Increased EBV Infection and Relapse Rates Following Haploidentical Hematopoietic Cell Transplantation in the Era of Letermovir for Cytomegalovirus Prophylaxis: A Propensity Score Matching Analysis

Background: The novel CMV DNA terminase inhibitor letermovir (LTV) has been approved effective for prophylaxis of CMV reactivation in HSCT recipients. Concerns have been raised about increased EBV reactivation and delayed immune reconstitution following hematopoietic cell transplantation with LTV prophylaxis. To date, the effect of prophylactic LTV on EBV infection, disease relapse, and early immune function remains unclear in haploidentical hematopoietic stem cell transplantation (haplo-HSCT) recipients. We conducted a retrospective propensity score (PS)-matched cohort study to assess and compare the transplant outcomes before and after LTV implementation for CMV prophylaxis after haplo-HSCT. Methods: A hundred and six CMV-seropositive adult haplo-HSCT recipients receiving LTV prophylaxis (LTV group) and 212 matched controls without LTV (non-LTV group) were included in this study. The incidences of EBV infection, primary disease relapse, immune reconstitution and survival were compared between the two groups. Results: The patient characteristics were well-balanced with PS matching, and there were no significant differences between the groups (all P > 0.05, SMD < 0.2). The 100-days cumulative incidence of CMV viremia was 23.6% (95% confidence interval (CI):16.5-32.5%) and 45.8% (95% CI: 39.2-52.5%) in the LTV and non-LTV groups (P< 0.001). The cumulative incidence of EBV viremia within 100 days after transplant was significantly higher in the LTV group compared to the non-LTV group [34.0% (95% CI, 25.7%-43.4%) vs. 11.3% (95% CI, 7.7%-16.3%), P < 0.001]. The cumulative incidence of EBV-associated diseases within 180 days after transplant was similar in the LTV group compared to the non-LTV group [1.9% (95% CI: 0.5%-6.6%) vs. 3.3% (95% CI: 1.6%-6.7%), P=0.478]. On multivariate analysis, LTV prophylaxis was an independent protective factor for CMV viremia (HR=0.45, 95% CI: 0.29-0.71, P<0.001) but an independent risk factor for EBV viremia (HR=3.37, 95% CI: 2.00-5.68, P<0.001) within 100 days after transplantation. The 6-month incidence of primary disease relapse post-transplantation was higher in the LTV group [11.3% (95% CI, 6.6%-18.8%) vs 4.7% (95% CI, 2.6%-8.5%); P = 0.029]. In multivariate analysis, LTV prophylaxis was identified an independent risk factor for relapse (HR, 2.52; 95% CI, 1.10-5.78; p=0.029). In +2 months post-transplant, the median percentage of CD8+ T cells was significantly lower in the LTV group compared with the non-LTV group [7.35% (range, 0.01%-34.60%) vs. 60.50% (range, 52.20%-66.30%), P=0.001].The median counts of lymphocytes [0.67 x109 cells/L (range, 0.15 x109 cells/L -1.27 x109 cells/L) vs. 1.36 x109 cells/L (range, 1.20 x109 cells/L -2.60 x109 cells/L), P=0.002] and CD8+ T cells [46.05 cells/uL (range, 0.23 cells/ uL -100.34 cells/uL) vs. 797.56 cells/uL (range, 626.40 cells/uL -1573.00 cells/uL), P=0.001)] in +2 months was significantly lower in the LTV group compared with the non-LTV group. At +2 months post-transplant, the percentage of CD8+ T cells expressing Granzyme B in the LTV group was significantly lower than in the non-LTV group [70.10% (range, 25.00%-85.00%) vs. 94.20% (range, 83.10%-99.90%), p=0.004]. Additionally, the percentage of CD4+ T cells expressing IFN-γ in the LTV group was significantly lower than in the non-LTV group [1.68% (range, 0.24%-14.40%) vs. 12.80% (range, 2.25%-15.70%), p=0.045]. Overall survival, Disease-Free Survival, and Graft-versus-host disease-free and relapse-free survival showed no differences between the two groups. Conclusions: LTV prophylaxis may be a risk factor for EBV viremia and primary disease relapse following haplo-HSCT. logo