Immunosuppression is associated with clinical features and relapse risk of B cell posttransplant lymphoproliferative disorder: A retrospective analysis based on the prospective, international, multicenter PTLD-1 trials

Background Current guideline recommendations for immunosuppression reduction after diagnosis of posttransplant lymphoproliferative disorder (PTLD) include stopping antimetabolites, reducing calcineurin inhibitors and maintaining corticosteroids. However, the effect of immunosuppression on PTLD relapse risk after up-to-date therapy is unclear. Methods This is a retrospective analysis of immunosuppression, patient baseline characteristics and relapse risk measured as landmark time to progression (TTP) starting 1 year after start of therapy in 159 patients with B cell PTLD after solid organ transplantation treated in the prospective, international, multicenter PTLD-1 trials with either sequential treatment (rituximab followed by CHOP chemotherapy) or risk-stratified sequential treatment (rituximab followed by rituximab or R-CHOP immunochemotherapy). Results Patient baseline characteristics at diagnosis of PTLD differed significantly depending on immunosuppression before diagnosis. Compared to immunosuppression before diagnosis, significantly fewer patients received an antimetabolite or a calcineurin inhibitor (CNI) after diagnosis of PTLD. Relapse risk measured as landmark TTP was significantly higher for patients on corticosteroids compared to all others (p=0.010) as well as for patients on ciclosporin compared to those on tacrolimus (p=0.002), but similar for those on antimetabolites compared to all others (p=0.912). In a Cox regression analysis of landmark TTP, corticosteroid-containing immunosuppression after diagnosis of PTLD (p=0.002, hazard ratio (HR) 11.195) and age (p=0.001, HR 1.076/year) were identified as independent, significant risk factors for PTLD relapse. Conclusions In the prospective PTLD-1 trials, corticosteroid use after diagnosis of PTLD is associated with an increased risk of relapse whereas the use of antimetabolites is not. These findings require prospective validation. Correspondence: Ralf Ulrich Trappe, DIAKO Hospital Bremen, Department of Internal Medicine II: Hematology and Oncology, Gröpelinger Heerstr. 406-408, 28239 Bremen, Germany, e-mail: rtrappe@gwdg.de Authorship HZ and RUT designed the study. RUT is the principal investigators and takes primary responsibility for the paper. RUT, SC and DD coordinated the research. HR, NB, SC, VL, FM, DD, PM, JMZ, MD, UD, PR, GV, MS, AH, TT, EB, IAH, CT, EVDN and OG recruited significant numbers of patients. HZ and RUT collected, analyzed and interpreted the data. IA served as reference pathologists. HZ, NB, DD, MD, SC, FM, JMZ, HR, and RUT wrote the paper. All authors had full access to the final version of the manuscript and agreed to publication. Disclosures H. Zimmermann reports grants form Roche, and nonfinancial support from Celgene Amgen, and Roche, outside the submitted work. F. Morschhauser reports personal fees from Celgene, Genentech/Roche, Gilead, and Janssen, outside the submitted work. P. Mollee reports grants from Celgene and Janssen as well as advisory boards membership for Celgene, Janssen, Amgen and BMS, outside the submitted work. J.M. Zaucha reports personal fees from Roche, Amgen, and Takeda, all outside the submitted work. M. Dreyling reports grants and personal fees from Roche, outside the submitted work. P. Reinke reports personal fees or travel support from Teva, Thermo Fisher, Pfizer, Astellas, Amgen, Baxalta, MSD, Pluristem, and Novartis, outside the submitted work. U. Dührsen reports and personal fees from Roche, outside the submitted work. M. Subklewe reports institutional grants from Roche, Amgen and OBT and personal fees or travel support from Amgen, Pfizer, Seattle Genetics, Gilead and Celgene, outside the submitted work. I.A. Hauser reports nonfinancial support from Astellas and Alexion as well as personal fees from Novartis, Roche, Chiesi, Sanofi, Hexal, and Teva, outside the submitted work. V. Leblond reports personal fees from Roche, Gilead, Janssen and Novartis, outside the submitted work. S. Choquet reports grants from Roche France and Chugai during the conduct of the study. R.U. Trappe reports grants from Hoffmann-La Roche, Amgen, Chugai France and Novartis during the conduct of the study; ongoing grants from Roche, and nonfinancial support from Abbvie, Celgene, Takeda, Teva, Janssen, Roche and Gilead, all outside the submitted work. All other authors declared no conflicts of interest. Funding The PTLD-1 trials were planned and initiated in 2003 and amended in 2006 as an investigator-initiated trial by the German and French PTLD Study Groups. In 2004, F Hoffmann-La Roche, AMGEN and Chugaï France granted financial support. Novartis provided funding for an analysis of the effect of immunosuppression on PTLD outcomes. The companies were neither involved in protocol design nor in data collection, analysis or interpretation. They had no role in writing the manuscript and were not involved in the decision to submit for publication. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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