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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

Zimmermann, Heiner, MD1,2; Babel, Nina, MD3; Dierickx, Daan, MD4; Morschhauser, Franck, MD5; Mollee, Peter, MBBS6; Zaucha, Jan M., MD7,8; Dreyling, Martin H., MD9; Dührsen, Ulrich, MD10; Reinke, Petra, MD11; Verhoef, Gregor, MD4; Subklewe, Marion, MD9; Hüttmann, Andreas, MD10; Tousseyn, Thomas, MD12; Bachy, Emmanuel, MD13; Hauser, Ingeborg A., MD14; Tarella, Corrado, MD15; Van Den Neste, Eric, MD16; Gheysens, Olivier, MD17; Anagnostopoulos, Ioannis, MD18; Leblond, Veronique, MD19; Riess, Hanno, MD20; Choquet, Sylvain, MD19; Trappe, Ralf U., MD1,2,20

doi: 10.1097/TP.0000000000002269
Original Clinical Science—General

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 cyclophosphamide (CHOP-21 chemotherapy) 750 mg/m2 intravenously [IV] day (d) 1, doxorubicin 50 mg/m2 IV d1, vincristine 1.4 mg/m2 (maximum, 2 mg) IV d1, and prednisone 50 mg/m2 PO d1-5, every 21 days) or risk-stratified sequential treatment (rituximab followed by rituximab or rituximab (R-CHOP-21 immunochemotherapy) 375 mg/m2 IV day (d) 1, cyclophosphamide 750 mg/m2 IV d1, doxorubicin 50 mg/m2 IV d1, vincristine 1.4 mg/m2 (max. 2 mg) IV d1, and prednisone 50 mg/m2 PO d1-5, every 21 days).

Results Patient baseline characteristics at diagnosis of PTLD differed significantly depending on immunosuppression before diagnosis. Compared with 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 with those on tacrolimus (P = 0.002), but similar for those on antimetabolites compared with 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, 11.195) and age (P = 0.001; hazard ratio, 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.

In this retrospective analysis the prospective PTLD-1 trials, the authors find a correlation between the risk of PTLD recurrence after treatment and both age at diagnosis and corticosteroids immunosuppression while the use of antimetabolites and CNIs is not which is an important statement to be prospectively validated.

1 Department of Hematology and Oncology, DIAKO Ev. Diakonie-Krankenhaus Bremen, Bremen, Germany.

2 Department of Internal Medicine II: Hematology and Oncology, University Medical Centre Schleswig-Holstein, Campus Kiel, Kiel, Germany.

3 Center for Translational Medicine and Department of Internal Medicine I, Marien Hospital Herne, Ruhr-University Bochum University Hospital, Herne, Germany.

4 Department of Hematology, Catholic University Leuven, Leuven, Belgium.

5 Département d'Hématologie, Hôpital Claude Huriez, Lille, France.

6 Department of Hematology, Princess Alexandra Hospital and University of Queensland, Brisbane, Australia.

7 Department of Oncological Propaedeutics and Department of Hematology and Transplantology, Medical University of Gdansk, Gdansk, Poland.

8 Polish Lymphoma Research Group, Warsaw, Poland.

9 Department of Medicine III, University Hospital, LMU Munich, Germany.

10 Department of Hematology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany.

11 Department of Nephrology and Intensive Care, Campus Virchow-Klinikum, Charité, Universitätsmedizin Berlin, Berlin, Germany.

12 Translational Cell and Tissue Research, Department of Pathology, Catholic University Leuven, Leuven, Belgium.

13 Hospices Civils de Lyon-Université de Lyon, Pierre-Bénite, France.

14 Department of Internal Medicine III, J.W. Goethe University Hospital, Frankfurt/Main, Germany.

15 Department of Clinical Haemato-Oncology, European Institute of Oncology, Milano, Italy.

16 Hematology Department, Cliniques Universitaires UCL Saint-Luc, Brussels, Belgium.

17 Department of Nuclear Medicine and Molecular Imaging, Catholic University Leuven, Leuven, Belgium.

18 Department of Pathology, Campus Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany.

19 Département d'Hématologie, Hopital Pitie-Salpêtriere, Université Pierre et Marie Curie, Paris, France.

20 Department of Hematology and Oncology, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Received 14 February 2018. Revision received 13 April 2018.

Accepted 17 April 2018.

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 article and were not involved in the decision to submit for publication.

H.Z. reports grants form Roche, and nonfinancial support from Celgene Amgen, and Roche, outside the submitted work. F.M. reports personal fees from Celgene, Genentech/Roche, Gilead, and Janssen, outside the submitted work. P.M. reports grants from Celgene and Janssen as well as advisory boards membership for Celgene, Janssen, Amgen and BMS, outside the submitted work. J.M.Z. reports personal fees from Roche, Amgen, and Takeda, all outside the submitted work. M.D. reports grants and personal fees from Roche, outside the submitted work. P.R. reports personal fees or travel support from Teva, Thermo Fisher, Pfizer, Astellas, Amgen, Baxalta, MSD, Pluristem, and Novartis, outside the submitted work. U.D. reports and personal fees from Roche, outside the submitted work. M.S. 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.H. 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.L. reports personal fees from Roche, Gilead, Janssen and Novartis, outside the submitted work. S.C. reports grants from Roche France and Chugai during the conduct of the study. R.U.T. 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.

H.Z. and R.U.T. designed the study. R.U.T. is the principal investigators and takes primary responsibility for the article. R.U.T., S.C., and D.D. coordinated the research. H.R., N.B., S.C., V.L., F.M., D.D., P.M., J.M.Z., M.D., U.D., P.R., G.V., M.S., A.H., T.T., E.B., I.A.H., C.T., E.V.D.N., and O.G. recruited significant numbers of patients. H.Z. and R.U.T. collected, analyzed and interpreted the data. I.A. served as reference pathologists. H.Z., N.B., D.D., M.D., S.C., F.M., J.M.Z., H.R., and R.U.T. wrote the article. All authors had full access to the final version of the article and agreed to publication.

Correspondence: Ralf U. Trappe, MD, Department of Internal Medicine II: Hematology and Oncology, DIAKO Hospital Bremen, Gröpelinger Heerstr. 406-408, 28239 Bremen, Germany. (rtrappe@gwdg.de).

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