Epstein-barr virus DNAemia monitoring for the management of post-transplant lymphoproliferative disorder AMIT KALRA 1 , CAMERON ROESSNER 2 , JENNIFER JUPP 2 , TYLER WILLIAMSON 1 , RAYMOND TELLIER 1 , AHSAN CHAUDHRY 1 , FAISAL KHAN 1 , MINAKSHI TAPARIA 3 , VICTOR H. JIMENEZ-ZEPEDA 1 , DOUGLAS A. STEWART 1,3 , ANDREW DALY 1 & JAN STOREK 1 1 University of Calgary, Calgary, Alberta, Canada, 2 Pharmacy Services, Alberta Health Services, Alberta, Canada, and 3 University of Alberta Edmonton, Alberta, Canada Abstract Background. Post-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication of allogeneic hema- topoietic cell transplantation (HCT). Epstein-Barr virus (EBV) reactivation (detectable DNAemia) predisposes to the development of PTLD. Methods. We retrospectively studied 306 patients monitored for EBV DNAemia after Thymoglobulin- conditioned HCT to determine the utility of the monitoring in the management of PTLD. DNAemia was monitored weekly for ≥12 weeks post-transplantation. Results. Reactivation was detected in 82% of patients. PTLD occurred in 14% of the total patients (17% of patients with reactivation). PTLD was treated with rituximab only when and if the diagnosis was established. This allowed us to evaluate potential DNAemia thresholds for pre-emptive therapy. We suggest 100,000– 500,000 IU per mL whole blood as this would result in unnecessary rituximab administration to only 4–20% of patients and near zero mortality due to PTLD. After starting rituximab (for diagnosed PTLD), sustained regression of PTLD oc- curred in 25/25 (100%) patients in whom DNAemia became undetectable. PTLD progressed or relapsed in 12/17 (71%) patients in whom DNAemia was persistently detectable. Discussion. In conclusion, for pre-emptive therapy of PTLD, we suggest threshold DNAemia of 100,000–500,000 IU/mL. Persistently detectable DNAemia after PTLD treatment with rituximab appears to have 71% positive predictive value and 100% negative predictive value for PTLD progression/relapse. Key Words: Epstein-Barr virus infections, hematopoietic stem cell transplantation, herpesvirus 4, post-transplantation lymphoproliferative disorders, retrospective studies, rituximab, thymoglobulin Introduction Hematopoietic stem cell transplantation (HCT) re- cipients are at risk of developing post-transplantation lymphoproliferative disorder (PTLD). Proliferation of Epstein-Barr virus (EBV)-transformed B cells due to insufficient control by EBV-specific T cells causes PTLD [1,2]. The incidence of PTLD among HCT recipients ranges from 0.2–71% depending on the type of transplant, conditioning, graft-versus-host disease (GVHD) prophylaxis and donor type [3–16]. EBV re- activation (detection of EBV DNA in blood) predisposes to the development of PTLD [17]. Treatment options for PTLD include rituximab (anti-CD20), chemotherapy, EBV-specific T cells, unselected donor lymphocytes and reduction of im- munosuppression [17–21]. In centers in which EBV- specific T cells are not available, rituximab is used most frequently. Rituximab can be administered pre- emptively (when EBV DNAemia has exceeded a threshold) or therapeutically (after PTLD has been diagnosed). Most centers have moved toward DNAemia monitoring and pre-emptive therapy with rituximab in patients with a risk factor for develop- ing PTLD such as GVHD prophylaxis with antithymocyte globulin (ATG) [22,23]. However, a disadvantage of pre-emptive therapy is that patients who would not develop PTLD get rituximab.This is not only expensive, but also causes toxicities. Moreover, there is no consensus on the EBV DNAemia threshold for initiation of pre-emptive therapy. Centers have developed their in-house quan- titative PCR assays for measuring the DNAemia.There is up to 4-log difference in the EBV DNAemia results between two laboratories [24]. Therefore, DNAemia threshold useful at one center (using that center’s assay) may lead to too high incidence of PTLD or too many patients getting rituximab unnecessarily if used at Correspondence: Amit Kalra, MBBS, MS, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta,T2N 4N1, Canada. E-mail: akalra@ucalgary.ca ARTICLE IN PRESS (Received 26 October 2017; accepted 13 February 2018) ISSN 1465-3249 Copyright © 2018 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jcyt.2018.02.367 Cytotherapy, 2018; ■■: ■■–■■