Results of the Largest Study on Post-Transplant-Lymphoproliferations (PTLDs) of the Central Nervous System (CNS) in the Rituximab Era: A Surprising Overrepresentation of Kidney Transplantations, Key Importance of Methotrexate (Mtx), Cytarabine (AraC) and Radiotherapy (RX) for Long Term Survival and Low Impact of Rituximab (R)
Authors: Choquet Sylvain , Oertel Stefan , Anagnostopoulos Ioannis , Riess Hanno , Uzunov Madalina , Leblond V.éronique , Trappe Ralf 
Published: October 2019

Abstract
Background: PTLD is a rare and severe complication of solid organ and hematopoetic stem cell transplantation and CNS localizations are well known to be associated with an unfavourable outcome. Published data on PTLD with CNS involvement (CNS-PTLDs) are nearly inexistent and the impact of rituximab is unknown.
Methods: We performed a retrospective analysis on CNS-PTLDs in two centres, the Pitié salpêtrière university hospital in Paris, France, and the Charité university hospital in Berlin, Germany, in order to have an homogeneous way to handle these diseases and to avoid biases of large national registers. PTLDs with extra-CNS localization were excluded. While attitudes for diagnosis, staging and initial immunosuppression diminution were identical, one centre largely used intravenous (iv) rituximab and radiotherapy while the other preferred high dose chemotherapy. The Pitié Salpêtrière series of 72 PTLD patients without CNS involvement served as a control population to identify specific disease characteristics of primary CNS-PTLD.
Results: 24 patients with CNS-PTLD (median age 55y) have been analyzed and compared to the non-CNS PTLD group (table I). The mean follow-up of patients alive is 5 years. Primary CNS-PTLD are clearly of late onset (mean 1366 days after transplantation) with only 3/24 patients diagnosed within the first year after transplantation. There was a significant overrepresentation of renal allografts in the CNS-PTLD group as compared to PTLDs without CNS involvement, (75% vs 29%). Primary CNS-PTLDs were always of B-cell phenotype and tumors were EBV positive in 88% of cases. Treatment of primary CNS-PTLDs consisted of chemotherapy (CT) alone with high dose (HD) Mtx and/or HD AraC in 8 cases, intrathecal (it) Mtx only in 1 case and it single agent rituximab in 1 case. Rituximab has been used in combination with CT in 2 cases. Radiotherapy (RX) was used at a mean dose of 30 Gy in combination with CT in 6 patients, and in combination with rituximab in 6 patients. The overall survival of patients suffering from primary CNS-PTLD was 180 days, but some patients obtained sustained complete remissions (CR) and 11 survived more than one year [395d – 3965d]. Eight patients are alive at the time of analysis, 9 died of PTLD progression and 2 by early sepsis. The mean DFS is 1456 days. Among the 13 patients obtaining a CR, only one relapsed 6 years after his first PTLD diagnosis in an extra CNS form. Five patients died, 3 by sudden death (d60, d408, d671), one by cerebral toxoplasmosis (d703) and one by sepsis (d91). Among patients with long term survival, 5 have been treated with CT alone, 3 by RX +/− R and 3 with combined CT-RX. The role of rituximab in primary CNS-PTLD is still unclear, as only 4/9 patients treated with rituximab achieved survival, all the more so since it as been always used but once in association.
Concusion: Primary CNS-PTLD is a specific entity inside the PTLD family, with a high representation of kidney grafts and EBV positive tumors. As in immunocompetent patients, long survival is possible, especially with HD CT with or without RX. The impact of rituximab seems to be reduced.
CNS-PTLD Non CNS PTLD n 24 72 Age (years) 55 47 Sex ratio (M/F) 12/12 49/72 Delay from transplantation 1366 days 830 Kidney transplantation 75% (18/24) 29% Monomorphic/polymorphic 86% (19/22) 68% B phenotype 100% (24/24) 90% EBV positive (tumor) 88% (21/24) 71% ECOG > 2 33% (7/21) 14% (18/70) Overall survival 180 days 372 days
Table1: comparison between primary CNS-PTLD and non CNS-PTLD