership. Watson: Atara Biotherapeutics, Inc: Employment, Equity Ownership.