High-Dose Intravenous Acyclovir Is Safe and Effective in the Treatment of EBV Reactivation Post Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Wang Yu , Ye Xuemei , Zheng Hong , Mao Yan , Wang Xuemei , Che Feifei , Wang Chunsen , Yang Xi , Huang Xiaobing 
Published: November 2021

Abstract
Backgroud:
Reactivation of nasopharyngeal carcinoma virus (EBV) post allogeneic hematopoietic stem cell transplantation(allo-HSCT) is very common, but sustained EBV activation maybe induce EBV-associated lymphoproliferative disease (PTLD), transplant-associated hemophagocytic syndrome and thrombocytopenia after transplantation, which is extremely harmful for long-term survival. Currently, the first-line therapeutic strategy for sustained EBV activation is rituximab, but rituximab leads to increased rates of infections and delayed immune reconstitution. Therefore, for the patients with EBV-DNA copies under 1000000/mL, the pros and cons of rituximab are worth weighing.
Objective:
To evaluate the efficacy and safety of high-dose intravenous acyclovir in the treatment of EBV reactivation post allo-HSCT.
Method:
Retrospective analysis of clinical data of patients with EBV reactivation post transplantation treated with high-dose intravenous acyclovir (0.5g Q8H) in Sichuan Provincial People's Hospital from January 2019 to May 2021. A total of 49 patients post allo-HSCT from from January 2019 to May 2021 were enrolled in this study. In this population, 38 patients accepted haplo-SCT and 11 patients accepted sibling-SCT. These patients all don't suffer from PTLD and transplant-associated hemophagocytic syndrome, but are resistant to oral antiviral drugs (Acyclovir, valacyclovir, and famciclovir). Simultaneously with intravenous acyclovir, all patients received human immunoglobulin with one dose of 0.4g/kg. The clinical efficacy was evaluated as follows: Overall response(ORR) was defined as the decrease of EBV copies; Complete remission(CR) was defined as the negative turn of EBV copies; Partial response(PR), Stable disease(SD) and Progression of disease(PD) were respectively defined as the decrease, no significant change and increase of EBV copies.
Results:
The median transplantation time was +86 (+38 to +1587) days. The median number of EBV-DNA copies/ml was 177000 (6620-8200000). After treatment with high-dose intravenous acyclovir, 29 (59.2%) of 49 patients achieved CR, 10 (20.4%) of 49 patients achieved PR, and 10 (20.4%) of 49 patients had no response, including 2 patients with SD and 8 patients with PD. All 49 patients had responded to this regimen with 79.6% ORR. The median time of response and negative turn was 4 days (2 to 11 days) and 9 days (2 to 23 days) respectively. After 100 days for follow-up, 14 of 39 responding patients suffered from EBV activation again, and the EBV copies were higher than that when high-dose acyclovir was initiated. All 24 patients who did not turn negative were recommended with the treatment of rituximab, and 19 of 20 patients who completed treatment turned negative during the three months post acyclovir treatment. The main adverse events (AEs) of this regimen were neutropenia (CTCAE grade 2-3, 8 in 49 patients), thrombocytopenia (CTCAE grade 2-3, 10 in 49 patients), increased serum creatinine (CTCAE grade 1-2, 4 in 49 patients), phlebitis (6 in 49 patients). These AEs were all reversible, which recovered after withdrawal. There was no significant change in the counts of CD4 + T cells and CD8 + T cells before and after intravenous high-dose acyclovir.
Conclusion:
High-dose intravenous acyclovir is safe and effective in the treatment of EBV reactivation post allo-HSCT, although nearly half of patients still need rituximab treatment. It is a reasonable strategy for patients with oral antiviral resistance. Most patients can avoid the prescription of rituximab in the first six months post allo-HSCT, without interference of immune reconstitution.

Disclosures
No relevant conflicts of interest to declare.