Attenuated Preemptive Therapy Against Cytomegalovirus (CMV) Reactivation/Disease Consisting of a Higher Cutoff Point and a Lower Initial Dose of Ganciclovir after Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) with an HLA-Identical Sibling Donor.
Authors: Onishi Yasushi , Mori Shin-ichiro , Kusumoto Shigeru , Akahane Daigo , Sugimoto Kyoko , Terada Yoshiki , Kim Sung-Won , Kami Masahiro , Heike Yuji , Tanosaki Ryuji , Tobinai Kensei , Takaue Yoichi 
Published: April 2020

Abstract
CMV continues to be a major cause of morbidity following allogeneic HSCT. Although preemptive ganciclovir therapy is widely used to prevent CMV disease, the optimal initial dose and timing of ganciclovir administration have not yet been determined. Unnecessary routine ganciclovir therapy is not acceptable, since it can cause considerable neutropenia and may impair the de novo recovery of CMV-specific T cell immunity. We performed a prospective study to evaluate the safety and effectiveness of a novel preemptive protocol with a higher cutoff point to initiate therapy and a lower initial dose of ganciclovir. The primary endpoint of this study was defined as the occurrence of CMV disease. CMV antigenemia was measured weekly after engraftment. The decision to start ganciclovir was based on the detection of ≥10 positive cells per 50,000 cells by the antigenemia assay, or by the clinical diagnosis of CMV disease with apparent infection-related symptoms. Intravenous ganciclovir was started at 5 mg/kg/day three times per week, and was continued until the positive cell count had decreased to &lt; 10 per 50,000 cells. If the number of positive cells increased or CMV-related symptoms worsened, the dose of ganciclovir was increased. Forty-six consecutive patients undergoing allogeneic HSCT from an HLA-identical sibling at National Cancer Center Hospital between April 2003 and March 2004 were enrolled. The median age of the patients was 51 years (range, 17 to 68 years). There were 40 cases of hematological malignancy and 6 solid tumor. The risk status of CMV was recipient (R) +/donor (D)+ in 39, R+/D- in 4, R−/D+ in 1, and R−/D− in 2. Fludarabine- or cladribine-based reduced-intensity regimens were used in 35 patients and conventional myeloablative in 11. All patients were given acyclovir 750 mg/day orally from day −7 to the discontinuation of GVHD prophylaxis. The median follow-up was 275 days (26 – 481). Twenty-six patients (57%) developed positive antigenemia at a median of 42 days (12 – 151) after transplantation. In 10 patients (22%), ≥10 positive cells per 50,000 cells were detected by the antigenemia assay, and these patients, except two with renal dysfunction, received low-dose ganciclovir. The dose of ganciclovir was increased in 5 patients. Three patients developed overt CMV gastroenteritis which was successfully treated with a regular therapeutic dose of ganciclovir at 10 mg/kg/day. No case of late CMV disease was observed in this study. Overall, the total dose of ganciclovir was significantly less than that in a previous protocol using a conventional double dose (5 mg/kg twice daily) of ganciclovir (111 mg/kg vs. 225 mg/kg on average, P=0.006), reducing the cost by as much as $ 1,500 per patient. The incidence of neutropenia after ganciclovir was significantly less than that in the previous approach (0% vs. 11% (4/36), P=0.038). In a multivariate analysis, factors associated with ≥10 positive antigenemia included grade II – IV acute GVHD (P &lt; 0.0001), the use of systemic steroid of ≥1.0 mg/kg/day (P &lt; 0.0001), and a reduced- intensity conditioning regimen (P =0.036). In conclusion, our attenuated preemptive treatment protocol appeared to be safe, better tolerated, less expensive, and effective at controlling CMV infection.