Rituximab Prophylaxis of EBV Reactivation after Unrelated Donor Transplants Using Anti-Thymocyte Globulin in the Conditioning Regimen.
Authors: Bacigalupo Andrea , Dominietto Alida , Soracco Monica , Pozzi Sarah , Raiola Anna Maria , van Lint Maria Teresa , Lamparelli Teresa , Ibatici Adalberto , Frassoni Francesco , Tedone Elisabetta 
Published: October 2019

Abstract
Background Epstein-Barr Virus (EBV) reactivation is a relatively common event in patients undergoing an unrelated donor transplant with anti-thymocyte globulin (ATG) in the conditioning regimen. In our first 71 patients monitored for EBV reactivartion, this occurred in 42 (59%) at a median interval of 48 days from transplant. Reactivation was higher (75%) in patients with acute lymphoblastic leukemia (ALL) non Hodgkin lymphoma (NHL) and Hodgkin’s disease (HD). When EBV reactivation exceeded 1000 copies /10^5 cells (n=12) the risk of developing a lymphoproliferative disease (LPD) was high (50%) and survival poor (30%).
Aim of the study. To test whether rituximab 100 mg/m^2 given on day +5 after transplant would prevent EBV reactivation. Patients eligible for this trial were ALL, NHL and HD undergoing an unrelated donor transplant in 2004-2005, receiving ATG (Genzyme, 7.5 mg/kg) in the conditioning regimen: these patients received rituximab 100 mg/m^2 on day +5 after transplant. Controls were patients with ALL, NHL and HD allografted from similar donors between year 2000 and 2005, receiving the same dose of ATG in the conditioning. Clinical data of patients are outlined in Table 1. Clinical characteristics of controls and rituximab patients were comparable. All patients who reactivated with over 1000 copies received rituximab 375 mg/m^2 one dose, and if they did not clear EBV in 1 week, a second dose.
Results. Patients receiving prophylactic rituximab on day+5 had similar neutrophil engraftment and acute GvHD as controls (Table 1). EBV reactivation occurred in 58% controls and 64% rituximab patients. There was a non significant delay of 20 days for time to reactivation (37 vs 57). The number of EBV copies at the time of reactivation was significantly higher in controls (334 vs 3, p=0.0001) and the maximum number of copies was also significantly higher in controls (1433 vs 11, p=0.001). Fourteen patients (34%) vs 1 (7%) (p=0.05) received rituximab for treatment of EBV reactivation. Transplant related mortality is 39% vs 21% (p=ns) and actuarial 1 year survival at 6 months 56% vs 63% (p=ns).
Conclusions. Rituximab on day +5 significantly reduces the number of EBV copies at reactivation, without interfering with engraftment and reduces the need to treat patients for potential LPD.
Table 1. Clinical data of patients Treatment group Controls Rituximab P Number 41 14 Patients age 31 27 ns ALL 27 7 NHL 7 5 HD 7 2 ns Advanced disease 75% 78% ns Day PMN 500/mmc 18 (15–31) 17 (14–21) ns GvHD grade II-IV 19% 29% 0.4 Number of EBV reactivation 24 (58%) 9 (64%) ns Day of EBV reactivation 37 (4–220) 57 (14–150) ns Copie EBV at reactivation 334 (2–5770) 3 (1–189) 0.0001 Man n. copies EBV 1433 (8–177000) 11 (3–2089) 0.001 N of patients >1000 copies 14 (34%) 1 (7%) 0.05 EBVLPD 6 (14%) 0 0.2 TRM 39% 21% 0.2 Survival at 180 days 56% 63% 0.4 Median follow up (dd) 274 131