Valganciclovir for CMV Prophylaxis After PTCy-Based Allogeneic Hematopoietic Cell Transplantation

Cytomegalovirus (CMV) reactivation is a serious complication after allogeneic hematopoietic cell transplantation (alloHCT), with heightened risk in recipients receiving post-transplant cyclophosphamide (PTCy)-based prophylaxis. Although letermovir reduces clinically significant CMV infection (csCMVi), its prohibitive cost limits access, highlighting the need for affordable alternatives. Unlike solid organ transplantation, there are no published studies reporting the utility of valganciclovir for CMV prophylaxis following PTCy-based alloHCT. The aim of this study was to evaluate the deliverability and efficacy of valganciclovir for CMV prophylaxis in adults undergoing alloHCT using PTCy-based graft-versus-host disease (GVHD) prophylaxis. We conducted a retrospective study screening 244 consecutive adults undergoing alloHCT at a single center (January 1, 2020 to October 31, 2024). Inclusion criteria were CMV-seropositive recipients receiving PTCy-based GVHD prophylaxis and intended for valganciclovir prophylaxis (900 mg daily) commencing after engraftment (neutrophils >1.0 × 10⁹/L and platelets >20 × 10⁹/L without platelet transfusion) and planned until day +100. For comparison with a pre-emptive strategy, outcomes were compared with a contemporaneous cohort of CMV-seropositive haploidentical transplant recipients from 2 additional Australian transplant centers. All patients underwent weekly quantitative CMV PCR monitoring from day 0 to day +100, and thereafter as clinically indicated. Primary endpoints were deliverability and csCMVi at day +100. Of the 244 screened patients, 124 (69 matched donor and 55 haploidentical donor alloHCT) met the inclusion criteria. Overall, 86 patients (69%) initiated valganciclovir prophylaxis, with a median time to commencement of 26 days post-transplant (IQR 21-34). The primary reason for noninitiation was inadequate hematopoietic recovery (31%). Prophylaxis initiation was significantly less frequent following haploidentical versus matched donor alloHCT (31/55 [56%] vs 55/69 [80%]; P = .005). The cumulative incidence of csCMVi in recipients commencing prophylaxis was 13% (95% CI, 7-21) compared with 63% (95% CI, 45-76) in those not commencing prophylaxis (HR .11; 95% CI, .05-.24; P < .0001). Among patients commencing prophylaxis, 13% experienced breakthrough csCMVi requiring escalation to therapeutic dose antiviral therapy after a median of 15 days of prophylaxis. In multivariable analysis, prophylaxis initiation was independently associated with a markedly reduced csCMVi risk (adjusted hazard ratio [aHR] .09; 95% CI, .04-.20; P < .001). Haploidentical donor alloHCT independently increased csCMVi risk 4.5-fold in landmark analysis. Comparison with a contemporaneous cohort of 119 haploidentical recipients managed with pre-emptive CMV therapy confirmed the benefit of prophylaxis (aHR .18; 95% CI, .08-.42; P < .001). Late csCMVi following prophylaxis cessation was uncommon (cumulative incidence 6%). In conclusion, valganciclovir offers a cost-effective alternative to letermovir for preventing csCMVi in CMV-seropositive PTCy-based alloHCT recipients, with delayed count recovery precluding initiation as the major constraint for haplo-identical transplantation.